Failure of Nonimmunogenic Islet Allografts to Induce Donor-Specific Immunological Unresponsiveness
Authors: Ketchum Robert J. , Moyer Carol , Su Hua-Chang , Moore Wayne V. 
Published: June 2017

Highly purified perinatal rat islets, isolated by a nonenzymic in vitro culture technique, have been successfully transplanted across complete MHC barriers without immunosuppression. Acceptance of these allogeneically transplanted islets is hypothesized to result from an absence of antigen presenting cells (APCs) within the islets. This study was designed to examine the effects of organ transplantation and cyclosporine (CsA) therapy on the development of immunological unresponsiveness in recipients receiving a graft of culture-isolated islets. Kidneys were successfully allotransplanted into unilaterally nephrectomized rats, across a complete MHC barrier (Rt1lv1 to Rt1u) using CsA therapy initiated on the day of transplantation (7.5 mg/kg, orally for 14 days). Remaining native kidneys were removed 14 days following renal allotransplantation. Limited mononuclear cell (MNC) infiltrates were observed in biopsies of renal allografts, taken 30 days posttransplant, but failure of the renal allograft was not observed. Animals bearing established renal allografts (n = 10) received allografts of ã 200 highly purified perinatal islets (ACI, n = 5; F-344, n = 5), transplanted to the kidney subcapsule of the established renal allograft at least 30 days following renal allotransplantation (at least 16 days following termination of CsA). Islet allografts were not rejected, and, as expected, did not initiate rejection of the renal allograft. Similar results were observed in renal allograft recipients rendered diabetic by a single injection of streptozotocin (STZ, 65 mg/kg, n = 5) and receiving islet allografts of sufficient mass (ã 1200-1400 islets) to reverse STZ-induced hyperglycemia. Further, neither islet nor renal allografts were rejected following challenge by 1 × 107 donor-strain dendritic cells (DCs). Control animals not bearing a renal allograft, which began CsA therapy either 30 days prior to, or on the day of islet allotransplantation, did reject their islet grafts following challenge with 1 × 107 donor-strain DCs. Further, recipients of perinatal islets not receiving CsA did not develop donor-specific tolerance at any time up to 300 days posttransplant. Islet allografts were rapidly rejected following challenge with as few as 5 × 105 donor-specific whole spleen cells. Transplantation of isolated perinatal islets, MHC-identical to the renal donor, neither compromised the established renal allograft, nor did the immune activity observed in the renal allograft affect the subsequent MHC-identical islet allograft. The inability to initiate rejection of the renal and islet allografts by DC challenge represents development of donor-specific immunological unresponsiveness in response to kidney allotransplantation and concomitant CsA therapy, although CsA therapy concomitant with transplantation of isolated perinatal islets did not induce development of donor-specific unresponsiveness. These observations suggest a possible requirement for donor-derived APCs, present in the renal allograft and absent from the islet allograft, in the establishment of immunological unresponsiveness in transplantation with concomitant CsA therapy.