Role of Host Immune System in BB/Wor Rat: Predisposition to Diabetes Resides in Bone Marrow

The role of the immune system in the development of autoimmune diabetes mellitus in the BB/Wor rat was studied with bone marrow transplantation methodology. In the first experiment, diabetes-prone (DP) and diabetes-resistant (DR) BB/Wor rats were irradiated and reconstituted with bone marrow to create both reciprocal (DP donor → DR host; DR donor → DP host) and syngeneic (DR → DR; DP → DP) histocompatible chimeras. Both susceptibility and resistance to subsequent spontaneous diabetes in these chimeras were found to be a function of the type of donor bone marrow transplanted and not the genetic background of the host. In a second experiment, rats from three strains that share the RT1^u major histocompatibility complex haplotype of the BB/Wor and rats from three non-RT1^u strains were lethally irradiated and reconstituted with DP BB/Wor bone marrow. To rapidly induce diabetes and/or insulitis, they were then injected with mitogen-activated spleen cells from acutely diabetic DP BB/Wor donors, with standard passive-transfer methods. Diabetes and pancreatic insulitis were observed in RT1^u recipients, whereas non-RT1^u rats developed insulitis but not diabetes. The data suggest that predisposition to spontaneous diabetes in BB rats resides in bone marrow cells.