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Two sequential ABO-compatible orthotopic liver allografts failed, despite excellent initial posttransplant function, in a patient with preformed donor-specific alloantibodies. There was no evidence of cell-mediated rejection. Retrospective crossmatching of recipient serum, obtained immediately prior to the first transplant, revealed the presence of lymphocytotoxic antibodies directed against donor class I HLA BIT, at a titer of greater than 1:32,768. Similarly, lymphocytotoxic antibodies directed against the second donor's class I HLA A2 phenotype were detected on retrospective crossmatching utilizing both the three-wash Amos technique (TWA-CDC), and the anti-human immunoglobulin augmented technique (AHG-CDC), at a titer of greater than 1:32,768. Anti-class I specific alloantibodies were eluted from both failed liver grafts at titers of 1:256. The hepatic necrosis in zones 3 and 2 that were observed on histologic examination, and the profound refractory consumptive thrombocytopenia subsequent to each transplant may have been the result of antibody-mediated rejection by preformed lymphocytotoxic antibodies. Despite the liver's remarkable capacity to withstand antibody-mediated injury, primary humoral rejection following ABO compatible liver transplantation may occur if extremely high titers of preformed allospecific lymphocytotoxic antibodies are present.

With the first demonstration of insulin independence following intraportal islet transplantation into a patient with type 1 diabetes, a new era of clinical islet transplantation will begin. This report provides our initial experience of clinical islet transplantion with a total of nine consecutive portal vein islet trasplants in seven diabetic recipients. The first three transplants were done in nonrenal failure diabetics (NRFI) using 6319±2173 islets/kg body weight with islets processed from single pancreas and cultured for 7 days at 24±C. Prednisone, azathioprine, and cyclosporine were initiated prior to transplant. While all three recipients demonstrated C-peptide function posttransplant, all three rejected their grafts at 2 weeks. Five days of OKT3 treatment failed to recover more than 10 of their rejecting islet grafts. The studies were then shifted to established kidney transplant recipients (EKI) maintaining their basal immunosuppression while adding 7 days of Minnesota antilymphoblast globulin (MALG) to the recipient using islets from single donor pancreas that had been cultured for 7 days at 24±C. There were an average of 6161 ± 911 islets transplanted intraportally into three EKI recipients. All three had C-peptide response from the transplant, but none achieved insulin independence. While the first patient rejected his graft at 2 weeks, two recipients demonstrated long-term islet function up to 10 months posttransplant. Sustacal challenge testing demonstrated C-peptide responsiveness, but in a delayed pattern suggesting insufficient islet mass had been transplanted. The next three kidney transplant recipients received islets from more than one donor pancreas averaging 13,916 ± 556 islets/kg body weight. The first of these was the first to achieve insulin independence from 10 to day 25 posttransplant when she appeared to have a rejection episode. The second and third recipients were retransplanted with islets from multiple donorshaving achieved partial islet function from single pancreas donor. The first patient on triple immunosuppression is demonstrating long-term partial function at 184 days but is not insulin independent. The third patient on prednisone and azathioprine received one half his islets after 7-day culture and the other half after 7-day culture combined with cryopreservation. He is continuing to demonstrate insulin independence for 154 days post-transplant with a glycated hemoglobin value of 5.6. Sustacal challenge data demonstrate a total stimulated C-peptide response of 155 ρmol/ml at 4 months posttransplant compared with 148±12 ρmol/ml for normal controls (NC) and 425 ρmol/ml for nondiabetic, established kidney transplant recipients on triple immunosuppression. These results demonstrate the feasibility of achieving insulin independence in type 1 patients after islet transplantation and justify continuing these studies to document how many recipients of islet transplantation can achieve insulin independence for what duration posttransplant.

We analyzed the role of CD4and CD8T cells in H-2-disparate skin allograft rejection in the mutant mouse strain C.B-17/Icr acidwith severe combined immunodeficiency. On the day of skin allografting, scidmice were adoptively transferred with negatively selected CD4or CD8splenocytes from normal unsensitized C.B-17/Icr mice. These populations were obtained using a double-mAb-plus-complement elimination protocol using anti-CD4 or anti-CD8 mAb that resulted in no detectable CD4or CD8cells by FACS and negligible numbers of cytolytic T lymphocytes by limiting dilution analysis in anti-CD8 treated populations. Spleen cells were removed from grafted mice at the time of rejection and were tested in vitro for antidonor reactivity in several assays: mixed lymphocyte culture, cell-mediated lympholysis, and LDA for CTL and for IL-2-producing HTL. The presence of Thy 1.2, CD4, or CD8cells was determined by FACS. All control C.B-17 mice and scidmice adoptively transferred with nondepleted CD4, and CD8cells rejected skin allografts with similar mean survival times (15.6±1.5, 18.8±3.4, 18.0±5.4, respectively), whereas control scidmice retain skin allografts indefinitely (all >100 days). C.B-17 syngeneic grafts survived indefinitely in all groups. At the time of rejection, splenocytes from scidmice receiving CD4cells had negligible donor-specific cytotoxicity in CML and negligible numbers of CTL by LDA, but demonstrated a good proliferative response in MLC and IL-2-producing cells by LDA (frequency = 1/1764). There were no detectable CD8cells present by FACS analysis. Conversely, splenocytes from scidmice adoptively transferred with CD8cells had strong donor-specific cytotoxicity in CML (58.8±16.1) and CTL by LDA (frequency = 1/3448), but no significant proliferation was detected in MLC. There were no detectable CD4cells by FACS, but there were small numbers of IL-2-producing cells by LDA (frequency = 1/10,204). These data demonstrate that CD4cells adoptively transferred into scidmice are capable of mediating skin allograft rejection in the absence of any detectable CD8cells or significant functional cytolytic activity. The adoptive transfer of CD8cells also results in skin allograft rejection in the absence of detectable CD4cells. The detection of small numbers of IL-2 secreting cells in these mice may indicate that CD8-mediated allograft rejection in this model is dependent on IL-2-secreting CD8cells.