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Background: Recurrent autoimmune beta-cell destruction may contribute to the poor results of clinical islet transplantation. Pancreas transplants from diabetes-resistant BB rats (BB-DR) are uniformly successful in autoimmune diabetic BB rats (BB-Ac), but isolated islets are destroyed, despite immunosuppression. In this study we tested the hypothesis that whole pancreas transplants abrogate autoimmunity by passive transfer to the host of an autoregulatory T-cell subset., Methods: BB-Ac rats served as recipients of BB-DR or Wistar Furth (WF) pancreas or islet transplants. Two cohorts of islet transplants included 50 or 100 x 10(6) peripancreatic lymph node cells (LNCs). Recipients were monitored for recurrent diabetes and subjected to fluorescence-activated cell sorter analysis of peripheral blood lymphocytes after 200 days by using monoclonal antibodies to class I, CD4, CD8, RT6.2, and RT6.1., Results: BB-DR pancreas transplants replete the RT6.1+ T-cell subset in BB-Ac rats, whereas BB-DR islet transplants, which are susceptible to recurrent autoimmunity, do not. Addition of 100 x 10(6) LNC results in repletion of RT6.1 to the same degree as the whole pancreas and leads to complete protection of the islets. WF pancreas transplants result in the appearance of RT6.2+ T cells in BB-Ac recipients, an RT allele that BB rats lack., Conclusions: BB-Ac rat recipients of whole pancreatic or islets plus LNCs transplants become chimeric for a donor T-cell population that prevents recurrent autoimmune diabetes. Deliberate inclusion of donor lymphoid cells with clinical islet transplants may be beneficial.

The shortage of suitable human organs currently limits widespread utilization of clinical transplantation. Successful xenotransplantation could potentially eliminate the shortage of suitable organs for transplantation. The present study determines the effect of intrathymic donor spleen cell injection on the survival of cardiac xenografts performed without post-transplant immunosuppression. Wistar-Furth rats served as recipients of Lewis rat cardiac allografts or Golden Syrian hamster cardiac xenografts either with or without intrathymic donor spleen cell injection. Some xenograft cohorts were pretreated with four doses of cyclophosphamide prior to cardiac transplantation. Graft function was assessed by daily graft palpation and rejection was defined as cessation of graft function. Cardiac allograft median survival time (MST) was 8 days in untreated recipients. Pretreatment with intrathymic donor spleen cell injection led to essentially indefinite allograft survival (MST > 100 days). Control xenograft survival was 3 days with no significant prolongation seen when intrathymic donor spleen cell injection was performed (MST = 2.5 days). The addition of pulse-dose cyclophosphamide resulted in markedly prolonged xenograft survival (MST = 30 days) compared to control (P < 0.01) and to cyclophosphamide alone (MST = 9.5 days, P < 0.01). Cardiac xenografts undergo a vigorous rapid rejection. The time course of rejection was not altered by the intrathymic presence of donor cells under conditions which lead to indefinite survival of cardiac allografts. A brief period of pretransplant cyclophosphamide treatment markedly improved the success of the thymic tolerance protocol in xenografts. This finding suggests that temporary inhibition of humoral immunity may be permissive for the development of thymic tolerance to cell-mediated immunity in xenotransplants.

Background: Clinically successful islet transplantation has been rare despite adequate isolation techniques. Reenactment of the original autoimmune beta-cell destruction may contribute to the poor results. Distinguishing autoimmune effects from rejection can be accomplished with isogeneic transplants exchanged between diabetes-prone (BB-DP) and diabetes-resistant (BB-DR) rats. These experiments determine the relative sensitivity of islet, whole pancreas, and composite kidney-islet transplants to recurrent autoimmunity., Methods: Acutely diabetic (BB-Ac) BB rats served as recipients of vascularized pancreas, intraportal (IPo) or renal capsular (KC) islet transplants, or vascularized composite kidney-islet grafts from BB-DR or BB-DP donors. Graft function was assessed by daily blood glucose level, and the outcome was confirmed on histologic examination. Cyclosporine 5 mg/kg/day intramuscularly was administered to assess its effect on recurrent beta-cell injury., Results: BB-DP pancreases developed recurrent autoimmunity in 55% of cases; cyclosporine afforded complete protection if maintained. Diabetes resistance was transplanted with 23 of 23 BB-DR pancreas grafts; however, islet isolation led to a loss of diabetes resistance for islet grafts to the KC and IPo. Cyclosporine protected KC but not IPo islets. Composite BB-DR kidney-islet transplants functioned indefinitely in all cases., Conclusions: Transplanted islets initially survive by passive diffusion but are ultimately revascularized by capillary ingrowth. The finding that composite kidney-islet transplants function indefinitely suggests that the revascularizing endothelium may play a role in resistance or susceptibility to autoimmune beta-cell destruction.