ALLOGENEIC CHIMERISM INDUCES DONOR-SPECIFIC TOLERANCE TO SIMULTANEOUS ISLET ALLOGRAFTS IN NONOBESE DIABETIC MICE

Background. Nonobese diabetic (NOD) mice develop a systemic autoimmune disease that resembles type I diabetes in human beings. Previous studies in NOD mice have shown that transplantation of bone marrow from normal donors to lethally conditioned recipients prevented the development of diabetes (B10.BR --> NOD, BALB/c --> NOD). The focus of the present study was to examine whether donor-specific transplantation tolerance islet allografts could be achieved if islet transplantations were performed coincident with the time of bone marrow infusion in diabetic NOD mice. Moreover, the transplanted islets were evaluated for evidence of recurrent autoimmunity. Methods. Female NOD mice were followed until autoimmune diabetes occurred (urine glucose, +++ to ++++; blood glucose level, 300 mg/dl or greater). Diabetic NOD mice were irradiated with 950 cGy total body irradiation and received 30 x 10(6) untreated B10.BR bone marrow cells (B10.BR --> NOD). A simultaneous islet allograft was placed under the renal capsule within 24 hours after infusion of the bone marrow cells. Mice were monitored by means of blood glucose levels, and histologic analyses were performed on the transplanted islet. Results. Islet allografts genetically matched to the bone marrow donor were significantly prolonged (n = 5; mean survival time, 206 days or more) and showed no evidence for chronic rejection or recurrent insulitis, whereas major histocompatibility complex-disparate third-party allografts were rejected (n = 3 mean survival time, 37 days) and exhibited lymphocytic infiltration compatible with rejection on histologic evaluation. Conclusions. These data suggest that permanent donor-specific tolerance to islet allografts placed simultaneously with bone marrow transplantation can be achieved in diabetic NOD mice. Moreover, recurrent autoimmune destruction of the pancreatic tissue is Prevented by the bone marrow chimerism.