PREVENTION OF OVERT DIABETES AND INSULITIS BY INTRATHYMIC INJECTION OF SYNGENEIC ISLETS IN NEWBORN NONOBESE DIABETIC (NOD) MICE

Based on previous studies showing that allogeneic islets transplanted into the thymus can induce donor-specific unresponsiveness, we investigated in the nonobese diabetic (NOD) mouse the effect of intrathymic islet isografts on preventing autoimmunity directed against pancreatic islet antigens. Islets prepared from newborn NOD pancreata were injected into one lobe of the thymus of 10- to 11-day-old female NOD mice (experimental group) with no immunosuppression. PBS alone was used for injection into age- and sex-matched litter mates (control group). Thirty of 32 (94%) experimental mice remained normoglycemic for over 30 weeks. Well-formed islets with no indication of insulitis were found in the thymus of these 30 mice, whereas no grafted islets were found in the 2 mice that became diabetic at 17 and 19 weeks, respectively (technical failures). In the control group, 10 of 32 (31%) mice became diabetic between 20 and 29 weeks. This diabetic incidence was, however, lower than that in our colony female mice. In the pancreas of experimental mice, 90.9% of islets were free of infiltrates, whereas only 13.1% of islets were intact in control mice. The spleens of 30-week-old experimental mice contained a slightly higher percentage of CD8+ T cells (P<0.05) than those of control mice. Cyclophosphamide injections at 30 weeks induced diabetes in 4 of 9 experimental mice. The 2 lines of evidence, (1) marked reduction in insulitis of intrathymic islet-grafted mice and (2) induction of diabetes after treatment with cyclophosphamide, suggest that both thymic clonal deletion and peripheral tolerance may play a role in preventing diabetes.