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Surgical Specialist
23 years of experience
Accepting new patients

Credentials

Education ?

Medical School Score Rankings
University of Pennsylvania (1989)
  •  
Top 25%

Awards & Distinctions ?

Awards  
One of America's Leading Experts on:
Liver Transplantation
Skin Transplantation
Castle Connolly America's Top Doctors® (2006 - 2007, 2009, 2011 - 2015)
Appointments
Massachusetts General Hospital
Associations
American Board of Surgery

Affiliations ?

Dr. Markmann is affiliated with 7 hospitals.

Hospital Affiliations

Score

Rankings

  • Hospital of the University of PA
    3400 Spruce St, Philadelphia, PA 19104
    •  
    Top 25%
  • Massachusetts General Hospital *
    55 Fruit St, Boston, MA 02114
    •  
    Top 25%
  • Children's Hospital of Philadelphia
    324 S 34th St, Philadelphia, PA 19104
    •  
  • Univ of Pennsylvania Medical Ctr Presbyterian Hosp
  • Boston: Massachusetts General Hospital
  • Mass General Hospital Out Pt
  • Mass General Hospital
  • * This information was reported to Vitals by the doctor or doctor's office.

    Publications & Research

    Dr. Markmann has contributed to 143 publications.
    Title Il-21 is an Antitolerogenic Cytokine of the Late-phase Alloimmune Response.
    Date January 2012
    Journal Diabetes
    Excerpt

    Interleukin-21 (IL-21) is a proinflammatory cytokine that has been shown to affect Treg/Teff balance. However, the mechanism by which IL-21 orchestrates alloimmune response and interplays with Tregs is still unclear.

    Title Hyperlipidemia Due to Biliary Stricture After Living-donor Liver Transplantation.
    Date November 2011
    Journal Transplantation
    Title Inhibition of Transplantation Tolerance by Immune Senescence is Reversed by Endocrine Modulation.
    Date September 2011
    Journal Science Translational Medicine
    Excerpt

    The senescent immune system responds poorly to new stimuli; thymic involution, accumulation of memory cells against other specificities, and general refractoriness to antigen signaling all may contribute to poor resistance to infection. These same changes may pose a significant clinical barrier to organ transplantation, as transplantation tolerance requires thymic participation and integrated, tolerance-promoting responses to novel antigens. We found that after the age of 12 months, mice became resistant to the tolerance-inducing capacity of the monoclonal antibody therapy anti-CD45RB. This resistance to tolerance to cardiac allografts could be overcome by surgical castration of male mice, a procedure that led to thymic regeneration and long-term graft acceptance. The potential for clinical translation of this endocrine-immune interplay was confirmed by the ability of Lupron Depot injections, which temporarily disrupt gonadal function, to restore tolerance in aged mice. Furthermore, we demonstrated that the restoration of tolerance after surgical or chemical castration depended on thymic production of regulatory T cells (T(regs)); thymectomy or T(reg) depletion abrogated tolerance restoration. The aging of the immune system ("immune senescence") is a significant barrier to immune tolerance, but this barrier can be overcome by targeting sex steroid production with commonly used clinical therapeutics.

    Title Renal Allograft Rupture: a Strategy for Graft Preservation.
    Date June 2011
    Journal Transplantation
    Title Early Onset Adenovirus Infection After Simultaneous Kidney-pancreas Transplant.
    Date June 2011
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    Adenoviruses (AdV) are increasingly recognized as important viral pathogens in immunocompromised hosts. The clinical spectrum ranges from asymptomatic viremia to allograft dysfunction, and death. Most of the medical literature is on AdV infection in children and bone marrow transplant recipients. We report a case of AdV in an adult recipient in the first month after simultaneous kidney-pancreas transplant with thymoglobulin induction. This is a rare report of adenovirus infection after multiorgan transplant, and is unique in that it exhibited tissue invasive disease without any localizing signs or allograft dysfunction, while other cases in medical literature had invasive disease of the allograft with allograft dysfunction, failure, or death. In addition, this is the first report of a radiologic presentation of AdV nephritis.

    Title Changing Pattern of Organ Donation at a Single Center: Are Potential Brain Dead Donors Being Lost to Donation After Cardiac Death?
    Date February 2011
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    Donation after cardiac death (DCD) has proven effective at increasing the availability of organs for transplantation.We performed a retrospective examination of Massachusetts General Hospital (MGH) records of all 201 donors from 1/1/98 to the 11/2008, including 54 DCD, 115 DBD and 32 DCD candidates that did not progress to donation (DCD-dnp). Comparing three time periods, era 1 (01/98-12/02), era 2 (01/03-12/05) and era 3 (01/06-11/08), DCD’s comprised 14.8,48.4% and 60% of donors, respectively (p = 0.002). A significant increase in the incidence of cardiovascular/cerebrovascular as cause of death was evident in era 3 versus eras 1 and 2; 74% versus 57.1% (p<0.001),as was a corresponding decrease in the incidence of traumatic death. Interestingly, we noted an increase in utilization of aggressive neurological management over time, especially in the DCD group.We detected significant changes in the make-up of the donor pool over the past decade. That the changes in diagnosis over time did not differ between DCD and DBD groups suggests this difference is not responsible for the increase in DCD rates. Instead, we suggest that changes in clinical practice, especially in management of patients with severe brain injury may account for the increased proportion of DCD.

    Title An Unexpected Counter-regulatory Role of Il-10 in B-lymphocyte-mediated Transplantation Tolerance.
    Date August 2010
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    Monoclonal antibody against the CD45RB protein induces stable transplantation tolerance to multiple types of allograft. We have previously established that this tolerance protocol relies on the regulatory function of B lymphocytes for its effect. B lymphocytes have also been reported to participate in immune regulation in several other settings. In most of these systems, the regulatory function of B lymphocytes depends on the production of IL-10. Therefore, we investigated the role of IL-10 in the anti-CD45RB model of B-cell-mediated transplantation tolerance. Surprisingly, using antibody-mediated neutralization of IL-10, IL-10-deficient recipients and adoptive transfer of IL-10-deficient B lymphocytes, we found that IL-10 actually counter-regulates tolerance induced by anti-CD45RB. Furthermore, neutralization of IL-10 reduced the development of chronic allograft vasculopathy compared to anti-CD45RB alone and reduced the production of graft reactive alloantibodies. These data suggest that the participation of regulatory B lymphocytes in transplantation tolerance may be distinct from how they operate in other systems. Identifying the specific B lymphocytes that mediate transplantation tolerance and defining their mechanism of action may yield new insights into the complex cellular network through which antigen-specific tolerance is established and maintained.

    Title Kidney Transplantation at the University of Pennsylvania: 1998-2008.
    Date July 2010
    Journal Clinical Transplants
    Excerpt

    Kidney transplantation at the University of Pennsylvania has grown substantially over the past 11 years. Although our transplant volume has increased primarily as a consequence of multiorgan transplants as well as the utilization of historically "marginal" allografts, our post-transplantation outcomes remain excellent in both children and adults. We attribute these outcomes to technical improvements in tissue typing and donor-recipient crossmatching, modification of immunosuppression protocols, and rigorous donor and recipient selection. In the next decade, we hope to substantially expand our living donor program and refine our overall donor and recipient selection process such that we maintain excellent post-transplant outcomes in the face of aging and increasingly comorbid donors and recipients. We further predict significant changes in post-transplant management of kidney recipients with respect to immunosuppression regimens. In particular, we anticipate the modulation of immunosuppression regimens in recipients with high titers of donor-specific antibody and the integration of B-cell specific immunosuppression into post-transplant patient care. Only time will tell whether such therapies will 1) improve long-term outcomes, 2) allow us to diminish the degree of non-specific pharmacologic immunosuppression currently in use, 3) or even promote donor-specific tolerance in kidney transplant recipients.

    Title Blockade of Gitr-gitrl Interaction Maintains Treg Function to Prolong Allograft Survival.
    Date June 2010
    Journal European Journal of Immunology
    Excerpt

    Involvement of Treg in transplant tolerance has been demonstrated in multiple models. During the active process of graft rejection, these regulatory cells are themselves regulated and inactivated, a process termed counter-regulation. We hypothesize that ligation of the costimulatory molecule glucocorticoid-induced TNF receptor-related protein (GITR) on Treg inhibits their ability to promote graft survival, and by blocking GITR ligation graft survival can be prolonged. To this aim, we have designed a soluble GITR fusion protein (GITR-Fc), which binds GITR ligand and inhibits activation of GITR. Here, we show that GITR-Fc prolonged mouse skin graft survival, and this prolongation is dependent on Treg. In a full MHC-mismatched skin graft setting, GITR-Fc significantly improved graft survival when used in combination with MR1, anti-CD40L, while GITR-Fc alone did not demonstrate graft prolongation. These results demonstrate that disruption of binding of GITR with GITR ligand may be an important strategy in prolonging allograft survival.

    Title Regulatory T-cell Counter-regulation by Innate Immunity is a Barrier to Transplantation Tolerance.
    Date March 2010
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    Innate immune signals foster adaptive immunity through activation of antigen-presenting cells. Recent in vitro evidence suggests that innate signaling may also contribute to immunity by countering the effects of regulatory T cells (T-regs), counter-regulation. We present in vivo evidence using a transgenic skin allograft model that the function of T-regs is lost in the setting of acute skin transplantation but remains intact when grafts were transplanted 1 month prior to allow surgery-induced inflammation to abate. Our findings identify T-reg counter-regulation as a naturally occurring process that accompanies transplantation and an important barrier to T-reg-mediated tolerance. Our finding further highlights the central role of regulatory cell deactivation in the initiation of the immune response.

    Title Gitr Blockade Facilitates Treg Mediated Allograft Survival.
    Date January 2010
    Journal Transplantation
    Excerpt

    Many models of transplant tolerance have been found to depend on the induction of regulatory T cells (Tregs). Innate immune signals are known to suppress Tregs thereby augmenting immunity by abrogating Treg function. Such signals may also provide a barrier to transplantation tolerance mediated by Tregs. A number of cell surface molecules expressed by Tregs have been found to inhibit Treg activity, the best characterized of which is the glucocorticoid-induced tumor necrosis factor receptor-related (GITR) protein.

    Title Asts Recommended Practice Guidelines for Controlled Donation After Cardiac Death Organ Procurement and Transplantation.
    Date December 2009
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    The American Society of Transplant Surgeons (ASTS) champions efforts to increase organ donation. Controlled donation after cardiac death (DCD) offers the family and the patient with a hopeless prognosis the option to donate when brain death criteria will not be met. Although DCD is increasing, this endeavor is still in the midst of development. DCD protocols, recovery techniques and organ acceptance criteria vary among organ procurement organizations and transplant centers. Growing enthusiasm for DCD has been tempered by the decreased yield of transplantable organs and less favorable posttransplant outcomes compared with donation after brain death. Logistics and ethics relevant to DCD engender discussion and debate among lay and medical communities. Regulatory oversight of the mandate to increase DCD and a recent lawsuit involving professional behavior during an attempted DCD have fueled scrutiny of this activity. Within this setting, the ASTS Council sought best-practice guidelines for controlled DCD organ donation and transplantation. The proposed guidelines are evidence based when possible. They cover many aspects of DCD kidney, liver and pancreas transplantation, including donor characteristics, consent, withdrawal of ventilatory support, operative technique, ischemia times, machine perfusion, recipient considerations and biliary issues. DCD organ transplantation involves unique challenges that these recommendations seek to address.

    Title Islet Alone Versus Islet After Kidney Transplantation: Metabolic Outcomes and Islet Graft Survival.
    Date December 2009
    Journal Transplantation
    Excerpt

    Isolated islet transplantation with infusions from two to three donor pancreata and Edmonton immunosuppression consistently achieves insulin independence in patients with type 1 diabetes. The success of this protocol has been attributed to a novel combination of immunosuppressive agents and avoidance of steroids; however, the outcome of islet transplantation may differ in kidney transplant recipients who are already immunosuppressed.

    Title Transplant Center Volume and Outcomes After Liver Retransplantation.
    Date March 2009
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    Liver retransplantation surgery has a high rate of allograft failure due to patient comorbidities and technical demands of the procedure. Success of liver retransplantation could depend on surgeon experience and processes of care that relate to center volume. We performed a retrospective cohort study of adult liver retransplantation procedures performed from January 1, 1996 through December 31, 2005 using registry data from the Organ Procurement Transplantation Network. The primary outcome was 1-year allograft failure. Liver transplant centers were categorized as small, intermediate or high volume by dividing overall liver transplants into three tertiles of approximately equal size. Mean annual volume of overall liver transplants was <50 for low-volume centers, 50-88 for intermediate-volume centers and >88 for high-volume centers. The primary analysis consisted of 3977 liver retransplantation patients. The unadjusted risk of 1-year allograft failure was 37.8%. In multivariable logistic regression, the risk of 1-year allograft failure was not significantly different between low- (reference), intermediate- (OR 0.86, CI 0.72-1.03, p = 0.11) and high-volume centers (OR 0.88, CI 0.74-1.04, p = 0.14). Results were similar when the analysis was limited to retransplantation performed >160 days after initial transplantation. Center volume is an imprecise surrogate measure for 1-year outcomes after liver retransplantation.

    Title A Direct Comparison of Rejection by Cd8 and Cd4 T Cells in a Transgenic Model of Allotransplantation.
    Date September 2008
    Journal Archivum Immunologiae Et Therapiae Experimentalis
    Excerpt

    INTRODUCTION: The relative contributions of CD4+ and CD8+ T cells to transplant rejection remain unknown. The authors integrated a previous model of CD4-mediated graft rejection with a complementary model of CD8-mediated rejection to directly compare the function of graft-reactive CD4+ and CD8+ lymphocytes in vivo in a model where rejection requires transgenic T cells. These studies allow direct comparison of CD4 and CD8 T cell responses to the same antigen without the confounding effects of T cell depletion or homeostatic proliferation. MATERIALS AND METHODS: Clone 4 and TS1 mice possess MHC class I- and II-restricted CD8+ and CD4+ T cells, respectively, which express transgenic T cell receptors that recognize the influenza hemagglutinin antigen (HA). We compared the in vivo response of CFSE-labeled, HA-specific transgenic CD8+ and CD4+ T cells after adoptive transfer into syngeneic BALB/c mice grafted with HA-expressing skin. RESULTS: As in the authors' CD4+ model, HA104 skin was consistently rejected by both Clone 4 mice (n=9, MST: 14.2) and by 5 x 10(5) Clone 4 lymphocytes transferred to naive BALB/c hosts that do not otherwise reject HA+ grafts. Rejection correlated with extensive proliferation of either graft-reactive T cell subset in the draining lymph nodes, and antigen-specific CD4+ and CD8+ cells acquired effector function and proliferated with similar kinetics. CONCLUSIONS: These data extend the authors' unique transgenic transplantation model to the investigation of CD8 T cell function. The initial results confirm fundamental functional similarity between the CD4 and CD8 T cell subsets and provide insight into the considerable redundancy underlying T cell mechanisms mediating allograft rejection.

    Title Donor Age and Cold Ischemia Interact to Produce Inferior 90-day Liver Allograft Survival.
    Date August 2008
    Journal Transplantation
    Excerpt

    BACKGROUND: Expanded regional sharing of liver allografts may increase cold ischemia and allograft failure, particularly with livers from older donors. The aim of this study was to examine whether older donor age and cold ischemic time interact to produce inferior allograft survival. METHODS: We undertook a retrospective cohort study of adult liver transplants in the United States performed between December 1, 1995 and December 31, 2005, using data from the Organ Procurement and Transplantation Network. The primary outcome was allograft failure within 90 days. RESULTS: Forty-four thousand seven hundred fifty-six liver transplant recipients were analyzed. Older age was defined as 45 years or more, and prolonged cold ischemia was defined as 12 hours or more. Using data from the pre-Model for End Stage Liver Disease (MELD), post-MELD and combined eras, three separate analyses of the interaction between older donor age and prolonged cold ischemia were performed. In multivariable logistic regression, the interaction of age 45 years or more and cold ischemia more than or equal to 12 hr reached statistical significance in the combined (OR 1.24, CI 1.08-1.42, P<0.01) and pre-MELD (OR 1.26, CI 1.08-1.46, P<0.01) datasets, but not in the smaller post-MELD dataset (OR 1.18, CI 0.81-1.72, P=0.38). In the combined dataset, recipients of livers from donors aged 45 years or more and cold ischemia more than or equal to 12 hr showed an adjusted absolute risk of allograft failure at 90 days of 17.3% (odds ratio 1.84), compared with 11.1% for recipients of livers from donors older than 45 years and cold ischemia less than 12 hr. CONCLUSIONS: These findings suggest that older donor age and prolonged cold ischemia interact to increase liver allograft failure at 90 days. Proposals to expand regional sharing of older livers should be regarded with caution.

    Title Tolerance: It's in Your Blood.
    Date June 2008
    Journal Clinical Immunology (orlando, Fla.)
    Title Inhibition of Icam-1/lfa-1 Interactions Prevents B-cell-dependent Anti-cd45rb-induced Transplantation Tolerance.
    Date May 2008
    Journal Transplantation
    Excerpt

    BACKGROUND: Allogeneic tolerance can be reliably obtained with monoclonal antibody therapy targeting CD45RB. Although regulatory T cells play an important role in the mechanism, we have recently demonstrated the active participation of host B lymphocytes. After anti-CD45RB therapy, B lymphocytes demonstrate phenotypic alterations that include up-regulation of CD54 (intercellular adhesion molecule [ICAM]-1). We have investigated the hypothesis that alteration in ICAM-1 expression is required for tolerance induction. MATERIALS AND METHODS: Recipients of heterotopic allogeneic cardiac grafts (C3H donors into B6 recipients) were treated with anti-CD45RB, anti-ICAM, anti-lymphocyte function-associated antigen-1 (LFA), or the combination of these agents. These data were extended by performing allogeneic cardiac transplants into ICAM or LFA recipients treated with a 5-day course of anti-CD45RB. Finally, B-cell-deficient animals were reconstituted with ICAM splenocytes to create a recipient with a selective deficiency of ICAM-1 restricted to the B-cell compartment. RESULTS: Anti-CD45RB alone or the combination of anti-LFA/anti-ICAM reliably induced transplantation tolerance. However, the triple combination was routinely unsuccessful and induced long-term graft survival in no recipients. ICAM-deficient or LFA-deficient recipients were also resistant to tolerance induced by anti-CD45RB. Finally, transfer of control splenocytes to B-cell-deficient recipients permitted anti-CD45RB-induced tolerance, whereas transfer of ICAM cells was unable to support tolerance induction. CONCLUSIONS: Expression of ICAM-1 by B lymphocytes and interaction with LFA-1 form a central aspect of transplantation tolerance induced by anti-CD45RB therapy. These data further elucidate the cellular mechanisms used by B lymphocytes in the induction of transplantation tolerance.

    Title Hla Sensitization in Islet Transplantation.
    Date May 2008
    Journal Clinical Transplants
    Excerpt

    Islet transplantation is an emerging therapy for poorly controlled type 1 diabetes. Currently, islets isolated from multiple donors not HLA-matched to recipients are usually required to achieve insulin-independence. Subsequent HLA sensitization is common following a reduction or discontinuation of immunosuppressive drugs and may be responsible for deterioration in islet graft function. Based on the evidence available to date concerning HLA sensitization in islet transplant recipients, we recommend that future islet transplantation protocols consider the following: (1) minimizing the number of islet donors by, for example, infusing high quality islet preparations of sufficient yield from a single donor rather than pooling islet preparations from multiple donors since a greater number of HLA class I mismatches appears to be associated with increased risk for sensitization; (2) ensuring negative cross-matching of donor lymphocytes and recipient sera by testing prior to islet infusions; (3) avoiding donor-recipient antigen mismatches when an identifiable alloantibody is present pre-transplant (i.e., in the case of a positive PRA pretransplant) but excluding potential recipients who are highly sensitized (e.g., have a PRA > or = 20%); and (4) performing an assessment for HLA sensitization using a sensitive flow cytometric method for alloantibody detection any time there is a reduction in immunosuppressant drug levels or worsening of metabolic control.

    Title Liver Transplantation in the Setting of Extra-hepatic Malignancy: Two Case Reports.
    Date February 2008
    Journal Transplantation Proceedings
    Excerpt

    Candidates for liver transplantation (OLT) may be found to have an incidental extrahepatic tumor, which is amenable to resection, and may be associated with variable long-term survival. Issues to be considered include: (1) Whether it is possible to define a tumor stage and survival expectancy, which makes the patient an acceptable transplant candidate; (2) Whether cancer surgery should be preformed prior, during, or after OLT; (3) Whether the recipient be placed on immunosuppression that is tailored to address concern related to cancer recurrence. These issues are illustrated in the context of OLT and nephrectomy for renal cell carcinoma (RCC). Two patients underwent a simultaneous OLT and curative radical nephrectomy for stage 1 RCC that was incidentally discovered during OLT evaluation, one of whom received a simultaneous kidney transplant. At 51 and 14 months postoperatively, the patients are alive and healthy, with no tumor recurrence. In selected extrahepatic malignancies, simultaneous curative resection and OLT may provide the optimal outcome. This is justifiable when curative cancer-related life expectancy exceeds OLT-expected graft and patient survival. Concomitant transplantation and cancer surgery provides an acceptable cancer-free survival, avoiding the high morbidity observed when cancer resection is done in the presence of decompensated liver disease.

    Title Progress Toward Antibody-induced Transplantation Tolerance.
    Date September 2007
    Journal Critical Reviews in Immunology
    Excerpt

    Transplantation tolerance remains an elusive goal. Despite multiple animal models of tolerance induction using a variety of agents and protocols, it has yet to be achieved in humans with any predictability. In this review, we examine some of the antibodies directed toward T cells that show promise in prolonging graft survival in animal models and in preliminary clinical assessment. Because these antibodies work through multiple pathways, including depletion, downregulation, receptor-ligand blockade, and direct signaling, they have also helped us tease out the various components of long-lived donor-specific tolerance. In particular, we review the role of the thymus in therapies targeted at the peripheral immune system; the importance of the thymus in tolerance induced by anti-CD45RB suggests that central tolerance mechanisms may be more important than previously appreciated.

    Title Evidence for Allograft Rejection in an Islet Transplant Recipient and Effect on Beta-cell Secretory Capacity.
    Date August 2007
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    CONTEXT: The majority of islet transplant recipients experience a gradual decline in islet graft function, but the identification of islet-specific immune responses remains uncommon. OBJECTIVES: The aim was to present a case in which decline in islet graft function was accompanied by the appearance of islet donor-specific alloantibodies and demonstrate the effect on beta-cell secretory capacity, an estimate of functional beta-cell mass. SETTING: The study was conducted at the Transplant Center and General Clinical Research Center of the University of Pennsylvania. RESULTS: A 42-yr-old woman with type 1 diabetes who had a living-related kidney transplant received two intraportal islet infusions of a total 17,525 islet equivalents per kg body weight under daclizumab, prednisone, tacrolimus, and rapamycin immunosuppression. She became insulin independent, but 4 months later, the rapamycin was discontinued for associated colitis. She remained normoglycemic for another 6 months before manifesting impaired fasting glucose and requiring 5-10 U insulin daily. The decline in clinical islet graft function coincided with the detection of islet donor-specific human leukocyte antigen class I antibodies. Beta-cell function and secretory capacity were assessed by the insulin secretory responses to iv glucose, arginine (AIR(arg)), and glucose-potentiated arginine (AIR(pot)) before and at alloantibody detection. The acute insulin response to glucose was almost entirely lost, whereas the AIR(arg) and AIR(pot) both decreased by approximately 50%. CONCLUSIONS: Because the AIR(pot), a measure of beta-cell secretory capacity, provides an estimate of functional beta-cell mass, this case documents that islet graft loss can coincide with donor human leukocyte antigen sensitization and that the effect on beta-cell mass may be best estimated from the AIR(arg) or AIR(pot).

    Title Availability of Suitable Islet Donors in the United States.
    Date August 2007
    Journal Transplantation
    Excerpt

    BACKGROUND: We characterize donor utilization for islet transplantation and estimate the number of recipients who could achieve normoglycemia through islet transplantation if the current donor pool were used. METHODS: Potential islet donors from all United Network for Organ Sharing donors (1/00-5/04) were identified and categorized into "optimal" islet donors (16-40 yr, body mass index >27 kg/m, hemodynamically stable) or "standard" donors (as traditionally described). RESULTS: Of 27,552 potential donors during this period, 6,140 donor pancreata were used for whole organ transplant. Of the remaining 21,412 donors, 10,417 potential islet donors were identified (9260 [88.9%] standard and 1157 [11.1%] optimal donors). Islets from only 218 donors were used for transplant, representing 8.7% of optimal donors and 2.1% of all potential islet donors. CONCLUSION: The widespread use of isolated islets could provide insulin independence for approximately 1000 type I diabetics a year, but at current rates of islet transplant, all recipients could be transplanted with islets from ideal donors.

    Title Effects of Sirolimus Vs. Calcineurin Inhibitors on Renal Dysfunction After Orthotopic Liver Transplantation.
    Date July 2007
    Journal Clinical Transplantation
    Excerpt

    Small uncontrolled series have suggested that sirolimus favorably impacts renal function after orthotopic liver transplantation (OLT). We sought to retrospectively compare renal dysfunction between cohorts exposed to sirolimus-based and calcineurin inhibitor-based immunosuppression. We retrospectively studied 79 patients converted to sirolimus-based immunosuppression and 100 control subjects continued on calcineurin inhibitor-based immunosuppression after OLT at our institution from 2000 to 2005. We collected clinical, demographic, and medication history. Renal dysfunction was defined as two or more wk of creatinine > or =2.0 mg/dL. Cohorts were compared using Kaplan-Meier survival analysis and Cox proportional hazards modeling. Patients began sirolimus a median 83 d post-OLT and were followed on the medication for median 359 d. Patients in both the sirolimus and calcineurin inhibitor cohorts had median creatinine 1.2 mg/dL at study entry. Sirolimus-based immunosuppression was associated with a 1.8 (0.8-4.3, p = 0.17) hazards ratio for renal dysfunction. Adjusting for presence of hepatocellular carcinoma, combined kidney/liver transplantation, and age, the hazards ratio was 2.0 (0.8-4.8, p = 0.13). These point estimates were not substantially altered after subgroup analysis of sirolimus as the lone immunosuppressant, duration of exposure, and time between OLT and sirolimus conversion. In conclusion, our retrospective, controlled study showed that conversion to sirolimus after OLT did not protect against renal dysfunction. The effect of sirolimus on renal function will need to be prospectively evaluated in a prospective, randomized trial.

    Title Cutting Edge: Transplant Tolerance Induced by Anti-cd45rb Requires B Lymphocytes.
    Date June 2007
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Selective interference with the CD45RB isoform by mAb (anti-CD45RB) reliably induces donor-specific tolerance. Although previous studies suggest participation of regulatory T cells, a mechanistic understanding of anti-CD45RB-induced tolerance is lacking. We report herein the unexpected finding that tolerance induced by this agent is not established in B cell-deficient mice but can be recovered by preemptive B lymphocyte transfer to B cell-deficient hosts. Using B cells from genetically modified donors to reconstitute B cell-deficient recipients, we evaluate the role of B lymphocyte-expressed CD45RB, T cell costimulatory molecules, and the production of Abs in this novel tolerance mechanism. Our data document an Ab-induced tolerance regimen that is uniquely B lymphocyte-dependent and suggest mechanistic contributions to tolerance development from the B cell compartment through interactions with T cells.

    Title Glycemic Thresholds for Activation of Counterregulatory Hormone and Symptom Responses in Islet Transplant Recipients.
    Date May 2007
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    CONTEXT: In patients with type 1 diabetes and reduced awareness of hypoglycemia, the glycemic thresholds for activation of counterregulatory hormone and symptom responses to hypoglycemia are impaired, in part due to recurrent episodes of hypoglycemia. Islet transplantation can ameliorate occurrences of hypoglycemia in these patients. OBJECTIVE: The objective of the study was to determine whether the avoidance of hypoglycemia achieved through islet transplantation results in improved glycemic thresholds for counterregulatory responses. SETTING: The study was conducted at a general clinical research center. PARTICIPANTS: Seven islet transplant recipients, six type 1 diabetic, and eight nondiabetic control subjects participated in the study. INTERVENTION: We performed a stepped hyperinsulinemic hypoglycemic clamp and, in 12 subjects, a paired hyperinsulinemic euglycemic clamp to calculate the glycemic thresholds for and magnitude of counterregulatory responses. RESULTS: The glycemic thresholds for all counterregulatory hormone and symptom responses in the islet transplant group were comparable with normal and higher than in the type 1 diabetes group (P < 0.01 for glucagon; P < 0.05 for epinephrine). The magnitude of the glucagon and epinephrine responses in the islet transplant group, although greater than in the type 1 diabetes group (P < 0.05 for both), remained less than normal (P < 0.01 for glucagon; P < 0.05 for epinephrine). The magnitude of GH secretion in the islet transplant group was comparable with normal and greater than in the type 1 diabetes group (P < 0.05). CONCLUSIONS: The glycemic thresholds for activation of counterregulatory hormone and symptom responses appear normal after islet transplantation; however, the magnitudes of the glucagon and epinephrine responses remain impaired.

    Title Salvage of Nonmaturing Native Fistulas by Using Angioplasty.
    Date February 2007
    Journal Radiology
    Excerpt

    PURPOSE: To retrospectively review outcomes following angioplasty of nonmaturing autogenous hemodialysis fistulas. MATERIALS AND METHODS: Institutional review board exemption was received for this HIPAA-compliant retrospective study; informed consent was waived. During 48 months, 101 patients underwent fistulography for percutaneous salvage of nonmaturing native fistulas. Clinical and technical success, need for secondary interventions, and complications were recorded according to consensus definitions. Patency following angioplasty was estimated with the Kaplan-Meier technique. Patient age, sex, ethnicity, fistula age, fistula type, number of stenoses, maximal angioplastic balloon diameter used, and presence of palpable thrill following angioplasty were examined as predictors of primary patency of the fistula following intervention by using Cox proportional hazards model. RESULTS: Mean patient age was 58 years; 35% were women. Median time from fistula creation to fistulography was 2.5 months. Hemodynamically significant (>50%) stenoses were identified in 88% (89 of 101) of patients; angioplasty was attempted in 96% (85 of 89). Technical success was achieved in 92% (78 of 85) of fistulas following angioplasty; clinical success of normal hemodialysis with total access blood flow of more than 500 mL/min occurred following 88% (75 of 85) of angioplastic interventions. No major and two minor complications occurred. Mean primary unassisted patency at 3, 6, and 12 months was 60%+/-6% (95% confidence interval), 45%+/-6%, and 34%+/-6%, respectively. Additional angioplasty (n=12), stent placement (n=1), or thrombectomy (n=1) during subsequent interventions resulted in mean secondary patency at 3, 6, and 12 months of 82%+/-4%, 79%+/-5%, and 75%+/-6%, respectively. Patients without thrill following angioplasty were more than twice as likely to lose patency as patients with thrill (P=.035). No relationship was seen between primary patency and other predictors examined. CONCLUSION: Early fistulography enables identification of underlying areas of stenosis in nonmaturing fistulas, which can be safely and effectively treated with angioplasty. With continued surveillance and repeat interventions, functional patency can be sustained in the majority of fistulas.

    Title Lack of Benefit of Pre-transplant Locoregional Hepatic Therapy for Hepatocellular Cancer in the Current Meld Era.
    Date September 2006
    Journal Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
    Excerpt

    The potential for disease progression in patients awaiting liver transplantation for hepatocellular carcinoma (HCC) has encouraged many centers to employ pre-transplant radiofrequency ablation or chemoembolization in an attempt to control tumor burden while patients are on the wait list. Despite general acceptance by the transplant community, few objective data demonstrate pre-transplant treatment efficacy or improved post-transplant outcomes in HCC patients listed with Model for End-Stage Liver Disease (MELD) exception points. To evaluate the utility of pre-transplant therapy in the current MELD era, we retrospectively compared 31 treated patients (T) with 33 untreated (U) controls. Study endpoints included patient and disease-free survival, tumor recurrence, explant tumor viability, and the ability of MRI to detect viable tumor after therapy. Both cohorts had similar demographic, radiographic, and pathologic characteristics, although untreated patients waited longer for transplantation [119 (U) vs. 54 (T) days after MELD assignment, (P = .05); range: 1 day to 21 months]. Only 20% of treated tumors demonstrated complete ablation (necrosis) as defined by histologic examination of the entire lesion. Only 55% of lesions with histologic viable tumor were detected by MRI after pre-transplant therapy. After 36 months of follow-up, there was no difference between the treated and untreated groups in overall survival (84 vs. 91%), disease free survival (74% vs. 85%), cancer recurrence (23% vs. 12%), or mortality from cancer recurrence (57% vs. 25%) (P > 0.1). In conclusion, viable tumor frequently persists after pre-transplant locoregional therapy, and neoadjuvant treatment does not appear to improve post-transplant outcomes in the current MELD era.

    Title T-reg Mediated Suppression of the Allograft Response in the Draining Lymph Node.
    Date August 2006
    Journal Transplantation
    Excerpt

    We previously demonstrated that T-regs inhibit proliferation of graft-reactive T cells in the draining lymph node (DLN), suggesting that this site may be important for regulation. TCR transgenic mice (TS1) specific for viral hemagglutinin (HA) provided antigen-specific T cells for adoptive transfer into syngeneic Balb/c hosts bearing HA+ skin grafts. T-regs were obtained from (TS1xHA28)F1 mice known to have an expanded population of HA-specific T-regs. To determine whether the lymph node is an independent site of suppression, we developed a model in which donor antigen that migrates from the allograft to the DLN drives T-cell activation after graft removal. T-regs that did not encounter the allograft itself remained able to inhibit graft antigen-specific T-cell proliferation in the DLN. Alloantigen-induced regulation can occur in the absence of the graft. This finding identifies the DLN as a potentially critical site of regulation in the early posttransplant period.

    Title Avenues for Immunomodulation and Graft Protection by Gene Therapy in Transplantation.
    Date July 2006
    Journal Transplant International : Official Journal of the European Society for Organ Transplantation
    Excerpt

    Organ transplantation represents the only definitive therapy for many causes of end-organ failure. However, the universal success of this therapy is limited by chronic allograft rejection, the side effects of chronic immunosuppressive therapy, and a severe shortage of donor organs. Presently, the success of solid-organ transplantation depends on the continuous administration of toxic and nonspecific immunosuppressive agents, therapies that present risks for opportunistic infection, malignancy, and a variety of agent-specific side effects. To promote the use of transplantation with limited risk of long-term sequelae, three dominant research challenges emerge: (i) elimination of the need for exogenous immunosuppression by immunological tolerance induction; (ii) prevention of chronic rejection/graft dysfunction; and (iii) expansion of available organs for transplantation. Gene therapy may provide significant advances and solutions in each of these areas. Rejection of the graft in the immediate post-transplant period has been attacked through the transfer of immunomodulatory molecules in addition to tolerance inducing approaches. Chronic graft rejection may be similarly addressed through permanent tolerance induction or alternatively through the introduction of molecules to resist chronic graft damage. Genetic manipulation of stem cells may ultimately produce transgenic animals to serve as tissue donors to overcome the limited donor organ supply. This review will highlight ongoing developments in the translation of gene therapy approaches to the challenges inherent in transplantation.

    Title Accelerated Memory Cell Homeostasis During T Cell Depletion and Approaches to Overcome It.
    Date May 2006
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Partial T cell depletion is used in solid organ transplantation as a valuable strategy of peritransplant induction immunosuppression. Using a murine cardiac allograft model, we recently demonstrated that this led to lymphopenia-induced (homeostatic) proliferation among the residual nondepleted lymphocytes. Rather than promoting tolerance, peritransplant T cell-depleting Abs actually resulted in resistance to tolerance induction by costimulatory blockade. In this study we show that memory T cells predominate shortly after subtotal lymphodepletion due to two distinct mechanisms: relative resistance to depletion and enhanced homeostatic proliferation. In contrast, regulatory cells (CD4+ CD25+ Foxp3+) are depleted as efficiently as nonregulatory cells and exhibit reduced homeostatic expansion compared with memory cells. The resistance to tolerance induction seen with subtotal T cell depletion can be overcome in two different ways: first, by the adoptive transfer of additional unprimed regulatory cells at the time of transplant, and second, by the adjunctive use of nondepleting anti-CD4 and anti-CD8 mAbs, which effectively block homeostatic expansion. We conclude that the resistance to tolerance induction seen after subtotal lymphocyte depletion can be attributed to alterations in the balance of naive, memory, and regulatory T cells. These data have clinically relevant implications related to the development of novel strategies to overcome resistance to tolerance.

    Title Antibody-induced Transplantation Tolerance That is Dependent on Thymus-derived Regulatory T Cells.
    Date April 2006
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Targeting of the CD45RB isoform by mAb (anti-CD45RB) effectively induces donor-specific tolerance to allografts. The immunological mechanisms underlying the tolerant state remain unclear although some studies have suggested the involvement of regulatory T cells (T-regs). Although their generative pathway remains undefined, tolerance promoting T-regs induced by systemic anti-CD45RB treatment have been assumed to originate in the peripheral immune system. We demonstrate herein that separable effects on the peripheral and central immune compartments mediate graft survival induced by anti-CD45RB administration. In the absence of the thymus, anti-CD45RB therapy is not tolerogenic though it retains peripheral immunosuppressive activity. The thymus is required for anti-CD45RB to produce indefinite graft survival and donor-specific tolerance, and this effect is accomplished through thymic production of donor-specific T-regs. These data reveal for the first time an Ab-based tolerance regimen that relies on the central tolerance pathway.

    Title Contrast-enhanced Mr Angiography for Evaluation of Vascular Complications of the Pancreatic Transplant.
    Date March 2006
    Journal Radiographics : a Review Publication of the Radiological Society of North America, Inc
    Excerpt

    Vascular complications are a common cause of postoperative dysfunction in a pancreatic transplant. Coronal three-dimensional (3D) contrast material-enhanced magnetic resonance (MR) angiography performed with high spatial and temporal resolution is a safe and effective method of assessing these vascular complications. A study was performed of selected patients who had undergone MR imaging and MR angiography during the past 6 years for evaluation of graft dysfunction following pancreatic transplantation. Thrombosis within peripheral stump vessels involving either the arterial or venous segments was a commonly observed vascular complication. Isolated distal arterial stump thrombi are incidental findings that may not require treatment, whereas venous stump thrombi may become clinically significant in patients in whom clot propagates proximally to occlude draining pancreatic veins and are typically treated with anticoagulants or thrombectomy. Because it is difficult to predict which patients will experience clot propagation, patients with venous stump thrombi may be followed up with serial imaging regardless of treatment initiated at presentation. Although susceptibility artifacts can mimic anastomotic stenoses at MR imaging, careful attention to the multiple sequences used allows recognition of this potential pitfall. Contrast-enhanced 3D MR angiography is an accurate method of evaluating the vascular anatomy of pancreatic transplants and can help guide clinical management.

    Title Successful Liver, Kidney, and Pancreas Transplantation from a Donor with Cerebral Emboli from a Left Atrial Myxoma.
    Date March 2006
    Journal Transplantation Proceedings
    Excerpt

    Although transmission and engraftment of donor-derived malignancies is rare in recipients of solid organ transplants, it is associated with unfavorable allograft and patient survival. Therefore, a recent history of malignancy is considered a contraindication to organ donation. Although atrial myxomas are benign cardiac tumors of stromal origin, they can lead to systemic embolization with ectopic myxoma formation. We report successful liver, kidney, and pancreas transplantation into 3 recipients from a donor with cerebral emboli from a left atrial myxoma. Eighteen months after transplantation, all 3 patients enjoy good allograft function and are free of donor-derived atrial myxoma. Although the duration of follow-up in this report is limited, we suggest that the presence of atrial myxoma should not be viewed as an absolute contraindication to organ recovery, particularly in view of the shortage of organ donors and the attendant morbidity and mortality for patients on waiting lists.

    Title Islet Cell Hormonal Responses to Hypoglycemia After Human Islet Transplantation for Type 1 Diabetes.
    Date January 2006
    Journal Diabetes
    Excerpt

    Islet transplantation can eliminate severe hypoglycemic episodes in patients with type 1 diabetes; however, whether intrahepatic islets respond appropriately to hypoglycemia after transplantation has not been fully studied. We evaluated six islet transplant recipients, six type 1 diabetic subjects, and seven nondiabetic control subjects using a stepped hyperinsulinemic-hypoglycemic clamp. Also, three islet transplant recipients and the seven control subjects underwent a paired hyperinsulinemic-euglycemic clamp. In response to hypoglycemia, C-peptide was similarly suppressed in islet transplant recipients and control subjects and was not detectable in type 1 diabetic subjects. Glucagon was significantly more suppressed in type 1 diabetic subjects than in islet transplant recipients (P < 0.01), although the glucagon in islet transplant recipients failed to activate as in the control subjects (P < 0.01). Pancreatic polypeptide failed to activate in both type 1 diabetic subjects and islet transplant recipients compared with control subjects (P < 0.01). In islet transplant recipients, glucagon was suppressed normally by hyperinsulinemia during the euglycemic clamp and was significantly greater during the paired hypoglycemic clamp (P < 0.01). These results suggest that after islet transplantation and in response to insulin-induced hypoglycemia, endogenous insulin secretion is appropriately suppressed and glucagon secretion may be partially restored.

    Title Appendicitis Among Liver Transplant Recipients.
    Date January 2006
    Journal Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
    Excerpt

    Appendicitis among liver transplant recipients has not been described in the current literature. We report 8 recipients who experienced appendicitis three weeks to 181 months after liver transplantation (LT). Initial presenting findings differed from the nonimmunosuppressed population in that a majority of the patients did not have leukocytosis (>10,000 cells/mm3). Four patients experienced perforation, three of whom presented three days after the development of abdominal pain. All patients recovered after surgery without untoward sequela.

    Title Renal Function After Orthotopic Liver Transplantation is Predicted by Duration of Pretransplantation Creatinine Elevation.
    Date December 2005
    Journal Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
    Excerpt

    In patients with recent onset renal insufficiency, the decision to perform combined kidney/liver transplantation (CKLT) vs. orthotopic liver transplantation alone (OLTa) can be difficult. We hypothesized that duration of renal dysfunction may correlate with creatinine elevation after liver transplantation. We retrospectively identified 69 liver transplantation patients with pretransplantation creatinine > or =1.5 mg/dL (53 OLTa, 13 CKLT). Variables analyzed were presence of hepatorenal syndrome, creatinine, Model for End-Stage Liver Disease score, albumin, age, race, gender, cause of liver disease, diabetes mellitus, hypertension, and history of ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, renal replacement therapy (RRT), and transjugular intrahepatic portosystemic shunting. Duration of pretransplantation renal dysfunction was predictive of 6- and 12-month creatinine post-OLTa. Area under the receiver operating characteristic (ROC) curve for prediction of 12-month renal insufficiency by renal dysfunction duration was 0.71; optimal duration cutoff was 3.6 weeks. We applied a multivariable model, derived from OLTa patients, to CKLT subjects with definite or possible hepatorenal syndrome. Predicted 12-month creatinine without renal transplantation was >2.0 mg/dL for each patient. CKLT patients as opposed to OLTa patients had longer duration of renal dysfunction (median, 18.1 vs. 2.7 weeks, P < 0.001), higher creatinine (median 4.0 versus 1.7 mg/dL, P < 0.001), and higher rate of pretransplantation RRT (62% vs. 7%, P < 0.001). Adjusting for baseline characteristics, CKLT patients had lower creatinine than OLTa patients at 6 months (P =0.15) and 12 months (P =0.01) after transplantation. In conclusion, duration, but not cause, of renal dysfunction predicts renal outcome in OLTa recipients. Prospective studies may use duration of renal dysfunction to help identify CKLT candidates.

    Title Comparison of Whole Organ Pancreas and Isolated Islet Transplantation for Type 1 Diabetes.
    Date November 2005
    Journal Advances in Surgery
    Title Pharmacologically Regulated Regeneration of Functional Human Pancreatic Islets.
    Date May 2005
    Journal Molecular Therapy : the Journal of the American Society of Gene Therapy
    Excerpt

    Transplantation of allogeneic islets can correct the metabolic abnormalities of Type I diabetes. Limited availability of donor pancreas tissues restricts the application of this therapeutic modality to a subset of eligible recipients. In an attempt to expand the utility of available donor human pancreas tissue, we developed a method to stimulate the proliferation of insulin-secreting beta-cells within human islets. A lentiviral vector was used to introduce into human islets chimeric signaling receptors that are activated to stimulate cell proliferation through interactions with a small-molecule drug called a chemical inducer of dimerization (CID). In vitro exposure of vector-transduced human islets to the CID expanded the number of cells and increased regulated insulin secretion. Transplantation of the regenerated islets into diabetic immunodeficient mice, followed by in vivo administration of the CID, corrected hyperglycemia. This strategy has the potential to reduce the quantity of human islets required for treatment of patients with Type I diabetes.

    Title {beta}-cell Function Following Human Islet Transplantation for Type 1 Diabetes.
    Date April 2005
    Journal Diabetes
    Excerpt

    Islet transplantation can provide metabolic stability for patients with type 1 diabetes; however, more than one donor pancreas is usually required to achieve insulin independence. To evaluate possible mechanistic defects underlying impaired graft function, we studied five subjects at 3 months and four subjects at 12 months following intraportal islet transplantation who had received comparable islet equivalents per kilogram (12,601 +/- 1,732 vs. 14,384 +/- 2,379, respectively). C-peptide responses, as measures of beta-cell function, were significantly impaired in both transplant groups when compared with healthy control subjects (P < 0.05) after intravenous glucose (0.3 g/kg), an orally consumed meal (600 kcal), and intravenous arginine (5 g), with the greatest impairment to intravenous glucose and a greater impairment seen in the 12-month compared with the 3-month transplant group. A glucose-potentiated arginine test, performed only in insulin-independent transplant subjects (n = 5), demonstrated significant impairments in the glucose-potentiation slope (P < 0.05) and the maximal response to arginine (AR(max); P < 0.05), a measure of beta-cell secretory capacity. Because AR(max) provides an estimate of the functional beta-cell mass, these results suggest that a low engrafted beta-cell mass may account for the functional defects observed after islet transplantation.

    Title Resistance to Anti-cd45rb-induced Tolerance in Nod Mice: Mechanisms Involved.
    Date March 2005
    Journal Transplant International : Official Journal of the European Society for Organ Transplantation
    Excerpt

    While great advances have been made in the success of islet transplantation to cure autoimmune diabetes, this protocol remains limited by our inability to induce donor-specific tolerance within the recipient. The profound resistance of the NOD mouse to tolerance-inducing regimens that are routinely successful in other strains further defines the imposing barriers that must be surmounted. Herein, we have assessed the utility of anti-CD45RB therapy to induce tolerance to allografts in C57BL/6 and NOD-strain mice. We find that, as with other therapies, NOD mice are also resistant to this manipulation, despite robust tolerance induction in the comparison strain. Analysis of cell surface markers revealed a number of changes within the B lymphocyte compartment following contact with antibody and alloantigen in the B6 strain. The absence of reciprocal changes within the NOD lymphocyte compartment suggests that B cells might contribute to the mechanism of action of this therapy and to the resistance to immunological tolerance noted in the NOD strain.

    Title Survival Among Pediatric Liver Transplant Recipients: Impact of Segmental Grafts.
    Date February 2005
    Journal Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
    Excerpt

    Segmental liver transplantation with living donor (LD), reduced cadaveric (Reduced), and split cadaveric (Split) allografts has expanded the availability of size-appropriate organs for pediatric recipients. The relevance of recipient age to the selection of graft type has not been fully explored, but could offer the potential to maximize recipient outcome and donor utilization. We conducted a retrospective cohort study among children 12 years of age or less utilizing the United Network of Organ Sharing (UNOS) database. Cox proportional-hazards analysis was used to explore the association of recipient age and graft type to graft and patient survival. Among children <1 year of age and those 1 to 2 years of age, 3-year LD graft survival was superior to whole cadaveric (CAD) organs, Split grafts, and Reduced grafts (for children <1 year of age: 79.4 vs. 61.5, 66.0, and 61.1%, respectively, P = .0003; and for children 1-2 years of age: 79.2 vs 66.9, 57.1, and 63.9%, respectively, P = .02). However, in children 3 to 12 years of age, after controlling for multiple donor and recipient factors, LD grafts failed to offer a survival advantage (hazard ratio = .61; 95% confidence interval = .37-1.02) compared to CAD organs. In an adjusted analysis examining patient survival, there appeared to be minimal association between recipient age and graft type. Much of the difference in graft survival could be attributed to events in the perioperative period. In conclusion, LD liver transplantation provides improved graft survival in children 2 years of age or less.

    Title Allograft Survival Following Adult-to-adult Living Donor Liver Transplantation.
    Date February 2005
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    Adult-to-adult living donor liver transplantation (AALDLT) is emerging as a method to treat patients with end-stage liver disease. The aims of this study were to identify donor and recipient characteristics of AALDLT, to determine variables that affect allograft survival, and to examine outcomes compared with those achieved following cadaveric transplantation. Cox proportional hazards models were fit to examine characteristics associated with the survival of AALDLT. Survival of AALDLT was then compared with cadaveric allografts in multivariable Cox models. Older donor age (>44 years), female-to-male donor to recipient relationship, recipient race, and the recipient medical condition before transplant were factors related to allograft failure among 731 AALDLT. Despite favorable donor and recipient characteristics, the rate of allograft failure, specifically the need for retransplantation, was increased among AALDLT (hazard ratio 1.66, 95% C.I. = 1.30-2.11) compared with cadaveric recipients. In conclusion, among AALDLT recipients, selecting younger donors, placing the allografts in recipients who have not had a prior transplant and are not in the ICU, may enhance allograft survival. Analysis of this early experience with AALDLT suggests that allograft failure may be higher than among recipients of a cadaveric liver.

    Title Expanded-criteria Donor Kidneys: a Single-center Clinical and Short-term Financial Analysis--cause for Concern in Retransplantation.
    Date December 2004
    Journal Transplantation
    Excerpt

    BACKGROUND: Expanded-criteria donor (ECD) kidneys are associated with a higher risk of posttransplant failure, but they remain a favorable alternative to dialysis. Now that a uniform definition of "expanded criteria" exists, it is more appropriate than ever to evaluate their utility compared with that seen with non-ECD kidneys. METHODS: The authors analyzed 202 cadaveric kidney-only recipients that underwent transplantation from January 1999 to September 2001, including 45 (22%) recipients whose donors met current ECD criteria. RESULTS: ECD and non-ECD kidney recipients had similar pretransplant characteristics except for older age and increased duration of renal failure in the ECD group. Patient, graft, and death-censored graft survival in both groups were similar in primary recipients but significantly worse in retransplant recipients of ECD kidneys. The relative risk of death-censored graft loss was 1.58 in the ECD group (P = 0.45). Overall inpatient charges (minus organ acquisition charge) for 1 year posttransplant were 76,962 US dollars (ECD) versus 71,026 US dollars (non-ECD) (P = 0.53); the same charges in retransplant recipients were 136,596 US dollars (ECD) versus 91,296 US dollars (non-ECD) (P = 0.25). ECD recipients, especially retransplant recipients, had consistently higher creatinine concentrations, although the average current value of all functioning ECD grafts remains less than 2 mg/dL. ECD recipients had a higher incidence of ureteral stricture (4.4% vs. 0%), but this never resulted in graft loss. CONCLUSIONS: Considering the widening disparity between renal allograft availability and need and the fact that ECD kidneys provide superior outcomes compared with dialysis, the authors' data encourage the continued use of ECD kidneys in primary recipients but justify caution in the retransplant setting.

    Title Transplantation for Type I Diabetes: Comparison of Vascularized Whole-organ Pancreas with Isolated Pancreatic Islets.
    Date October 2004
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: We sought to compare the efficacy, risks, and costs of whole-organ pancreas transplantation (WOP) with the costs of isolated islet transplantation (IIT) in the treatment of patients with type I diabetes mellitus. SUMMARY BACKGROUND DATA: A striking improvement has taken place in the results of IIT with regard to attaining normoglycemia and insulin independence of type I diabetic recipients. Theoretically, this minimally invasive therapy should replace WOP because its risks and expense should be less. To date, however, no systematic comparisons of these 2 options have been reported. METHODS: We conducted a retrospective analysis of a consecutive series of WOP and IIT performed at the University of Pennsylvania between September 2001 and February 2004. We compared a variety of parameters, including patient and graft survival, degree and duration of glucose homeostasis, procedural and immunosuppressive complications, and resources utilization. RESULTS: Both WOP and IIT proved highly successful at establishing insulin independence in type I diabetic patients. Whole-organ pancreas recipients experienced longer lengths of stay, more readmissions, and more complications, but they exhibited a more durable state of normoglycemia with greater insulin reserves. Achieving insulin independence by IIT proved surprisingly more expensive, despite shorter initial hospital and readmission stays. CONCLUSION: Despite recent improvement in the success of IIT, WOP provides a more reliable and durable restoration of normoglycemia. Although IIT was associated with less procedure-related morbidity and shorter hospital stays, we unexpectedly found IIT to be more costly than WOP. This was largely due to IIT requiring islets from multiple donors to gain insulin independence. Because donor pancreata that are unsuitable for WOP can often be used successfully for IIT, we suggest that as IIT evolves, it should continue to be evaluated as a complementary alternative to rather than as a replacement for the better-established method of WOP.

    Title Transduction of Human Islets with Pseudotyped Lentiviral Vectors.
    Date October 2004
    Journal Human Gene Therapy
    Excerpt

    Type I diabetes is caused by an autoimmune-mediated elimination of insulin-secreting pancreatic islets. Genetic modification of islets offers a powerful molecular tool for improving our understanding of islet biology. Moreover, efficient genetic engineering of islets could allow for evaluation of new strategies aimed at preventing islet destruction. The present study evaluated the ability of a human immunodeficiency virus (HIV)-based lentiviral vector pseudotyped with various viral envelopes to target human islets ex vivo, with the goal of improving efficiency while minimizing toxicity. Transfer of the enhanced green fluorescent protein reporter gene in human islets was first evaluated with an HIV-based vector pseudotyped with the vesicular stomatitis virus (VSV), murine leukemia virus, Ebola, rabies, Mokola, or lymphocytic choriomeningitis virus (LCMV) envelope glycoprotein to optimize transduction efficiency. Results indicated that LCMV-pseudotyped vector transduced insulin-secreting beta cells with the highest efficiency. Moreover, toxicity associated with transduction of islets was found to be lower with LCMV-pseudotyped vector than with VSV-G-pseudotyped vector, the second most efficient vector for islet transduction. Overall, our study describes an improved methodology for achieving safe and efficient gene transfer into cells of human islets.

    Title Factors Differentially Correlated with the Outcome of Liver Transplantation in Hcv+ and Hcv- Recipients.
    Date August 2004
    Journal Transplantation
    Excerpt

    BACKGROUND: Survival following liver transplantation for hepatitis C virus (HCV) is significantly poorer than for liver transplants performed for other causes of chronic liver disease. The factors responsible for the inferior outcome in HCV+ recipients, and whether they differ from factors associated with survival in HCV- recipients, are unknown. METHODS: The UNOS database was analyzed to identify factors associated with outcome in HCV+ and HCV- recipients. Kaplan-Meier graft and patient survival and Cox proportional hazards analysis were conducted on 13,026 liver transplants to identify the variables that were differentially associated with outcome survival in HCV- and HCV+ recipients. RESULTS: Of the 13,026 recipients, 7386 (56.7%) were HCV- and 5640 were HCV+. In HCV- and HCV+ recipient populations, five-year patient survival rates were 83.5% vs. 74.6% (P<0.00001) and five-year graft survival rates 80.6% vs. 69.9% (P<0.00001), respectively. In a multivariate regression model, donor age and recipient creatinine were observed to be significant covariates in both groups, while donor race, cold ischemia time (CIT), female to male transplants, and recipient albumin were independent predictors of survival of HCV- recipients. In the HCV+ cohort, recipient race, warm ischemia time (WIT), and diabetes also independently predicted graft survival. CONCLUSIONS: A number of parameters are differentially correlated with outcome in HCV- and HCV+ recipients of orthotopic liver transplantation. These findings may not only have practical implications in the selection and management of liver transplant patients, but also may shed new insight into the biology of HCV infection posttransplant.

    Title Promotion of Allograft Survival by Cd4+cd25+ Regulatory T Cells: Evidence for in Vivo Inhibition of Effector Cell Proliferation.
    Date August 2004
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Regulatory T cells preserve tolerance to peripheral self-Ags and may control the response to allogeneic tissues to promote transplantation tolerance. Although prior studies have demonstrated prolonged allograft survival in the presence of regulatory T cells (T-reg), data documenting the capacity of these cells to promote tolerance in immunocompetent transplant models are lacking, and the mechanism of suppression in vivo remains unclear. We used a TCR transgenic model of allograft rejection to characterize the in vivo activity of CD4(+)CD25(+) T-reg. We demonstrate that graft Ag-specific T-reg effectively intercede in the rejection response of naive T cells to established skin allografts. Furthermore, CFSE labeling demonstrates impaired proliferation of naive graft Ag-specific T cells in the draining lymph node in the presence of T-reg. These results confirm the efficacy of T-reg in promoting graft survival and suggest that their suppressive action is accomplished in part through inhibition of proliferation.

    Title Structural and Functional Abnormalities in the Islets Isolated from Type 2 Diabetic Subjects.
    Date June 2004
    Journal Diabetes
    Excerpt

    Type 2 diabetic subjects manifest both disordered insulin action and abnormalities in their pancreatic islet cells. Whether the latter represents a primary defect or is a consequence of the former is unknown. To examine the beta-cell mass and function of islets from type 2 diabetic patients directly, we isolated islets from pancreata of type 2 diabetic cadaveric donors (n = 14) and compared them with islets from normal donors (n = 14) matched for age, BMI, and cold ischemia time. The total recovered islet mass from type 2 diabetic pancreata was significantly less than that from nondiabetic control subjects (256,260 islet equivalents [2,588 IEq/g pancreas] versus 597,569 islet equivalents [6,037 IEq/g pancreas]). Type 2 diabetic islets were also noted to be smaller on average, and histologically, islets from diabetic patients contained a higher proportion of glucagon-producing alpha-cells. In vitro study of islet function from diabetic patients revealed an abnormal glucose-stimulated insulin release response in perifusion assays. In addition, in comparison with normal islets, an equivalent number of type 2 diabetic islets failed to reverse hyperglycemia when transplanted to immunodeficient diabetic mice. These results provide direct evidence for abnormalities in the islets of type 2 diabetic patients that may contribute to the pathogenesis of the disease.

    Title Early Kidney Dysfunction Post Liver Transplantation Predicts Late Chronic Kidney Disease.
    Date April 2004
    Journal Transplantation
    Excerpt

    BACKGROUND: Acute and chronic renal dysfunction (ARD, CRD) are common complications after liver transplantation and are associated with poor outcome. METHODS: We reviewed the results of 181 liver transplants performed in our institution between January 1, 1998 and December 31, 2000 in which the recipients were alive with good liver function at the end of the follow-up period (mean 2.7 years). Renal dysfunction was defined as a serum creatinine (Cr) greater than or equal to 2 mg/dL in both acute and chronic settings. RESULTS: The incidence of ARD during the first posttransplant week was 39.2% (n=71), whereas late CRD occurred in 6.0% (n=11) of the patients by the end of the follow-up period. Among the variables we examined for association with CRD, five factors were found to be statistically significant in univariate analysis: pretransplant diabetes (PRTDM) (0.000), Cr greater than or equal to 2 during the first postoperative week (0.003), posttransplant diabetes (POTDM) (0.014), age greater than 50 (0.025), and tacrolimus level greater than 15 ng/mL at postoperative day 15 (0.058). In binary logistic regression analysis, PRTDM (odds ratio [OR]=5.7, 95% confidence interval [CI]) and early postoperative ARD (OR=10.2 95% CI) remained consistently significant. Nine of 11 patients with CRD also had a history of ARD during the first postoperative week. These patients progressed to CRD despite the fact that seven of nine had normalized their renal function by day 90 posttransplant. CONCLUSION: We suggest that a combination of events during the first postoperative week after liver transplant serve as a physiologic "stress test" for the kidneys. Patients who fail the test (peak Cr >/=2 mg/dL during the first postoperative week) as well as the patients with diabetes mellitus are at increased risk of CRD. In such cases, conversion to a less nephrotoxic regimen may be beneficial.

    Title Homeostatic Proliferation is a Barrier to Transplantation Tolerance.
    Date April 2004
    Journal Nature Medicine
    Excerpt

    Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells. Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials. But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation, may induce acquisition of functional memory T cells. Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.

    Title Predicting Outcome After Liver Transplantation: Utility of the Model for End-stage Liver Disease and a Newly Derived Discrimination Function.
    Date February 2004
    Journal Transplantation
    Excerpt

    BACKGROUND: The Model for End-Stage Liver Disease (MELD) has been found to accurately predict pretransplant mortality and is a valuable system for ranking patients in greatest need of liver transplantation. It is unknown whether a higher MELD score also predicts decreased posttransplant survival. METHODS: We examined a cohort of patients from the United Network for Organ Sharing (UNOS) database for whom the critical pretransplant recipient values needed to calculate the MELD score were available (international normalized ratio of prothrombin time, total bilirubin, and creatinine). In these 2,565 patients, we analyzed whether the MELD score predicted graft and patient survival and length of posttransplant hospitalization. RESULTS: In contrast with its ability to predict survival in patients with chronic liver disease awaiting liver transplant, the MELD score was found to be poor at predicting posttransplant outcome except for patients with the highest 20% of MELD scores. We developed a model with four variables not included in MELD that had greater ability to predict 3-month posttransplant patient survival, with a c-statistic of 0.65, compared with 0.54 for the pretransplant MELD score. These pretransplant variables were recipient age, mechanical ventilation, dialysis, and retransplantation. Recipients with any two of the three latter variables showed a markedly diminished posttransplant survival rate. CONCLUSIONS: The MELD score is a relatively poor predictor of posttransplant outcome. In contrast, a model based on four pretransplant variables (recipient age, mechanical ventilation, dialysis, and retransplantation) had a better ability to predict outcome. Our results support the use of MELD for liver allocation and indicate that statistical modeling, such as reported in this article, can be used to identify futile cases in which expected outcome is too poor to justify transplantation.

    Title Survival Following Liver Transplantation from Non-heart-beating Donors.
    Date January 2004
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: To determine whether patient and graft survival following transplantation with non-heart-beating donor (NHBD) hepatic allografts is equivalent to heart-beating-donor (HBD) allografts. SUMMARY BACKGROUND DATA: With the growing disparity between the number of patients awaiting liver transplantation and a limited supply of cadaveric organs, there is renewed interest in the use of hepatic allografts from NHBDs. Limited outcome data addressing this issue exist. METHODS: Retrospective evaluation of graft and patient survival among adult recipients of NHBD hepatic allografts compared with recipients of HBD livers between 1993 and 2001 using the United Network of Organ Sharing database. RESULTS: NHBD (N = 144) graft survival was significantly shorter than HBD grafts (N = 26856). One- and 3-year graft survival was 70.2% and 63.3% for NHBD recipients versus 80.4% and 72.1% (P = 0.003 and P = 0.012) for HBD recipients. Recipients of an NHBD graft had a greater incidence of primary nonfunction (11.8 vs. 6.4%, P = 0.008) and retransplantation (13.9% vs. 8.3%, P = 0.04) compared with HBD recipients. Prolonged cold ischemic time and recipient life support were predictors of early graft failure among recipients of NHBD livers. Although differences in patient survival following NHBD versus HBD transplant did not meet statistical significance, a strong trend was evident that likely has relevant clinical implications. CONCLUSIONS: Graft and patient survival is inferior among recipients of NHBD livers. NHBD donors remain an important source of hepatic grafts; however, judicious use is warranted, including minimization of cold ischemia and use in stable recipients.

    Title Elevated Portal Vein Drug Levels of Sirolimus and Tacrolimus in Islet Transplant Recipients: Local Immunosuppression or Islet Toxicity?
    Date January 2004
    Journal Transplantation
    Excerpt

    The recent success of islet transplantation using the Edmonton protocol involved the use of sirolimus, tacrolimus, and daclizumab for immunosuppression. Islets were infused into the portal circulation after transhepatic access. This protocol provided a unique opportunity to measure sirolimus and tacrolimus levels from the portal vein and compare them to systemic venous levels. A total of 11 portal venous samples with a corresponding peripheral venous sample were obtained from patients undergoing a first or second islet infusion and medication levels were obtained on both types of specimens. The portal-to-systemic drug level ratio ranged from 0.95 to 2.71 for sirolimus and 1.0 to 3.12 for tacrolimus. Given the potential toxicity of these agents to islets, the findings in this study may have implications for designing the next generation of immunosuppressive protocols for islet transplantation.

    Title Insulin Gene Transfer Enhances the Function of Human Islet Grafts.
    Date December 2003
    Journal Diabetologia
    Excerpt

    AIMS/HYPOTHESIS: Recent success in islet transplantation renews the hope for the complete cure of patients afflicted with Type 1 diabetes. However, in the Edmonton series, two to four pancreas donors were required to obtain a sufficient islet mass to reverse the diabetes of each patient. In view of the donor shortage, this represents a major obstacle preventing greater application of islet transplantation to diabetic patients. We hypothesised that increasing the expression of the insulin gene in transplanted islets would augment their capacity for insulin production, thereby allowing reversal of diabetes with a reduced islet mass. METHODS: We used a replication defective adenovirus to deliver the human proinsulin gene (Ad-Ins) to isolated human islets. The function of Ad-Ins-transduced human islets was compared to islets transduced with a control vector (Ad-lacz). RESULTS: Ad-Ins-transduced islets produced two to three times more insulin than normal islets or those infected with Ad-lacz, as assessed by in vitro perifusion tests of glucose stimulated insulin release. When transplanted, Ad-Ins-transduced islets normalised the blood glucose of diabetic immunodeficient NOD-Scid mice, and less than half as many Ad-Ins islets were required for reversal of diabetes than when normal islets were transplanted. CONCLUSION/INTERPRETATION: Our results suggest a simple and effective approach that could enhance the efficiency of islet transplantation for treatment of diabetes in humans.

    Title Treatment of Obstructive Nephroureteral Clot with a Rheolytic Mechanical Thrombectomy Device.
    Date November 2003
    Journal Journal of Vascular and Interventional Radiology : Jvir
    Excerpt

    Thrombus within the renal collecting system and ureter after percutaneous intervention is usually self-limited, but when it is obstructive enough to produce anuria, it can cause deterioration of renal function. Herein a case of a patient with a transplant kidney in whom clot anuria developed after conversion of a nephroureteral stent to a nephrostomy catheter is presented. Internal urine drainage was restored with the use of a rheolytic mechanical thrombectomy device, with subsequent return of normal renal function.

    Title Regulatory Cd4+cd25+t Cells in Prevention of Allograft Rejection.
    Date October 2003
    Journal Frontiers in Bioscience : a Journal and Virtual Library
    Excerpt

    Long-term survival of transplanted organs currently requires chronic immunosuppressive treatment of recipients. While the efficacy of these therapies is satisfactory, their toxicity to host tissues and non-specific inhibition of the immune response are disadvantageous. The ideal in transplantation is a situation of donor-specific unresponsiveness, but agents capable of effecting specific tolerance to transplanted tissues have been elusive. Accumulating evidence suggests that immunoregulatory CD4+CD25+T cells are essential in regulating the immune response to self and foreign antigen. As these cells are capable of suppressing the alloresponse, they represent a potentially invaluable tool for prolonging survival of allografts. In this report, we summarize studies characterizing regulatory T cells and addressing their ability to extend allograft survival. While the capacity of this population to promote allograft tolerance has been demonstrated, many questions remain to be answered before their potential for clinical applicability can be fully defined. Despite this, it is clear from initial studies that regulatory T cells represent an exciting avenue for further investigation in the quest to induce donor-specific unresponsiveness.

    Title Pancreatic-derived Factor (fam3b), a Novel Islet Cytokine, Induces Apoptosis of Insulin-secreting Beta-cells.
    Date October 2003
    Journal Diabetes
    Excerpt

    PANDER (PANcreatic DERived factor, FAM3B), a newly discovered secreted cytokine, is specifically expressed at high levels in the islets of Langerhans of the endocrine pancreas. To evaluate the role of PANDER in beta-cell function, we investigated the effects of PANDER on rat, mouse, and human pancreatic islets; the beta-TC3 cell line; and the alpha-TC cell line. PANDER protein was present in alpha- and beta-cells of pancreatic islets, insulin-secreting beta-TC3 cells, and glucagon-secreting alpha-TC cells. PANDER induced islet cell death in rat and human islets. Culture of beta-TC3 cells with recombinant PANDER had a dose-dependent inhibitory effect on cell viability. This effect was also time-dependent. PANDER caused apoptosis of beta-cells as assessed by electron microscopy, annexin V fluorescent staining, and flow-cytometric terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. PANDER did not affect cytosolic Ca(2+) levels or nitric oxide levels. However, PANDER activated caspase-3. Hence, PANDER may have a role in the process of pancreatic beta-cell apoptosis.

    Title Magnetic Resonance-defined Periportal Steatosis Following Intraportal Islet Transplantation: a Functional Footprint of Islet Graft Survival?
    Date August 2003
    Journal Diabetes
    Excerpt

    There is growing interest in more widespread application of isolated islet transplantation for the treatment of type 1 diabetes; however, the sequelae of long-term islet residence within the liver are unknown. We report herein a consequence of intraportal islet transplantation, specifically the development of periportal hepatic steatosis apparently induced by the local secretion of insulin within the liver.

    Title Insulin Independence Following Isolated Islet Transplantation and Single Islet Infusions.
    Date July 2003
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: To restore islet function in patients whose labile diabetes subjected them to frequent dangerous episodes of hypoglycemic unawareness, and to determine whether multiple transplants are always required to achieve insulin independence. SUMMARY BACKGROUND DATA: The recent report by the Edmonton group documenting restoration of insulin independence by islet transplantation in seven consecutive patients with type 1 diabetes differed from previous worldwide experience of only sporadic success. In the Edmonton patients, the transplanted islet mass critical for success was approximately more than 9,000 IEq/kg of recipient body weight and required two or three separate transplants of islets isolated from two to four cadaveric donors. Whether the success of the Edmonton group can be recapitulated by others, and whether repeated transplants using multiple donors will be a universal requirement for success have not been reported. METHODS: The authors report their treatment with islet transplantation of nine patients whose labile type 1 diabetes was characterized by frequent episodes of dangerous hypoglycemia. RESULTS: In each of the seven patients who have completed the treatment protocol (i.e., one or if necessary a second islet transplant), insulin independence has been achieved. In five of the seven patients only a single infusion of islets was required. To date, only one recipient has subsequently lost graft function, after an initially successful transplant. This patient suffered recurrent hyperglycemia 9 months after the transplant. CONCLUSIONS: This report confirms the efficacy of the Edmonton immunosuppressive regimen and indicates that insulin independence can often be achieved by a single transplant of sufficient islet mass.

    Title Predictors of Late Kidney Dysfunction Post-liver Transplantation.
    Date June 2003
    Journal Transplantation Proceedings
    Title Transgenic T Cells Persist in an Adoptive Transfer Model of Mouse Liver Transplantation Tolerance.
    Date June 2003
    Journal Transplantation Proceedings
    Title The Use of Non-heart-beating Donors for Isolated Pancreatic Islet Transplantation.
    Date June 2003
    Journal Transplantation
    Excerpt

    Recent improvements in isolated islet transplantation indicate that this therapy may ultimately prove applicable to patients with type I diabetes. An obstacle preventing widespread application of islet transplantation is an insufficient supply of cadaveric pancreata. Non-heart-beating donors (NHBDs) are generally not deemed suitable for whole-organ pancreas donation and could provide a significant source of pancreata for islet transplantation. Isolated pancreatic islets prepared from 10 NHBDs were compared with those procured from 10 brain-dead donors (BDDs). The success of the isolation for the two groups was analyzed for preparation purity, quality, and recovered islet mass. The function of NHBD and BDD islets was evaluated using in vitro and in vivo assays. On the basis of the results of this analysis, an NHBD isolated islet allograft was performed in a type I diabetic. The recovery of islets from NHBDs was comparable to that of control BDDs. In vitro assessment of NHBD islet function revealed function-equivalent BDD islets, and NHBD islets transplanted to non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice efficiently reversed diabetes. Transplantation of 446,320 islet equivalents (IEq) (8,500 IEq/kg of recipient body weight) from a single NHBD successfully reversed the diabetes of a type I diabetic recipient. Normally functioning pancreatic islets can be isolated successfully from NHBDs. A single donor transplant from an NHBD resulted in a state of stable insulin independence in a type I diabetic recipient. These results indicate that NHBDs may provide an as yet untapped source of pancreatic tissue for preparation of isolated islets for clinical transplantation.

    Title Operative Parameters That Predict the Outcomes of Hepatic Transplantation.
    Date May 2003
    Journal Journal of the American College of Surgeons
    Excerpt

    BACKGROUND: A growing discrepancy between the number of patients awaiting liver transplantation and the number of organs available mandates the use of even marginal organ donors in whom there is major risk of suboptimal graft function. A comprehensive analysis of operative parameters on the outcomes of liver transplantation has not been reported. STUDY DESIGN: We analyzed the impact of 24 operative variables on the survival of 942 consecutive primary liver allografts performed at a single center from June 1992 through December 1997. Univariate and Cox proportional hazards analysis was used to identify those variables with independent prognostic significance in graft survival. Resource utilization for variables with multivariate significance was also analyzed. RESULTS: Of 12 intraoperative variables found to have significance in univariate analysis, three were significant by Cox multivariate analysis: 1) lack of immediate bile production by the graft intraoperatively, 2) platelet transfusion > or = 20 U, and 3) recipient urine output < or =2.0 mL/kg/h intraoperatively. Each of the three variables was associated with marked increases in hospital and Intensive Care Unit length of stay and hospital charges accrued during the admission for transplantation. CONCLUSION: We identified three operative parameters that predict a poor outcome after liver transplantation. The presence of these indicators suggests that early retransplantation should be considered. Early identification of grafts likely to have poor function might also provide an opportunity for therapeutic intervention to salvage graft function.

    Title Cd25+ Immunoregulatory Cd4 T Cells Mediate Acquired Central Transplantation Tolerance.
    Date March 2003
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Transplantation tolerance is induced reliably in experimental animals following intrathymic inoculation with the relevant donor strain Ags; however, the immunological mechanisms responsible for the induction and maintenance of the tolerant state remain unknown. We investigated these mechanisms using TCR transgenic mice (TS1) that carry T cells specific for an immunodominant, MHC class II-restricted peptide (S1) of the influenza PR8 hemagglutinin (HA) molecule. We demonstrated that TS1 mice reject skin grafts that have transgene-encoded HA molecules (HA104) as their sole antigenic disparity and that intrathymic but not i.v. inoculation of TS1 mice with S1 peptide induces tolerance to HA-expressing skin grafts. Intrathymic peptide inoculation was associated with a dose-dependent reduction in T cells bearing high levels of TCR specific for HA. However, this reduction was both incomplete and transient, with a full recovery of S1-specific thymocytes by 4 wk. Peptide inoculation into the thymus also resulted in the generation of immunoregulatory T cells (CD4+CD25+) that migrated to the peripheral lymphoid organs. Adoptive transfer experiments using FACS sorted CD4+CD25- and CD4+CD25+ T cells from tolerant mice revealed that the former but not the latter maintain the capacity to induce rejection of HA bearing skin allografts in syngeneic hosts. Our results suggest that both clonal frequency reduction in the thymus and immunoregulatory T cells exported from the thymus are critical to transplantation tolerance induced by intrathymic Ag inoculation.

    Title Toward Further Expansion of the Organ Pool for Adult Liver Recipients: Splitting the Cadaveric Liver into Right and Left Lobes.
    Date January 2003
    Journal Transplantation
    Excerpt

    BACKGROUND: Current methods of living donor right lobe transplantation can be expanded for use in the cadaveric setting. The aim of this study is to discuss alternative methods for the management of large-for-size cadaveric livers and determine the feasibility of splitting these organs into left and right hemi-livers using similar techniques to those used in the living donor setting. METHODS: The indication for an in situ right-left split procedure was an offer of a large liver for a small recipient with a recipient-donor ratio of greater than 1.5. A total of three livers were split. Mean donor age was 33.3 (range, 22-40) years. Mean weight was 118 (range, 90-150) kg. All donors were without significant medical history and were hemodynamically stable, with normal liver function and short hospital stay. Mean duration of the procurement procedure was 235 (range, 210-270) min. Mean cold ischemia time was 8.5 hr. Mean recipient weight was 58.3 kg, and mean donor to recipient weight ratio was 2.0 (1.6-2.6). United Network for Organ Sharing statuses at the time of transplantation were 1 (n=1), 2A (n=1), and 2B (n=4). RESULTS: Immediate graft function was seen in five recipients. Delayed nonfunction was identified in one recipient of a left lobe, who did not undergo transplantation because of sepsis that resulted in death at 30 days. A second mortality occurred in a left lobe recipient, from a fungal brain abscess at 90 days. Complications related to the split included bile leaks in two patients, one necessitating operative revision. CONCLUSIONS: Splitting of livers from appropriate brain-dead donors into right and left lobes is technically and logistically feasible. The large-for-size organ provides a more substantial amount of liver tissue to each of the adult recipients, which may result in a greater graft to recipient weight ratio than the current standard that is used in the living donor grafting. The importance of this variable will need to be studied, because it may positively impact on the ability of the reduced-size graft to withstand donor-related organ system stress and injury, which is associated with brain death and the inevitable longer period of cold preservation.

    Title Pretransplant Model to Predict Posttransplant Survival in Liver Transplant Patients.
    Date September 2002
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: To develop a prognostic model that determines patient survival outcomes after orthotopic liver transplantation (OLT) using readily available pretransplant variables. SUMMARY BACKGROUND DATA: The current liver organ allocation system strongly favors organ distribution to critically ill recipients who exhibit poor survival outcomes following OLT. A severely limited organ resource, increasing waiting list deaths, and rising numbers of critically ill recipients mandate an organ allocation system that balances disease severity with survival outcomes. Such goals can be realized only through the development of prognostic models that predict survival following OLT. METHODS: Variables that may affect patient survival following OLT were analyzed in hepatitis C (HCV) recipients at the authors' center, since HCV is the most common indication for OLT. The resulting patient survival model was examined and refined in HCV and non-HCV patients in the United Network for Organ Sharing (UNOS) database. Kaplan-Meier methods, univariate comparisons, and multivariate Cox proportional hazard regression were employed for analyses. RESULTS: Variables identified by multivariate analysis as independent predictors for patient survival following primary transplantation of adult HCV recipients in the last 10 years at the authors' center were entered into a prognostic survival model to predict patient survival. Accordingly, mortality was predicted by 0.0293 (recipient age) + 1.085 (log10 recipient creatinine) + 0.289 (donor female gender) + 0.675 urgent UNOS - 1.612 (log10 recipient creatinine times urgent UNOS). The above variables, in addition to donor age, total bilirubin, prothrombin time (PT), retransplantation, and warm and cold ischemia times, were applied to the UNOS database. Of the 46,942 patients transplanted over the last 10 years, 25,772 patients had complete data sets. An eight-factor model that accurately predicted survival was derived. Accordingly, the mortality index posttransplantation = 0.0084 donor age + 0.019 recipient age + 0.816 log creatinine + 0.0044 warm ischemia (in minutes) + 0.659 (if second transplant) + 0.10 log bilirubin + 0.0087 PT + 0.01 cold ischemia (in hours). Thus, this model is applicable to first or second liver transplants. Patient survival rates based on model-predicted risk scores for death and observed posttransplant survival rates were similar. Additionally, the model accurately predicted survival outcomes for HCV and non-HCV patients. CONCLUSIONS: Posttransplant patient survival can be accurately predicted based on eight straightforward factors. The balanced application of a model for liver transplant survival estimate, in addition to disease severity, as estimated by the model for end-stage liver disease, would markedly improve survival outcomes and maximize patients' benefits following OLT.

    Title Comparison of Open, Laparoscopic, and Hand-assisted Approaches to Live-donor Nephrectomy.
    Date August 2002
    Journal Transplantation
    Excerpt

    BACKGROUND: Minimally invasive donor nephrectomy has become a favored procedure for the procurement of kidneys from live donors. The optimal minimally invasive surgical approach has not been determined. In the current work, we compared the outcome of kidneys procured using the traditional open approach with two minimally invasive techniques: the standard laparoscopic procedure and a hand-assist procedure. METHODS: The function of live-donor kidneys procured by open versus minimally invasive procedures was compared (procedures compared were the traditional open donor nephrectomy [ODN], the standard laparoscopic [LAP] approach, and the hand-assisted [HA] laparoscopic technique). The length of donor operation, donor length of stay in the hospital, surgical complications, and cost of hospitalization for three groups of patients were assessed in a series of 150 live-donor nephrectomies. RESULTS: We found that both minimally invasive procedures yielded kidney allografts with excellent early function and a minimum of complications in the donor. The open procedure was associated with a reduced operative time but increased donor length of stay in the hospital. Resource utilization analysis revealed that both minimally invasive techniques were associated with a slight increase in costs compared with the open procedure, despite a shorter hospital stay. CONCLUSIONS: Minimally invasive donor nephrectomy is safe and effective for procuring normally functioning organs for live-donor transplantation. Of the two minimally invasive approaches examined, the hand-assisted technique was found to afford a number of important advantages, including facilitating teaching of residents and students, that it is more readily mastered by transplant surgeons, and that it may provide an additional margin of safety for the donor.

    Title The Outcome of Liver Grafts Procured from Hepatitis C-positive Donors.
    Date April 2002
    Journal Transplantation
    Excerpt

    BACKGROUND: The growing prevalence of hepatitis C virus (HCV) infection in the general population has resulted in an increased frequency of potential organ donors that carry the virus. The survival of grafts from HCV+ donors has not been studied in detail. METHODS: Two study populations were examined retrospectively to assess the survival of liver grafts procured from HCV+ donors. First, we evaluated the survival of all 13 HCV+ and 103 HCV- grafts that were transplanted at our institution to HCV+ recipients from January 1, 1995 to December 31, 1999. In parallel, we analyzed a subset of the United Network for Organ Sharing (UNOS) liver transplant database from the same 5-year time period that was comprised of 14,195 adult patients for whom donor and recipient HCV serologies were known. Kaplan-Meier graft survival for both patient populations was calculated based on donor and recipient HCV serologic status. A Cox proportional hazards analysis was performed on UNOS data to identify variables independently predicting graft survival. RESULTS: For transplants performed at our institution, we found no statistically significant difference in the Kaplan-Meier graft survival of HCV+ and HCV- grafts transplanted to HCV+ recipients (P=0.68). The incidence of biopsy-proven, recurrent HCV posttransplant was similar in recipients receiving either HCV+ or HCV- grafts (4/13 vs. 18/103, chi-square P=0.211). Analysis of UNOS data revealed that the survival of HCV+ grafts in HCV+ recipients was equivalent to the survival of HCV- grafts in HCV+ recipients. Unexpectedly, the survival of grafts in HCV+ recipients in general was significantly inferior to that of grafts in HCV- recipients. Multivariate analysis of all patients found recipient but not donor HCV status to be independently predictive of graft survival. CONCLUSIONS: Analysis of data from a single center and the national UNOS database suggests that transplantation of liver allografts from HCV+ donors to HCV+ recipients results in graft survival comparable to HCV- grafts transplanted to HCV+ recipients. In contrast, recipient HCV positivity is an independent predictor of graft failure compared with patients transplanted for other causes of liver disease.

    Title Surgical Options for Live-donor Nephrectomy.
    Date March 2002
    Journal Transplantation Proceedings
    Title Effect of Donor Hepatitis C on Liver Graft Survival.
    Date March 2002
    Journal Transplantation Proceedings
    Title Immunomodulation by Intrathymic Injection of Donor Leukocytes in Rhesus Monkeys. Transplantation 2001; 72: 1432.
    Date December 2001
    Journal Transplantation
    Title Preoperative Factors Associated with Outcome and Their Impact on Resource Use in 1148 Consecutive Primary Liver Transplants.
    Date October 2001
    Journal Transplantation
    Excerpt

    BACKGROUND: Hepatic transplantation is a highly effective but costly treatment for end-stage hepatic dysfunction. One approach to improve efficiency in the use of scarce organs for transplantation is to identify preoperative factors that are associated with poor outcome posttransplantation. This may assist both in selecting patients optimal for transplantation and in identifying strategies to improve survival. METHODS: In the present work, we retrospectively reviewed consecutive liver transplants performed at the University of California at Los Angeles during a 6-year period and determined preoperative variables that were associated with outcome in primary grafts. In addition, we used the hospital's cost accounting database to determine the impact of these variables on the degree of resource use by high-risk patients. RESULTS: We found five variables to have independent prognostic value in predicting graft survival after primary liver transplantation: (1) donor age, (2) recipient age, (3) donor sodium, (4) recipient creatinine, and (5) recipient ventilator requirement pretransplant. Recipient ventilator requirement and elevated creatinine were associated with significant increases in resource use during the transplant admission. CONCLUSIONS: Patients at high risk for graft failure and costly transplants can be identified preoperatively by a set of parameters that are readily available, noninvasive, and inexpensive. Selection of recipients on the basis of these data would improve the efficiency of liver transplantation and reduce its cost.

    Title Annual Literature Review--clinical Transplants 2000.
    Date September 2001
    Journal Clinical Transplants
    Title Comparison of Activation Requirements and Activation Phenotype of Allogeneic and Xenogeneic Rodent Responses in Vivo and in Vitro.
    Date September 2001
    Journal Transplantation
    Excerpt

    BACKGROUND: Both discordant and concordant xenogeneic responses are dominated by humoral immunity. Recent advances in molecular engineering approaches may largely prevent rejection by means of this pathway, leaving the cellular arm of the immune response as the principal remaining barrier to successful engraftment. METHODS: To characterize further the cellular response to xenogeneic tissues, we used the intracellular fluorescent marker CFSE (5-(and-6)-carboxyfluorescein diacetate succinimidyl ester) to track the mitotic record of T cells (and T cell subsets) after either xenogeneic or allogeneic activation in vitro or in vivo. Activation marker expression was monitored by simultaneous labeling with antibodies for either CD25 or CD134. RESULTS: The in vitro and in vivo responses of Lewis lymphocytes were generally similar in magnitude and timing comparing activation with allogeneic or xenogeneic stimulators. However, the xenogeneic T cell precursor frequency was found to be markedly higher than that previously reported and were comparable to that seen in allogeneic responses. Xenogeneic responses were unique in the continued expression of activation markers in later division cycles. In addition, CD4 and CD8 T-cell proliferation was highly dependent on stimulator class II expression, highlighting the importance of CD4 T cells and the indirect pathway in the xenogeneic response. CONCLUSIONS: An unexpectedly high precursor frequency was detected for xenogeneic cellular responses in the rat anti-mouse combination and was comparable to that seen in allogeneic responses. Differences in xenogeneic versus allogeneic activation profiles exist that may result from the cellular pathways used for activation.

    Title The Fate of Liver Grafts Declined for Subjective Reasons and Transplanted out of a Local Organ Procurement Organization.
    Date November 2000
    Journal Transplantation
    Excerpt

    BACKGROUND: Decisions made by transplant surgeons to decline liver grafts for local use are based on both objective and ill-defined subjective parameters. These livers may be offered and subsequently transplanted at non-local centers. We analyzed the fate of these exported livers, focusing on the outcome of grafts declined for subjective reasons. The aim is to determine whether local surgeons' concerns about inferior graft function are justified. METHODS: Over a 3-year period, 13.3% of 555 livers in our organ procurement organization (OPO) were exported and transplanted out of the local area. Donor data and reason for decline were obtained from an extensive OPO database. Objective reasons for decline were based on no appropriate matched recipient due to donor size, serologies, or malignancy with potential for spread. Subjective parameters were related to the procuring surgeon's assessment and included variables such as medical and social history, abnormal liver enzymes, older age, organ visualization, and biopsy. Recipient data were obtained from questionnaires sent to outside transplant centers. RESULTS: There was a significantly higher rate of nonfunction in the subjective group (17.1%), compared to the objective group (0%). One-year graft and patient survival were 79 and 83% for the objective group and 59 and 68% for the subjective group (P=NS). When donors declined for medical/social history were excluded from the subjective group, leaving only grafts declined based solely on the surgeon's assessment of graft quality, there is a significant difference in graft survival (79% for objective and 46% for this subjective subgroup, P=0.03). CONCLUSIONS: Livers declined for local use based on subjective assessment by the procuring surgeon have a high nonfunction rate, associated with a high morbidity. Therefore, the use of these grafts should be restricted to recipients at the most urgent status.

    Title Liver Transplantation at the University of Pennsylvania and the Children's Hospital of Philadelphia.
    Date November 2000
    Journal Clinical Transplants
    Excerpt

    The liver transplant program at the University of Pennsylvania and the Children's Hospital of Philadelphia experienced healthy growth in its clinical activity in the past 5 years. Patterns of referral and patient evaluation were established, care of patients while waiting on the list or being followed after transplantation was streamlined. We are now achieving excellent outcomes while transplanting relatively sicker patients. Innovative surgical procedures are implemented resulting in more efficient utilization of cadaveric and living-donor liver grafts. The protocols that are used for patient care are more standard, yet flexible and accommodate recent advancement in transplantation immunobiology. This progress of the clinical program was enhanced by careful preservation of the academic mission of the institution, which encourages the liver transplant faculty to be involved in NIH-supported clinical and basic science research.

    Title Orthotopic Liver Transplantation for Hepatitis C: Outcome, Effect of Immunosuppression, and Causes of Retransplantation During an 8-year Single-center Experience.
    Date July 1999
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: To determine the outcome of orthotopic liver transplantation (OLT) for end-stage liver disease caused by hepatitis C virus (HCV). SUMMARY BACKGROUND DATA: HCV has become the leading cause of cirrhosis and hepatic failure leading to OLT. Recurrent HCV after OLT is associated with significant complications and may lead to graft loss that requires retransplantation (re-OLT). The authors studied the outcome of transplantation for HCV, the effect of primary immunotherapy, and causes of retransplantation. METHODS: The authors conducted a retrospective review of their experience during an 8-year period (1990-1997), during which 374 patients underwent transplants for HCV (298 [79.6%] received one OLT; 76 [20.4%] required re-OLT). Median follow-up was 2 years (range 0 to 8.3). Immunosuppression was based on cyclosporine in 190 patients and tacrolimus in 132 patients. In a third group of patients, therapy was switched from cyclosporine to tacrolimus or from tacrolimus to cyclosporine (cyclosporine/tacrolimus group). RESULTS: Overall, 1-, 2-, and 5-year actuarial patient survival rates were 86%, 82%, and 76%, respectively. The 2-year patient survival rate was 81 % in the cyclosporine group, 85% in the tacrolimus group, and 82% in the cyclosporine/tacrolimus group. In patients receiving one OLT, overall 1-, 2-, and 5-year patient survival rates were 85%, 81%, and 75%, respectively. The 2-year patient survival rate was 79% in the cyclosporine group, 84% in the tacrolimus group, and 80% in the cyclosporine/tacrolimus group. The overall graft survival rates were 70%, 65%, and 60% at 1, 2, and 5 years, respectively. The graft survival rate at 2 years was similar under cyclosporine (68.5%), tacrolimus (64%), or cyclosporine/tacrolimus (60%) therapy. Re-OLT was required in 42 (11.2%) patients for graft dysfunction in the initial 30 days after OLT. Other causes for re-OLT included hepatic artery thrombosis in 10 (2.6%), chronic rejection in 8 (2.1%), and recurrent HCV in 13 (3.4%) patients. The overall survival rates after re-OLT were 63% and 58% at 1 and 2 years. The 1-year survival rate after re-OLT was 61 % for graft dysfunction, 50% for chronic rejection, 60% for hepatic artery thrombosis, and 60% for recurrent HCV. At re-OLT, 85.3% of the patients were critically ill (United Network for Organ Sharing [UNOS] status 1); only 14.7% of the patients were UNOS status 2 and 3. In re-OLT for chronic rejection and recurrent HCV, the 1-year survival rate of UNOS 1 patients was 38.4%, compared with 87.5% for UNOS 2 and 3 patients. In patients requiring re-OLT, there was no difference in the 1-year patient survival rate after re-OLT when cyclosporine (60%), tacrolimus (63%), or cyclosporine/tacrolimus (56%) was used for primary therapy. With cyclosporine, three patients (1.5%) required re-OLT for chronic rejection versus one patient (0.7%) with tacrolimus. Re-OLT for recurrent HCV was required in four (3%) and seven (3.6%) patients with tacrolimus and cyclosporine therapy, respectively. CONCLUSIONS: Orthotopic liver transplantation for HCV is performed with excellent results. There are no distinct advantages to the use of cyclosporine versus tacrolimus immunosuppression when patient and graft survival are considered. Re-OLT is an important option in the treatment of recurrent HCV and should be performed early in the course of recurrent disease. Survival after re-OLT is not distinctively affected by cyclosporine or tacrolimus primary immunotherapy. The incidence of re-OLT for recurrent HCV or chronic rejection is low after either tacrolimus or cyclosporine therapy.

    Title Cellular Immunity Delimits Adenoviral Gene Therapy Strategies for the Treatment of Neoplastic Diseases.
    Date April 1999
    Journal Annals of Surgical Oncology
    Excerpt

    BACKGROUND: Adenoviral gene therapy is a promising new approach for the treatment of neoplastic diseases. To design rational clinical trials and distinguish the effects of therapeutic transgene expression from those caused by viral infection alone, the immune response to the vector must be understood. In these experiments, we further define cellular immunity to recombinant adenovirus. METHODS: The immune response to hepatic adenoviral gene transfer was studied in infected mice by depleting T cells with an anti-CD3 antibody, measuring splenocyte cytokine production, determining the impact of transgene expression on inflammation, and assessing liver MHC protein expression. RESULTS: The cellular immune response to recombinant adenovirus is (1) averted by T lymphocyte depletion, (2) marked by a TH1 response with increased IL-2 production, (3) directed against both the transgene product and viral proteins, and (4) associated with increased hepatocyte MHC Class I expression. CONCLUSIONS: It is necessary to take into consideration the constraints imposed by the immunogenicity of recombinant adenovirus and its transient transgene expression in the clinical application of adenoviral gene transfer for the treatment of cancer.

    Title A Simple Model to Estimate Survival After Retransplantation of the Liver.
    Date March 1999
    Journal Transplantation
    Excerpt

    To formulate a model predicting survival after liver retransplantation, we analyzed in detail the last 150 cases of hepatic retransplantation at UCLA. Cox proportional hazards regression analysis identified five variables that demonstrated independent simultaneous prognostic value in estimating patient survival after retransplantation: (1) age group (pediatric or adult), (2) recipient requiring preoperative mechanical ventilation, (3) donor organ cold ischemia > or =12 hr, (4) preoperative serum creatinine, and (5) preoperative serum total bilirubin. The Cox regression equation that predicts survival based on these covariates was simplified by assigning individual patients a risk classification based on a 5-point scoring system. We demonstrate that this system can be employed to identify a subgroup of patients in which the expected outcome is too poor to justify retransplantation. These findings may assist in the rational selection of patients suitable for retransplantation.

    Title Experience with Combined Liver-small Intestine Transplantation at the University of California, Los Angeles.
    Date October 1998
    Journal Transplantation Proceedings
    Title Mycotic Aneurysm of Arterial Conduit Presenting As Massive Upper Gastrointestinal Hemorrhage After Liver Transplantation.
    Date October 1998
    Journal Liver Transplantation and Surgery : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
    Title Prophylaxis Against Hepatitis B Recurrence Following Liver Transplantation Using Combination Lamivudine and Hepatitis B Immune Globulin.
    Date August 1998
    Journal Hepatology (baltimore, Md.)
    Excerpt

    Patients undergoing liver transplantation for hepatitis B-related liver disease are prone to recurrence. The mainstay of prophylaxis has been passive immunotherapy with hepatitis B immune globulin (HBIG). Antiviral therapy with lamivudine has proven effective in lowering hepatitis B virus (HBV) DNA and improving histology in patients with hepatitis B infection; its role in prophylaxis against hepatitis B recurrence following liver transplantation is under investigation. Viral breakthrough and resistance, however, are a significant problem with monotherapy with either HBIG or lamivudine. The efficacy of combination lamivudine/HBIG prophylaxis has not been reported. Fourteen patients underwent transplantation for decompensated liver disease owing to hepatitis B. Lamivudine (150 mg p.o./d) was begun before transplantation in 10 patients, including 4 who were HBV DNA-positive. In addition, 1 patient was HBV DNA-positive when transplanted. HBIG was given perioperatively and continued thereafter; treatment with lamivudine was maintained or initiated at the time of transplantation and continued indefinitely. The median follow-up was 387 days. Actuarial 1-year patient and graft survival was 93% (1 patient died of unrelated causes). At a median interval of 28 days following lamivudine treatment, all 5 HBV DNA-positive patients cleared HBV DNA from the serum; 1 went on to clear hepatitis B surface antigen (HBsAg), before transplantation, at day 148 of lamivudine treatment. By the highly sensitive polymerase chain reaction (PCR), at a median of 346 days (range, 130-525 days) following transplantation, all 13 surviving patients had no detectable serum HBV DNA. Lamivudine suppresses HBV replication in patients awaiting liver transplantation. At a median follow-up of 1.1 years, combination prophylaxis with lamivudine and HBIG prevented hepatitis B recurrence following liver transplantation.

    Title Liver Transplantation for Decompensated Cirrhosis After Jejunoileal Bypass: a Strategy for Management.
    Date March 1998
    Journal Transplantation
    Excerpt

    BACKGROUND: Although jejunoileal bypass results in end-stage liver disease in up to 100% of patients, little is known about outcome after liver transplantation. METHODS: The clinical courses of six patients who underwent liver transplantation at UCLA for decompensated cirrhosis owing to a jejunoileal bypass were reviewed. Liver function, allograft pathology, renal function, and nutritional status were assessed. RESULTS: Of the four patients with an intact jejunoileal bypass, two of the three who were biopsied had recurrent steatotic liver disease. The two patients whose jejunoileal bypass was reversed at the time of liver transplantation had lower alkaline phosphatase, lower creatinine, higher albumin, and higher cholesterol, and were more obese than their counterparts with intact bypasses. CONCLUSIONS: Patients undergoing liver transplantation for jejunoileal bypass-associated liver disease should, if possible, have their bypass reversed at the time of transplantation; otherwise, they must be followed closely and be biopsied routinely. Recurrent liver disease should prompt reversal of the jejunoileal bypass.

    Title Long-term Survival After Retransplantation of the Liver.
    Date November 1997
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: The authors determined the long-term outcome of patients undergoing hepatic retransplantation at their institution. Donor, operative, and recipient factors impacting on outcome as well as parameters of patient resource utilization were examined. SUMMARY BACKGROUND DATA: Hepatic retransplantation provides the only available option for liver transplant recipients in whom an existing graft has failed. However, such patients are known to exhibit patient and graft survival after retransplantation that is inferior to that expected using the same organs in naiive recipients. The critical shortage of donor organs and resultant prolonged patient waiting periods before transplantation prompted the authors to evaluate the results of a liberal policy of retransplantation and to examine the factors contributing to the inferior outcome observed in retransplanted patients. METHODS: A total of 2053 liver transplants were performed at the UCLA Medical Center during a 13-year period from February 1, 1984, to October 1, 1996. A total of 356 retransplants were performed in 299 patients (retransplant rate = 17%). Multivariate regression analysis was performed to identify variables associated with survival. Additionally, a case-control comparison was performed between the last 150 retransplanted patients and 150 primarily transplanted patients who were matched for age and United Network of Organ Sharing (UNOS) status. Differences between these groups in donor, operative, and recipient variables were studied for their correlation with patient survival. Days of hospital and intensive care unit stay, and hospital charges incurred during the transplant admissions were compared for retransplanted patients and control patients. RESULTS: Survival of retransplanted patients at 1, 5, and 10 years was 62%, 47%, and 45%, respectively. This survival is significantly less than that seen in patients undergoing primary hepatic transplantation at the authors' center during the same period (83%, 74%, and 68%). A number of variables proved to have a significant impact on outcome including recipient age group, interval to retransplantation, total number of grafts, and recipient UNOS status. Recipient primary diagnosis, cause for retransplantation, and whether the patient was retransplanted before or after June 1, 1992, did not reach statistical significance as factors influencing survival. In the case-control comparison, the authors found that of the more than 25 variables studied, only preoperative ventilator status showed both a significant difference between control patients and retransplanted patients and also was a factor predictive of survival in retransplanted patients. Retransplant patients had significantly longer hospital and intensive care unit stays and accumulated total hospitalization charges more than 170% of those by control patients. CONCLUSIONS: Hepatic retransplantation, although life-saving in almost 50% of patients with a failing liver allograft, is costly and uses scarce donor organs inefficiently. The data presented define patient characteristics and preoperative variables that impact patient outcome and should assist in the rational application of retransplantation.

    Title In Situ Splitting of the Cadaveric Liver for Transplantation.
    Date October 1997
    Journal Transplantation
    Excerpt

    BACKGROUND: The shortage of cadaveric donor livers is the rate-limiting step in clinical liver transplantation. Split liver transplantation provides a means to expand the cadaveric donor pool. However, this concept has not reached its full potential because of inferior patient and graft survival and high complication rates when traditional ex vivo split techniques are used. Therefore we sought to evaluate the safety, applicability, and effectiveness of a new technique for split liver transplantation. METHODS: This study consists of 15 in situ split liver procurements, which resulted in 28 liver transplants. In situ splitting of selected livers from hemodynamically stable cadaveric donors was performed at the donor hospital without any additional work-up or equipment being needed. In situ liver splitting is accomplished in a manner identical to the living-donor procurement. This technique for liver splitting results in a left lateral segment graft (segments 2 and 3) and a right trisegmental graft (segments 1 and 4-8). This procedure required the use of the donor hospital operating room for an additional 1.5-2.5 hr and did not interfere with the procurement of 30 kidneys, 12 hearts, 7 lungs, and 9 pancreata from these same donors. RESULTS: The 6-month and 1-year actuarial patient survival rates were 92% and 92%, respectively, while the 6-month and 1-year actuarial graft survival rates were 86% and 86%, respectively. The 6-month and 1-year actuarial patient survival rate of patients who received a left lateral segment graft was 100% and 100%, respectively, while those who received a right trisegmental graft had 6-month and 1-year rates of 86% and 86%, respectively. The actuarial death-censored graft survival rates at 6 months and 1 year were 80% and 80%, respectively, for the left lateral segment grafts, and 93% and 93%, respectively, for the right trisegmental grafts. Alograft and patient survival was independent of United Network for Organ Sharing status at the time of liver transplantation. No patient developed a biliary stricture, required re-exploration for intra-abdominal hemorrhage, or suffered from portal vein, hepatic vein, or hepatic artery thrombosis CONCLUSIONS: In situ split liver transplantation can be accomplished without complications and provides results that are superior to those obtained previously with ex vivo methods. It abolishes ex vivo benching and prolonged ischemia times and provides two optimal grafts with hemostasis accomplished. This technique decreases pediatric waiting time and allows adult recipients to receive right-sided grafts safely. In situ splitting is the method of choice for expanding the cadaveric liver donor pool.

    Title Long-lasting Adenovirus Transgene Expression in Mice Through Neonatal Intrathymic Tolerance Induction Without the Use of Immunosuppression.
    Date July 1997
    Journal Journal of Virology
    Excerpt

    The major barrier to the clinical application of adenovirus gene therapy for diseases that require stable transgene expression is the immunogenicity of recombinant adenovirus, which ordinarily limits the duration of its effects to a period of about 2 weeks. We postulated that tolerance to adenovirus could be induced and transgene expression could be prolonged if T lymphocytes underwent thymic selection in the presence of adenovirus antigens. Mice were inoculated in the thymus with a recombinant adenovirus containing the lacZ marker gene during the neonatal period at a time before T-cell maturation had occurred. When the virus was administered intravenously to these mice in adulthood, they were found to have an impaired adenovirus-specific cytotoxic T-lymphocyte response which allowed prolonged hepatic lacZ expression, for up to 260 days. The ability to achieve unresponsiveness to a recombinant adenovirus after inoculation of the thymus in neonates extends the paradigm of intrathymic tolerance induction. Furthermore, this model will enable the study of stable adenovirus transgene expression in vivo without the use of immunosuppression and ultimately may have clinical utility.

    Title Xenogeneic but Not Allogeneic Pancreatic Islet Graft Survival in Recipients Lacking Humoral Immunity and Major Histocompatibility Complex Class Ii Antigens.
    Date April 1997
    Journal Transplantation Proceedings
    Title Prolongation of Adenoviral Transgene Expression in Mouse Liver by T Lymphocyte Subset Depletion.
    Date March 1997
    Journal Gene Therapy
    Excerpt

    Although first generation recombinant adenoviruses are efficient vehicles for gene transfer, their immunogenicity precludes long-term persistence. We show that adenoviral transgene expression in the liver of normal mice is prolonged from a baseline of less than 2 weeks to 7 weeks by depleting CD4+ T lymphocytes with thymectomy and a 3-day course of anti-CD4 monoclonal antibody or by nonselectively depleting T cells with a single dose of anti-thymocyte serum (ATS). Transgene expression persisted despite the development of an antiviral humoral immune response by 3 weeks after virus administration. In vitro assays of T lymphocyte function revealed an initial diminished capacity to proliferate in the presence of adenoviral antigens in animals depleted of CD4+ T cells or given anti-thymocyte serum. Eventual loss of recombinant gene expression coincided with the development of adenovirus-specific cytotoxic T lymphocyte activity in vitro. Immunosuppression provides a useful experimental tool to elucidate the immunobiology of recombinant adenoviruses and may have clinical application to adenovirus-mediated gene therapy.

    Title Immunologic Barriers to Hepatic Adenoviral Gene Therapy for Transplantation.
    Date February 1997
    Journal Transplantation
    Excerpt

    Adenoviral gene transfer has potential use to attenuate the immunogenicity of hepatic allografts. However, the clinical application of adenoviral gene therapy is currently impeded by the potent host immune response to the virus that limits the duration of its effects. In these studies, we identify the cellular and humoral immune responses to recombinant adenovirus in the liver of mice and define the immunologic barriers to the successful application of this technology to transplantation. The immunobiology of recombinant adenovirus was studied in mouse liver using vectors containing the lacZ and alkaline phosphatase marker genes. The duration of transgene expression was studied in various immunodeficient mice to determine the mechanism of viral clearance. Adoptive transfer of serum to B lymphocyte deficient mice and neutralizing antibody assays were used to define the antiviral humoral response. Hepatic adenoviral transgene expression was prolonged in animals deficient in CD4+ or CD8+ T cells indicating their importance in viral clearance. Unexpectedly, mice lacking B lymphocytes also had delayed elimination of virus suggesting that B cells play a role in the primary immune response. Effective repeat gene transfer was blocked by adenoviral-specific neutralizing antibody. Therefore, a T lymphocyte response results in viral elimination after a primary intravenous inoculation of recombinant adenovirus and a potent humoral response inhibits effective repeat adenoviral gene transfer. The immunogenicity of the vector must be overcome for adenoviral gene therapy to have therapeutic application for hepatic transplantation.

    Title Hemopneumothorax Missed by Auscultation in Penetrating Chest Injury.
    Date February 1997
    Journal The Journal of Trauma
    Excerpt

    OBJECTIVE: To determine the frequency and extent of hemothorax, pneumothorax, and hemopneumothorax missed by auscultation in penetrating chest injury. DESIGN: A retrospective chart and chest radiograph review. MATERIALS AND METHODS: One hundred and eighteen patients suffering penetrating chest injuries during 1993 were studied. A missed auscultation was defined as a patient with normal breath sounds but shown by chest radiograph to have a hemothorax, pneumothorax, or hemopneumothorax. The amount of hemothorax was recorded after chest tube placement or at thoracotomy. The degree of pneumothorax was determined by Rhea's method. RESULTS: Seventy-one patients (60%) had a hemothorax, pneumothorax, or hemopneumothorax. Auscultation to detect hemothorax, pneumothorax, or hemopneumothorax had a sensitivity of 58%, a specificity of 98%, and a positive predictive value of 98%. Thirty of 71 patients (42%) were found to have pleural space blood or air missed by auscultation. Twelve patients (41%) had a hemopneumothorax, 11 patients (36%) had hemothorax, and seven patients (23%) had pneumothorax. Auscultation missed hemothorax up to 600 mL, pneumothorax up to 28%, and hemopneumothorax up to 800 mL and 28%. CONCLUSION: Hemopneumothorax and hemothorax are the conditions most likely to be missed by auscultation, especially in patients with gunshot wounds. Auscultation has a high positive predictive value because it indicates injury with a fair degree of certainty; however, a negative auscultation does not rule out injury.

    Title Role of Humoral Immunity in Pancreatic Islet Allo- and Xenograft Rejection.
    Date June 1996
    Journal Transplantation Proceedings
    Title Cellular Requirements for Pancreatic Islet Xenograft Rejection.
    Date February 1996
    Journal Transplantation Proceedings
    Title Gene Transfer to the Thymus. A Means of Abrogating the Immune Response to Recombinant Adenovirus.
    Date October 1995
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: The authors investigated whether adenoviral gene transfer to the thymus could be accomplished in vivo and whether immunologic unresponsiveness to recombinant adenovirus could be induced by intrathymic inoculation. SUMMARY BACKGROUND DATA: A major barrier to the clinical application of adenovirus-mediated gene therapy for diseases requiring long-lasting gene expression is the immunogenicity of adenoviral vectors, which limits the duration of its effects. In other experimental models, intrathymic inoculation of foreign proteins or cells has proven to be an effective means to induce immunologic tolerance. METHODS: The efficiency of gene transfer to the mouse thymus after direct inoculation of recombinant adenovirus was compared with that of several other vectors. Animals inoculated with adenovirus-infected pancreatic islets into the thymus were tested for unresponsiveness to the virus with a subsequent challenge of adenovirus administered into the liver by intravenous injection. RESULTS: Adenovirus accomplished highly efficient gene transfer to the thymus, unlike plasmid DNA, DNA-liposome complexes, retrovirus, and adeno-associated virus. Adenoviral transgene expression was transient in the thymus of immunocompetent mice but persistent in CD8+ T-cell-deficient and severe combined immunodeficiency (SCID) mice, implicating the role of cytotoxic T lymphocytes in viral clearance. Intrathymic transplantation of syngeneic pancreatic islet cells infected with adenovirus impaired the normal antiviral cytotoxic T-lymphocyte response and prolonged hepatic transgene expression after an intravenous challenge with adenovirus. CONCLUSIONS: Recombinant adenovirus accomplishes highly efficient gene transfer to the thymus in vivo. Intrathymic inoculation of adenovirus-infected islets can be used to induce immunologic unresponsiveness to the adenoviral vector and, potentially, to other proteins that it might be engineered to encode.

    Title An Improved Technique of Thymectomy in the Adult Mouse.
    Date April 1995
    Journal Transplantation
    Title Survival of Mhc Deficient Mouse Heterotopic Cardiac Allografts and Xenografts.
    Date April 1995
    Journal Transplantation Proceedings
    Title Survival of Mhc-deficient Mouse Heterotopic Cardiac Allografts.
    Date March 1995
    Journal Transplantation
    Excerpt

    The immunologic mechanisms involved in the destruction of murine cardiac allografts were evaluated using MHC-deficient mice. Specifically, we examined the survival of immediately vascularized heterotopic adult cardiac grafts deficient in MHC class I, MHC class II, or both MHC class I and II antigens following transplantation to allogeneic hosts. We observed indefinite cardiac graft survival when donors lacked MHC class II or both MHC I and II antigens. In parallel experiments, we studied the survival of cardiac grafts harvested from normal donors in recipients severely depleted of either CD4 (class II-deficient mice) or CD8 (class I-deficient mice) T cells. Graft survival was dramatically prolonged in the absence of CD4 but not CD8 T cells. Collectively, our results demonstrate that the interaction of host CD4 T cells with donor class II antigens is critical to the rejection of murine cardiac grafts.

    Title Genetically Engineered Grafts to Study Xenoimmunity: a Role for Indirect Antigen Presentation in the Destruction of Major Histocompatibility Complex Antigen Deficient Xenografts.
    Date August 1994
    Journal Surgery
    Excerpt

    BACKGROUND. The genetic engineering of xenogeneic donor species for transplantation may provide a means of attenuating the potent immune response elicited by tissues from foreign species. Because of their well-established role in allograft rejection, a logical target for genetic manipulation is the genes encoded by the major histocompatibility complex (MHC). In the current study we examined whether skin, heart, or pancreatic islet xenografts harvested from lines of transgenic mice rendered deficient in MHC antigen expression by gene disruption would exhibit a survival benefit when transplanted to xenogeneic rat recipients. In addition, we characterized the in vitro response of rat T cells to normal and MHC-deficient mouse cells. METHODS. Skin, heart, and pancreatic islet grafts were harvested from control C57Bl/6 and each of three lines of mice deficient in MHC antigen expression. MHC-deficient lines included (1) mice selectively lacking MHC class I antigens (CID), produced by disruption of the beta-2 microglobulin gene; (2) mice lacking MHC class II expression (CIID), produced by targeting the I-A beta-chain gene; and (3) mice devoid of both class I and class II molecules (CI,IID). RESULTS. In contrast to the prolonged survival that has been observed for certain allografts deficient in MHC antigen expression, we did not detect significant extension of survival in the case of xenografts. Using in vitro assays of T-cell function, we demonstrated that rats that rejected grafts lacking MHC expression evidenced sensitization of T cells specific for graft antigens presented by rat antigen-presenting cells. CONCLUSIONS. The strategies of gene targeting of donor species to produce less immunogenic xenografts may be hampered by the presence of a strong response through the indirect pathway of immunity. Immune intervention directed at the indirect antigen presentation pathway may be of benefit in xenotransplantation.

    Title Delayed Allograft Rejection by T Cell Receptor V Beta 8.1 Transgenic Mice Peripherally Tolerized to Mls-1.
    Date August 1994
    Journal European Journal of Immunology
    Excerpt

    One commonly studied model system for peripheral tolerance is the antigen-specific unresponsiveness of T cells from mice previously inoculated with superantigens such as Mls-1a. In this study, we used a TcR V beta 8.1 transgenic mouse model to investigate whether mice peripherally tolerized to Mls-1a exhibit delayed skin allograft rejection. We report dramatic prolongation of skin allograft survival in V beta 8.1 transgenic but not in non-transgenic mice tolerized to Mls-1a. Peripherally induced unresponsiveness to Mls-1a can, therefore, be considered true tolerance.

    Title Prolonged Survival of Class I Deficient Mouse Islet Allografts but Not Xenografts.
    Date June 1994
    Journal Transplantation Proceedings
    Title Basic and Clinical Considerations in the Use of Xenografts.
    Date May 1994
    Journal Current Problems in Surgery
    Title Allograft Rejection by T Cell Receptor Transgenic Mice.
    Date September 1993
    Journal The Journal of Surgical Research
    Excerpt

    We have used a line of T cell receptor (TcR) transgenic mice, in which a significant portion of CD8+ T cells expresses a TcR that is specific for the minor histocompatibility antigen H-Y presented by the H-2Db Class I molecule, to examine the immune response to H-Y-incompatible skin or pancreatic islet allografts. Our results indicate that, in contrast to the conclusions of previous reports, pancreatic islet endocrine cells are invulnerable or only weakly vulnerable to an H-Y-directed immune response. An even more unexpected finding was that unlike normal female mice of the C57BL/6 background which consistently reject male skin within a few weeks, TcR transgene+ littermates reject male skin only infrequently. Our results are consistent with the conclusion that the inability of H-Y TcR females to reject male skin is due to a deficiency of cells with male-specific helper activity. Long-term acceptance of male grafts by H-Y TcR females leads to a state of T cell hyporesponsiveness to male skin grafts. In addition, T cells harvested from long-term skin acceptors were hyporesponsive to in vitro stimulation by a clonotype-specific monoclonal antibody. Transgenic mice with TcRs having antigenic specificity for defined transplantation antigens provide a unique model for study of the allograft response.

    Title Promotion of Rat Cardiac Allograft Survival by Intrathymic Inoculation of Donor Splenocytes.
    Date June 1993
    Journal Transplantation
    Excerpt

    Donor-specific unresponsiveness to LEW heterotopic cardiac allografts was induced in WF rats following intrathymic inoculation of LEW splenocytes in conjunction with a single intraperitoneal dose of antilymphocyte serum. In contrast, LEW cardiac allografts were promptly rejected in WF recipients pretreated with an intravenous inoculation of donor splenocytes. Without transient immunosuppression with antilymphocyte serum neither intrathymic nor intravenous inoculation of splenocytes led to allograft survival. Substitution of antilymphocyte serum by a short course of cyclosporine did not permit allograft survival, suggesting that a T-cell-depleting regimen is crucial to tolerance induction by this protocol. The unresponsive state could be transferred to secondary syngeneic hosts by spleen cells from long-term recipients of intrathymic splenocytes and cardiac allografts but not by spleen cells from recipients of intrathymic splenocytes alone. This suggests that persistence of donor alloantigen from the graft is necessary for maintenance of the tolerant state. The unresponsive state after intrathymic inoculation of allogeneic splenocytes may be mediated through interaction of maturing host thymocytes with donor alloantigen.

    Title Deletion of Donor-reactive T Lymphocytes in Adult Mice After Intrathymic Inoculation with Lymphoid Cells.
    Date May 1993
    Journal Transplantation
    Excerpt

    Clonal deletion of self antigen-reactive T lymphocytes is known to be a dominant mechanism of tolerance induction in the normal immune system. This report considers whether deletion of antigen-reactive T cells is also the immunologic basis for the recently described model of transplantation tolerance that follows intrathymic inoculation with allogeneic lymphoid cells. We found that the outcome of injecting Mlsa- hosts with lymphocytes from Mlsa+ donors was depletion of V beta 6+ T cells (which are known to be reactive with the Mlsa superantigen). The process was found to be specific in that a similar reduction was not seen in an irrelevant T cell population (V beta 8+) in IT injected hosts. Deletion was observed in this model only if immunosuppression with ALS or anti-CD4 accompanied intrathymic injection. When the inoculum of allogeneic lymphocytes was administered intravenously instead of intrathymically only minimal deletion was observed. The induction of transplantation tolerance by intrathymic injection of donor lymphoid cells may prove especially efficacious since it relies on deletion of only those T cells specifically reactive to donor antigens, a process analogous to tolerance induction to self antigens.

    Title Islet Allograft, Islet Xenograft, and Skin Allograft Survival in Cd8+ T Lymphocyte-deficient Mice.
    Date May 1993
    Journal Transplantation
    Excerpt

    Despite extensive study, the immunologic mechanisms mediating allograft rejection have not been completely defined. In the current study, we evaluated the T cell subsets important in islet allograft, skin allograft, and islet xenograft rejection using a genetically engineered line of mice deficient in beta 2-microglobulin expression. Because these mice lack cell surface MHC class I expression, they are deficient in T cells of the CD8 subset (class I-restricted cytotoxic T cells). Pancreatic islet allografts transplanted to CD8+ T cell-deficient recipients showed prolonged survival compared with controls. No prolongation was observed in the survival of pancreatic islet xenografts or in the survival of skin allografts transplanted to the CD8+ T cell--deficient hosts. We conclude that CD8+ T cells play a prominent role in islet allograft, but not islet xenograft or skin allograft, rejection in mice.

    Title Pancreatic Islet Allograft and Xenograft Survival in Cd8+ T-lymphocyte-deficient Recipients.
    Date March 1993
    Journal Transplantation Proceedings
    Title Prolonged Survival of Rat Cardiac Allografts After Intrathymic Inoculation of Donor Thymocytes.
    Date March 1993
    Journal Transplantation Proceedings
    Title Donor Antigen-specific T-lymphocyte Deletion After Intrathymic Inoculation.
    Date March 1993
    Journal Transplantation Proceedings
    Title Intrathymic Transplantation As a Model for Tolerance.
    Date March 1993
    Journal Advances in Nephrology from the Necker Hospital
    Title Indefinite Survival of Mhc Class I-deficient Murine Pancreatic Islet Allografts.
    Date January 1993
    Journal Transplantation
    Excerpt

    To examine the immune response to class I-deficient allogeneic tissue, we used beta 2-microglobulin-deficient mice as graft donors. These mice lack cell surface class I major histocompatibility complex antigen expression. Pancreatic islet allografts from class I-deficient donors survived indefinitely in a majority of fully allogeneic BALB/c recipients. In contrast, host recognition of graft class I antigen was unnecessary for prompt destruction of skin allografts of for autoimmune damage of transplanted pancreatic islet grafts in nonobese diabetic mice. These studies provide evidence that intentional genetic elimination of immunologically relevant donor antigens may prove an effective strategy for preventing allograft rejection.

    Title Direct Assessment of the Role of Nk Cells in Autoimmune Diabetes.
    Date October 1992
    Journal The Journal of Surgical Research
    Excerpt

    Considerable indirect evidence implicates participation of natural killer cells (NK) in the pathogenesis of diabetes in BB rats. The most convincing evidence derives from studies showing that anti-CD8 antibody effectively prevents both primary disease onset and autoimmune damage to transplanted islets. However, anti-CD8 treatment depletes both NK and cytotoxic T cells (CTL) since both cell types express the CD8 marker. To study directly the role of NK in diabetic BB rats we used MCA 3.2.3, a monoclonal antibody which selectively depletes normal Lewis rats of NK cells but not CTL. A regimen of ip injected antibody achieved rapid reduction of NK cells in diabetic and nondiabetic BB rats by FACS analysis. NK cell activity remained low in rats treated weekly as evidenced by YAC tumor cell killing. We next studied the effect of NK depletion on disease incidence in diabetes-prone BB rats of which about one half are expected to develop diabetes. Onset and incidence of diabetes in 3.2.3-treated and control antibody-treated aged matched litter mates were equal. These studies suggest that NK cells are not necessary for autoimmune islet destruction in spontaneously diabetic BB rats and support a role for CTL in pathogenesis of the disease.

    Title Xenografts: is There a Future?
    Date August 1992
    Journal Surgery
    Title Successful Islet Transplantation in the Thymus of Spontaneously Diabetic Bb Rats.
    Date July 1992
    Journal Transplantation Proceedings
    Title Intrathymic Islet Transplantation in the Spontaneously Diabetic Bb Rat.
    Date December 1991
    Journal Annals of Surgery
    Excerpt

    Recently it was demonstrated that pancreatic islet allografts transplanted to the thymus of rats made diabetic chemically are not rejected and induce specific unresponsiveness to subsequent extrathymic transplants. The authors report that the thymus can also serve as an effective islet transplantation site in spontaneously diabetic BB rats, in which autoimmunity and rejection can destroy islets. Intrathymic Lewis islet grafts consistently reversed hyperglycemia for more than 120 days in these rats, and in three of four recipients the grafts promoted subsequent survival of intraportal islets. In contrast intraportal islet allografts in naive BB hosts all failed rapidly. The authors also show that the immunologically privileged status of the thymus cannot prevent rejection of islet allografts in Wistar Furth (WF) rats sensitized with donor strain skin and that suppressor cells are not likely to contribute to the unresponsive state because adoptive transfer of spleen cells from WF rats bearing established intrathymic Lewis islets fails to prolong islet allograft survival in secondary hosts.

    Title Major-histocompatibility-complex Restricted and Nonrestricted Autoimmune Effector Mechanisms in Bb Rats.
    Date November 1991
    Journal Transplantation
    Excerpt

    To investigate whether the immunologic mechanisms of autoimmune pancreatic beta-cell destruction are MHC restricted, we examined the relative vulnerability of islet allografts from a panel of MHC-compatible and -incompatible donors to autoimmune damage after transplantation to spontaneously diabetic BB recipients. To circumvent a potentially confounding allograft response to the foreign islet graft, we utilized two strategies: (1) pretransplant in vitro culture of islets to delete intraislet APCs; and (2) induction of islet donor-specific immunologic tolerance in diabetes-prone BB rats. Experiments employing organ culture to prevent rejection demonstrated that MHC-incompatible grafts were significantly less vulnerable to autoimmunity than MHC-compatible grafts. In contrast, when we used the model of immunologic tolerance to exclude rejection, both MHC-compatible and -incompatible islet grafts were equally susceptible to autoimmune damage. The reason for this discrepancy has not been defined fully but may be related to our observation that tolerant BB animals exhibit increased peripheral blood NK-cell activity. NK cells are known to be cytotoxic to islets in vitro and could play a role in a non-MHC-restricted diabetogenic response in vivo. We conclude that both MHC-restricted and nonrestricted mechanisms are capable of contributing to anti-beta-cell autoimmunity in BB rats.

    Title Studies of Privileged Sites and Islet Transplantation.
    Date September 1991
    Journal Transplantation Proceedings
    Title The Contribution of Mhc Antigen Modulation to Islet Allograft Rejection.
    Date May 1991
    Journal Hormone and Metabolic Research. Supplement Series
    Title Islet Transplantation to Study Autoimmune Pathogenesis of Diabetes in Bb Rat.
    Date May 1991
    Journal Hormone and Metabolic Research. Supplement Series
    Title The in Vitro Immunogenicity of Antigen-presenting Cell-free Endocrine Cells: the Role of Antigen Presenting Cells.
    Date March 1991
    Journal Transplantation Proceedings
    Title Induction of Donor-specific Unresponsiveness by Intrathymic Islet Transplantation.
    Date October 1990
    Journal Science (new York, N.y.)
    Excerpt

    The application of isolated pancreatic islet transplantation for treatment of diabetes mellitus has been hampered by the vulnerability of islet allografts to immunologic rejection. Rat islet allografts that were transplanted into the thymus of recipients treated with a single injection of anti-lymphocyte serum survived indefinitely. A state of donor-specific unresponsiveness was achieved that permitted survival of a second donor strain islet allograft transplanted to an extrathymic site. Maturation of T cell precursors in a thymic microenvironment that is harboring foreign alloantigen may induce the selective unresponsiveness. This model provides an approach for pancreatic islet transplantation and a potential strategy for specific modification of the peripheral immune repertoire.

    Title Immunologic Consequence of Class Ii+ Pancreatic Islet Allografts on Recipient Responsiveness.
    Date September 1990
    Journal Transplantation Proceedings
    Title Effect of Transplant Site on Islet Allograft Survival in Bb Rats.
    Date July 1990
    Journal Transplantation Proceedings
    Title Retransplantation of Rat Islet Allografts Following Residence in an Interim Host.
    Date July 1990
    Journal Transplantation Proceedings
    Title Islet Endocrine Cell Mhc Antigen Expression in Allograft Rejection.
    Date May 1990
    Journal Transplantation Proceedings
    Title Immunologic Consequences of Islet Mhc Antigen Modulation in Autoimmune Diabetes.
    Date May 1990
    Journal Transplantation Proceedings
    Title The Effect of Islet Cell Culture in Vitro at 24 Degrees C on Graft Survival and Mhc Antigen Expression.
    Date March 1990
    Journal Transplantation
    Excerpt

    A period of in vitro culture prior to transplantation has been shown to prolong the survival of many types of MHC-incompatible endocrine grafts. The effectiveness of this strategy has been attributed to a selective depletion of intragraft antigen-presenting cells. We report that in vitro culture at 24 degrees C results in a significantly better survival of rat isolated islet allografts than does culture at 37 degrees C. Using in vitro assays of APC activity, we were unable to detect differences in the quantity of residual intraislet APCs between 24 degrees C and 37 degrees C culture preparations. In contrast, islet endocrine cells cultured at 24 degrees C evidenced a reduced level of cell surface class I MHC antigen expression and were significantly less vulnerable to lysis in vitro by CTL. These findings suggest that culture at 24 degrees C produces islet alterations other than APC depletion, and that its beneficial effect on graft survival correlates with a reduction in endocrine cell class I MHC antigen expression.

    Title Modulation of the Major Histocompatibility Complex Antigen and the Immunogenicity of Islet Allografts.
    Date October 1989
    Journal Transplantation
    Excerpt

    Modulation of major histocompatibility complex (MHC) antigen by parenchymal cells and "passenger leukocytes" is a common feature of allograft rejection. To assess its significance we have examined the fate of antigen-presenting cell (APC)-depleted pancreatic islet allografts subsequent to increasing their expression of MHC antigens by in vitro exposure to the lymphokine interferon-gamma (gIFN). While most untreated grafts survived indefinitely, gIFN-exposed grafts were acutely rejected. Using in vitro islet cell-lymphocyte coculture assays, we attempted to dissect the underlying mechanism of enhanced islet cell immunogenicity resulting from gIFN treatment. We determined that gIFN exposure did not affect the capacity of islet cells to serve as APC for T lymphocytes, however islet cell exposure to gIFN was associated with enhanced vulnerability to allogeneic cytotoxic T lymphocyte (CTL) lysis in vitro by an CD5+ (OX-19+), CD8+ (OX-8+), CD4- (W3/25-), class I-restricted CTL. On the basis of these findings, we conclude that antigenic modulation can be a decisive factor in the survival of engrafted tissues by augmenting the interaction of the graft antigens with cytolytic effector T lymphocytes.

    Title Immunomodulation of Pre-diabetes in Bb Rats for Prevention of the Disease.
    Date July 1989
    Journal Advances in Experimental Medicine and Biology
    Title Studies of Prediabetes in the Spontaneously Diabetic Bb Rat.
    Date July 1989
    Journal Advances in Experimental Medicine and Biology
    Title Prevention of Autoimmune Damage to Islet Grafts in Bb Rats by Antibody Therapy.
    Date May 1989
    Journal Transplantation Proceedings
    Title Effect of Lymphokine-induced Mhc Antigen Expression on Islet Allograft Survival.
    Date May 1989
    Journal Transplantation Proceedings
    Title Prolongation of Cardiac Allograft Survival by Suppressor T Cells (ts) Generated in Vitro Using Cyclosporine.
    Date May 1989
    Journal Transplantation Proceedings
    Title Effect of Elimination of Ox-19+ and Ox-8+ T-cell Subsets Upon Pancreatic Allograft Survival.
    Date May 1989
    Journal The Journal of Surgical Research
    Excerpt

    Depletion of T cell subsets with monoclonal antibody (mAb) permits analysis of cellular events mediating allograft destruction. Mab OX-19 and mAb OX-8 were used singly and in combination together with a short pretransplant course of cyclosporine A (CsA) to deplete OX-19+ cells (all T cells) and OX-8+ cells (cytotoxic/suppressor and NK cells), respectively, in diabetic Lewis (Lew) recipients of a Wistar Furth (WF) pancreatic allograft. Depletion of lymph node T cell subsets was assessed at rejection (blood sugar greater than 250 mg/dl) by flow cytometry. Untreated Lew recipients (Group 1) rapidly rejected their allograft (11.5 +/- 2.5 days). MAb OX-19 administration on the day prior to surgery (Day -1), on the day of surgery (Day 0), and alternate days thereafter until rejection (Group 2) prolonged graft survival (15.0 +/- 1.6 days, P less than 0.05). MAb OX-19 administration on alternate days beginning 14 days prior to transplantation (Day -14) until rejection (Group 3) further prolonged graft survival (22.6 +/- 3.4 days, P less than 0.01). At rejection large numbers of OX-19+ cells were present in both groups. Administration of mAb OX-8 alone (Group 4) failed to prolong graft survival despite marked depletion of OX-8+ cells at rejection. Administration of mAb OX-19 from Day -14 together with CsA (15 mg/kg) from Days -14 to -8 inclusive (Group 5) resulted in a marked and sustained depletion of OX-19+ cells at rejection but only a modest prolongation of graft survival (27.6 +/- 6.0 days, P = 0.11). CsA alone from Days -14 to -8 failed to prolong graft survival.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Prevention of Recurrent Diabetes in Bb Rats After Islet Transplantation by Monoclonal Antibody Therapy.
    Date February 1989
    Journal Diabetes
    Excerpt

    Two immune responses imperil pancreatic islet allografts transplanted into subjects afflicted with autoimmune diabetes: 1) the well-described allograft response that is mounted against tissues bearing foreign transplantation antigens and 2) a recurrence of the beta-cell-specific autoimmune process responsible for the primary disease. To define the role of autoimmune response to transplanted islets, the possibility of a rejection response must be prevented. To accomplish this in spontaneously diabetic BB rats, we induced neonatal tolerance. We found that recurrent autoimmunity in tolerant BB rats can be prevented by treatment of recipients with the monoclonal antibody OX8 (specific for cytotoxic T-lymphocytes) but not W3/25 (specific for helper T-lymphocytes). These findings provide direct evidence for the role of OX8-bearing lymphocytes in autoimmune diabetogenesis.

    Title Regulation of Lymphocyte Growth by Antagonists of Interleukin-2 or Its Cellular Receptor.
    Date August 1988
    Journal Immunologic Research
    Excerpt

    The dependence of T cell proliferation on the production, binding and utilization of the lymphokine growth factor IL-2 has fostered the development and testing of new classes of drugs which act to either inhibit IL-2 production or the interaction of IL-2 with its cellular receptor. We have reviewed evidence which documents the potent immunosuppressive effects of inhibitors of IL-2 synthesis and secretion, such as Ciclosporin A, and of anti-IL-2 receptor MAb. The similarities of the potency and specificity of these agents and their effectiveness in a wide range of clinical settings encourage further studies on their mechanism of action. Perhaps the most dramatic similarity is the induction of long-term nonresponsiveness after drug removal to antigens present at the time of drug therapy. This observation has profound importance both on clinical manipulation with these agents and n the origins and maintenance of self-tolerance.

    Title Prevention of Recurrent Autoimmune Diabetes in Bb Rats by Anti-asialo-gm1 Antibody.
    Date August 1988
    Journal Diabetes
    Excerpt

    BB rats exhibit a syndrome of spontaneous diabetes that has clinical and pathological characteristics analogous to those found in human insulin-dependent diabetes mellitus (IDDM). Islet tissue transplanted into spontaneously diabetic BB rats is uniformly destroyed by a recurrence of the autoimmune response that destroyed the diabetic subject's native islets. To examine recurrent autoimmune destruction of transplanted islets, it is necessary to exclude islet damage that might result from allograft rejection. We utilized neonatal tolerance induction to prevent rejection of Wistar-Furth (WF) (RT1u) islet allografts by spontaneously diabetic BB recipients. We determined that islet-recipient treatment with anti-asialo-GM1 (anti-AGM1) antibody prevents recurrent autoimmune diabetes that would otherwise destroy transplanted WF islet grafts. Anti-AGM1 therapy significantly decreased peripheral blood natural killer (NK) cell activity. These data suggest a role for NK cells in the pathogenesis of recurrent diabetes in neonatally tolerant BB rats.

    Title Immunobiology of the Allograft Response.
    Date January 1988
    Journal Diabetes/metabolism Reviews
    Title Gamma Interferon Induces Novel Expression of Ia Antigens by Rat Pancreatic Islet Endocrine Cells.
    Date October 1987
    Journal Pancreas
    Excerpt

    Pancreatic endocrine cells normally express only Class I gene products of the major histocompatibility complex (MHC). Recently it has been shown that in both patients with recent onset type I diabetes and acutely diabetic BB rats, residual islet beta cells express Class II MHC antigens. In an attempt to define a potential inducer of this aberrant Class II antigen expression, we have investigated the effect of in vitro incubation of rat isolated pancreatic islets with the lymphokine gamma interferon (IFN-gamma) on MHC antigen expression. Our results demonstrate that in vitro exposure to IFN-gamma induces novel expression of Class II antigens on the surface of rat islet endocrine cells and increases the level of pre-existing Class I antigen expression.

    Title Transplantation of Cultured Pancreatic Islets to Bb Rats.
    Date September 1986
    Journal Surgery
    Excerpt

    Pancreatic islets held in tissue culture before transplantation into artificially induced diabetics are not rejected. In animals and human identical twin transplants, the autoimmunity of naturally occurring diabetes may destroy islets, even if rejection is avoided. Therefore we studied whether autoimmune damage of islets can be avoided by pretransplant culture. Recipients were BB rats, which spontaneously developed diabetes. Donors were either Wistar Furth (WF) (major histocompatibility [MHC] identical to BB rats) or Lewis (MHC nonidentical to BB rats). Islets were inoculated into the portal vein either immediately after isolation or after 14 days in tissue culture (95% air, 5% CO2, 24 degrees C). Recipients of cultured islets received a single injection of 1 ml of antilymphocyte serum at the time of transplant. Recurrence of diabetes after transplantation of freshly isolated MHC incompatible Lewis islets occurred rapidly on the basis of rejection or autoimmune damage (or both). Precultured Lewis islets had prolonged or permanent survival. Freshly isolated MHC compatible WF islets were destroyed, and no improvement was seen with culture. We conclude that autoimmune destruction of transplanted islets can be avoided by tissue culture, as can rejection. This is important because this strategy is effective only if recipient and donor differ at the MHC locus. Islet donors may need to be selected on the basis of disparity of histocompatibility factors.

    Title Analytical and Functional Studies on the T Cells of Untreated and Immunologically Tolerant Diabetes-prone Bb Rats.
    Date May 1983
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Lymphocyte profiles of untreated diabetes-prone BB rats (BBDP) and their normal marrow-inoculated tolerant littermates were determined with the aid of a fluorescence-activated cell sorter by using monoclonal antibodies specific for rat T cell (W3/13) and T cell subsets (W3/25, T helper; OX8, T cytotoxic/suppressor). In contrast to non-diabetes-prone rats and to their marrow-inoculated littermates, untreated BBDP rats were found to be T lymphocytopenic with reduced W3/25+ cells and with a major loss of OX8+ cells. Moreover, their lymphocytes displayed depressed alloreactivity that was not restored by addition of exogenous IL 2.

    Title Spontaneous Diabetes in Bb Rats: Evidence for a T Cell Dependent Immune Response Defect.
    Date January 1983
    Journal Diabetologia
    Excerpt

    Approximately 50% of BB rats develop insulinopenic hyperglycaemia and ketosis spontaneously in association with insulitis. Amelioration of the syndrome by immunosuppression suggests a cell mediated immune pathogenesis. Analysis of the cell-mediated immune profile of overtly diabetic and normoglycaemic diabetes prone BB rats indicates that they are lymphocytopenic relative to non-diabetes prone BB rats and that the T cell pool is particularly affected. Furthermore, lymphocytes from diabetic and diabetes prone BB rats, while producing normal responses to the T cell mitogen concanavalin A, do not respond when mixed in vitro with major histocompatibility complex incompatible lymphocytes. This anergy is not restored either by enriching the responding cell population for T cells or by adding exogenous T cell growth promoting factor. Thus BB rats have a numerical and regulatory deficit of their T cells which could be related to their propensity for diabetes.

    Title Financial Issues Constraining the Use of Pancreata Recovered for Islet Transplantation: a White Paper.
    Date
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    Islet transplantation is a very promising therapy for select patients with type 1 diabetes. Continued clinical investigation is required to define the long-term safety and efficacy outcomes before the procedure will be accepted as a standard of care even for those with the most severe manifestations of diabetes. Threatening successful accomplishment of these and other innovative studies designed to advance the field are the complex financial cost accounting issues that pose undue burden on organ procurement organizations and transplant centers trying to manage the costs of the pancreata from deceased donors needed to isolate islets. Compounding the problem is the recent ruling by CMS regarding 'intent to transplant' (CMS-1543-R Dec. 21, 2006: Allocation of Donor Acquisition Costs Incurred by Organ Procurement Organizations) that does not account for the clinical need to complete the manufacturing process for islets before suitability and transplant intent of the pancreata involved can be determined. We provide a consensus document supported by a diverse group of stakeholders in islet transplantation to suggest actions to address this problem.

    Title Effect of Glucagon-like Peptide-1 on {beta}- and {alpha}-cell Function in Isolated Islet and Whole Pancreas Transplant Recipients.
    Date
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    Context: Glucose-dependent insulin secretion is often impaired after islet transplantation where reduced beta-cell secretory capacity indicates a low functional beta-cell mass. Objective: We sought to determine whether glucagon-like peptide-1 (GLP-1) enhanced glucose-dependent insulin secretion and glucagon suppression in islet recipients, and whether GLP-1 effects were dependent on functional beta-cell mass by simultaneously studying recipients of whole pancreas transplants. Setting: The study was performed in a clinical and translational research center. Participants: Five intraportal islet and six portally drained pancreas transplant recipients participated in the study. Intervention: Subjects underwent glucose-potentiated arginine testing with GLP-1 (1.5 pmol . kg(-1) . min(-1)) or placebo infused on alternate randomized occasions, with 5 g arginine injected under basal and hyperglycemic clamp conditions. Results: Basal glucose was lower with increases in insulin and decreases in glucagon during GLP-1 vs. placebo in both groups. During the hyperglycemic clamp, a significantly greater glucose infusion rate was required with GLP-1 vs. placebo in both groups (P < 0.05), an effect more pronounced in the pancreas vs. islet group (P < 0.01). The increased glucose infusion rate was associated with significant increases in second-phase insulin secretion in both groups (P < 0.05) that also tended to be greater in the pancreas vs. islet group (P = 0.08), whereas glucagon was equivalently suppressed by the hyperglycemic clamp during GLP-1 and placebo infusions in both groups. The GLP-1-induced increase in second-phase insulin correlated with the beta-cell secretory capacity (P < 0.001). The proinsulin secretory ratio (PISR) during glucose-potentiated arginine was significantly greater with GLP-1 vs. placebo infusion in both groups (P < 0.05). Conclusions: GLP-1 induced enhancement of glucose-dependent insulin secretion, but not glucagon suppression, in islet and pancreas transplant recipients, an effect dependent on the functional beta-cell mass that may be associated with depletion of mature beta-cell secretory granules.

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