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Objectives The use of deceased after circulatory death liver allografts in patients with primary sclerosing cholangitis is controversial, given the increased risk of graft complications in patients with primary sclerosing cholangitis. We hypothesized that transplant of deceased after circulatory death livers into recipients with primary sclerosing cholangitis when appropriately selected using the UK deceased after circulatory death scoring system is not associated with increased graft failure and mortality. Materials and methods We analyzed 99 229 transplants (between January 2001 and December 2018) from the Organ Procurement and Transplantation Network database. Deceased after circulatory death transplants were stratified by the UK scoring system as low risk or high risk. We identified 3958 patients with primary sclerosing cholangitis who received deceased after brain death transplant and 95 patients with primary sclerosing cholangitis who received deceased after circulatory death transplant. Results As expected, 5-year graft survival was lower in the circulatory death recipient group (69.0% vs 78.4%; P = .02). However, 5-year graft survival was significantly lower in the high-risk versus low-risk UK scoring system group (60.0% vs 75.4%; P = .02), with rate in the low-risk group similar to the brain death recipient group (78.4% vs 75.4%; P = .52). On multivariate analysis, the high-risk group had significantly increased risk of graft loss (hazard ratio of 1.92; P = .01). However, the low-risk group had equivalent graft survival to the brain death recipient group (hazard ratio of 1.23; P = .31). Conclusions Graft failure was higher in patients with primary sclerosing cholangitis who received livers from deceased after circulatory death donors; however, the risk of graft loss was abrogated using appropriately matched donor and recipient combinations.

We studied the effects of indirect allorecognition on the induction and maintenance phases of tolerance in miniature swine cotransplanted with heart and kidney allografts. MHC class I-mismatched heart and kidney grafts were cotransplanted in recipients receiving CyA for 12 days. Recipients were unimmunized or immunized with a set of donor-derived or control third-party MHC class I peptides either 21 days prior to transplantation or over 100 days after transplantation. T-cell proliferation, delayed type hypersensitivity reaction (DTH) and antibody production were assessed. All animals injected with donor MHC class I peptides developed potent indirect alloresponses specific to the immunizing peptides. While untreated recipients developed stable tolerance, all animals preimmunized with donor allopeptides rejected kidney-heart transplants acutely. In contrast, when peptide immunization was delayed until over 100 days after kidney-heart transplantation, no effects were observed on graft function or in vitro measures of alloimmunity. Donor peptide immunization prevented tolerance when administered to recipients pre transplantation but did not abrogate tolerance when administered to long-term survivors post transplantation. This suggests that the presence of T cells activated via indirect allorecognition represent a barrier to the induction but not the maintenance of tolerance.

Over a 23-year period, our center performed 82 renal retransplants in prior simultaneous pancreas–kidney recipients with functioning pancreatic allografts. All patients were insulin-independent at retransplantation. We aimed to quantify the risk of returning to insulin therapy and to identify factors that predispose patients to pancreatic allograft failure after renal retransplantation. Among these 82 patients, pancreatic allograft survival after renal retransplantation was 78%, 49% and 40% at 1, 5 and 10 years. When analyzing risk factors, we unexpectedly found no clear relationship between the cause of primary renal allograft failure, hemoglobin A1c (HbA1c) or fasting C-peptide level at retransplant and subsequent pancreatic allograft failure. An elevated HbA1c in the month after renal retransplant correlated with subsequent pancreatic graft loss and patients experiencing pancreatic graft loss were more likely to subsequently lose their renal retransplant. Although it is difficult to prospectively identify those patients who will return to insulin therapy after repeat renal transplantation, the relatively high frequency of this event mandates that this risk be conveyed to patients. Nonetheless, the survival benefit associated with renal retransplantation justifies pursuing retransplantation in this population.

The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.

Background. The authors have examined the mechanism whereby co-transplantation of a kidney and heart from the same donor induces and maintains tolerance to both organs in miniature swine. Methods. Transplants were performed across a major histocompatibility complex class I mismatch, and recipients received cyclosporine for 12 days. Group 1 animals received heart transplants alone (n=5), and all other groups received both heart and kidney allografts. Group 2 animals received no further intervention (n=2). Group 3 animals underwent transplant nephrectomy 8 days after heart and kidney co-transplantation (n=2). Group 4 animals underwent transplant nephrectomy 100 days after co-transplantation (n=2). Skin grafts were placed on group 4 animals, on one group 3 animal, and on two animals from group 2. Group 5 animals underwent thymectomy 100 days after co-transplantation (n=4). Results. Group 1 animals developed cardiac allograft vasculopathy (CAV) and rejection. Group 2 animals never developed CAV and demonstrated in vitro donor-specific unresponsiveness. Group 3 animals suffered CAV and rejection. Group 4 animals developed CAV without concomitant donor-specific cell-mediated lympholysis reactivity, interstitial rejection, or cessation of graft function. Skin grafts on group 3 and group 4 animals led to fulminant rejection of heart and skin grafts, in contrast to grafts on group 2 animals that had no in vivo effect. Group 5 animals developed CAV but no significant increase in interstitial infiltrates. Conclusions. Both the kidney and thymus were necessary for maintenance of tolerance to heart allografts.

Background To determine the mechanism by which cotransplantation of a donor kidney and heart allograft induces tolerance to both organs in miniature swine, we examined the renal elements responsible for tolerance induction. Methods Recipients received 12 days of cyclosporine, and transplants were performed across a major histocompatibility complex (MHC) class I mismatch. Group 1 animals received heart transplants (n=5); group 2 animals received heart and kidney allografts with no other manipulation (n=4); group 3 animals received heart transplants and donor-specific renal parenchymal cells (n=4); group 4 animals received heart and kidney allografts from lethally irradiated donors (n=7); group 5 animals received irradiated hearts and nonirradiated kidneys (n=2); group 6 animals received nonirradiated hearts and peripheral blood leukocytes from swine MHC matched to recipients and becoming tolerant to donor antigen (n=2); group 7 animals received nonirradiated hearts and donor-specific peripheral blood monocyte cells (PBMC) (n=2). Results Animals in group 1 developed vasculopathy and fulminant rejection by day 55. Animals in group 2 never developed vascular lesions. Parenchymal kidney cell infusion (group 3) did not prolong cardiac survival. Animals in group 4 developed arteriopathy by postoperative day (POD) 28. Group 5 recipients accepted allografts without vascular lesions. Adoptive transfer of leukocytes from tolerant swine (group 6) prolonged cardiac graft survival as much as 123 days, whereas donor PBMC infusion (group 7) did not affect cardiac survival or development of arteriopathy. Conclusions Radiosensitive elements in kidney allograft may be responsible for tolerance induction and prevention of chronic vascular lesions in recipients of simultaneous heart and kidney allografts.

To determine the mechanism by which cotransplantation of a kidney allograft induces tolerance to a donor heart in miniature swine, we examined the role of CD25+ cells in heart/kidney recipients. Tolerance was induced to class-I MHC mismatched hearts by cotransplanting a donor-specific kidney with a 12-day course of cyclosporine. Peripheral blood leukocytes (PBL) were isolated from tolerant heart/kidney recipients and used in cell-mediated lympholysis (CML) coculture assays as either unmodified PBL, PBL enriched for CD25+ cells or PBL depleted of CD25+ cells to assess their ability to suppress CML responses of naive recipient-matched leukocytes against mismatched target cells. Primed PBL from tolerant heart/kidney recipients completely suppressed lysis by naive cells. Complete suppression of the response of naive recipient-matched leukocytes against donor-matched target cells was lost following the depletion of CD25+ cells from tolerant heart/kidney animal PBL, but it was reestablished by incubation of naive cells with small populations of CD25+ cells from tolerant heart/kidney animals. These data suggest that peripheral blood from tolerant heart/kidney recipients contains regulatory cells that, upon priming, can suppress the response of naive-matched PBL in coculture CML assays, and that suppression appears to be dependent on cells expressing CD25.

Background. Chronic rejection, as manifested by cardiac allograft vasculopathy, remains the leading cause of late graft failure in heart transplant recipients. Despite recent clinical trials, the efficacy of mycophenolate mofetil in preventing human cardiac allograft vasculopathy remains controversial. We investigated whether mycophenolate mofetil would prevent cardiac allograft vasculopathy and prolong cardiac allograft survival in our well-established miniature swine model of heart transplantation. Methods. Hearts disparate at the major histocompatibility complex class I locus were heterotopically transplanted into miniature swine recipients treated with a 12-day course of mycophenolate mofetil (n 3) or cyclosporine A (n 3). Allograft survival, acute rejection, and chronic rejection were monitored in the two groups. Results. Hearts transplanted with 12 days of cyclosporine were rejected between 46 and 61 days, whereas two of the three hearts transplanted with mycophenolate mofetil remained beating beyond 120 days (p 0.02). At necropsy, there was a 4.9% mean prevalence of cardiac allograft vasculopathy in the mycophenolate mofetil group as compared with 16.6% in the cyclosporine group (p 0.03). Cardiac allograft rejection and vasculopathy in the cyclosporine-treated group was associated with prominent myocardial interferon- gene expression, a finding absent in two thirds of the mycophenolate mofetil-treated swine. Moreover, the mycophenolate mofetil-treated swine failed to develop IgM or IgG alloantibodies. Conclusions. A short course of mycophenolate mofetil resulted in a longer allograft survival than a similar course of cyclosporine. Moreover, mycophenolate mofetil reduced the prevalence of cardiac allograft vasculopathy as compared with cyclosporine-treated controls. The salutary effect of mycophenolate mofetil may be related to its ability to decrease interferon- expression in the myocardium and prevent the generation of alloantibodies. (Ann Thorac Surg 2005;80:1787‐93) © 2005 by The Society of Thoracic Surgeons

patient sera, 14.9% vs 2.1% control for the Mab), a reduction in platelet counts, and macroscopic blood cell agglutination. This effect was not produced by the control IgM Mab.Depletion of AVA’s from patient sera with vimentin-coated agarose beads or addition of recombinant vimentin to the blood mixture, abrogated these effects. Flow cytometry demonstrated that AVA do not bind to resting platelets in whole blood but they bind to approximately 10% of neutrophils. Binding of AVA to neutrophils resulted in complement dependent cytolysis (50%) and nuclear condensation. Supernatant derived from AVA activated neutrophils, transferred to fresh purified plalelets, caused platelet activation as measured by generation of platelet microparticles. Experiments performed in the presence of CV-6209, a PAF receptor inhibitor, prevented blood cell agglutination and platelet depletion, suggesting that PAF is one of the mediators released from AVA activated neutrophils. Conclusions: We propose a novel pathogenic mechanism whereby AVA may contribute to atherogenesis and thrombosis.

suppression without rejection episodes. All control animals (n 6), irrespective if they were treated with FK or CsA, rejected within 60 days after immunosuppression withdrawal. In the MphTX group, animals rejected on POD 84, 99 and 131 (FK immunosuppression) and on POD 79 (CsA). One animal is currently alive on POD 180 (FK). Donor cell chimerism peaked early after transplantation and decreased steadily thereafter in all animals. One animal that received a modified protocol with CsA and MphTX on POD 0 and 7 developed donor-specific tolerance in the MLR and is currently alive at POD 306. Conclusion: Tolerance induction is possible in this model of macrophage cotransplantation, but is not as efficient as pretransplant recipient whole body and thymus irradiation. Therefore, further refinement of the protocol is required to improve graft acceptance.

logical reactivity to donor antigens, followed by vascularized heterotopic heart transplantation to determine if CAV still develops in the tolerant recipient. Procedures: In mice, specific immunological nonreactivity was achieved in recipients by (1) neonatal administration of allogeneic spleen cells from F1 donors between class I mismatched donor and recipient strains, (2) acheivement of mixed chimerism by bone marrow infusion of irradiated adult recipients, (3) use of genetically immunodeficient recipients (RAG1-/or SCID). In swine, reduced reactivity was achieved through the induction of mixed chimerism. After nonreactivity was induced and verified through extended persistence of skin grafts, hearts from donors were heterotopically transplanted into the recipients. Results: Most hearts transplanted into tolerant or immunodeficeint mice developed striking vasculopathy in their coronary arteries (neonatal tolerance: 12 of 15, mixed chimeras: 15 of 23, immunodeficient recipients: 16 of 31). In contrast, isotransplants were virtually free of CAV. Three of the four transplanted swine hearts showed neointimal proliferation characteristic of CAV in 1%-6% of donor coronary arteries. Control hearts transplanted into untreated recipients across similar minor antigen barriers were acutely rejected within 44 days whereas control isografts survived indefinitely without evidence of CAV. Conclusions: Elimination of T and B cell immune responses was not sufficient to prevent the development of CAV. Other immune effectors, perhaps NK cells, could play a role in the development of CAV in this immunodeficient state. Additional results on these alternate effectors will be presented.

Purpose: The effect of interferon(IFN) on allograft rejection remains controversial. Some have proposed that IFNhas a protective effect on the microcirculation of allografts, while others have shown IFNto be deleterious. We investigated the effects of intracoronary IFNon cardiac rejection in a preclinical large animal model. Methods: MHC class I disparate hearts were heterotopically transplanted into swine treated with a 12-day course of cyclosporine (10-14mg/kg/day) (n 3). An Alzet osmotic mini-pump delivered IFNinto the coronary vasculature at a rate of 100ng/day. Control recipients were treated with a similar course of cyclosporine but without IFN(n 3). Results: Swine treated with IFNdeveloped an earlier onset of high grade acute rejection as compared to controls, and rejected their allografts in 19 days vs. 46 days for controls (p 0.02). Elastin staining of the cytokine treated allografts showed severe endothelialitis and intimal thickening as early as POD 13. Conclusion: The delivery of IFNinto the coronary circulation of cardiac allografts appears to accelerate both acute and chronic rejection. Targeting IFNin antirejection regimens may ameliorate both of these processes.

that CM/IFA-injected animals grafted with MHC class II KO hearts experienced significant prolongation of heart survival as compared to untreated mice (11 1 d vs 24 2 d). We conclude that modulation of CM response can on its own achieve graft prolongation when CD4 alloresponse is oligoclonal, i.e. mediated via indirect allorecognition. Our findings have important implications for the design of future therapies in heart transplantation.