Insulin-dependent diabetes mellitus (IDDM) in the BB/W rat appears to result from a T cell-mediated autoimmune insulitis that destroys the pancreatic beta cells. However, little is known about the predisposing events that lead to the generation of the autoreactive T cells. This proposal is designed to test the hypothesis that the T cell abnormalities that lead to IDDM in BB/W rats result from defects in the development of prothymocytes and/or their differentiation in the thymus. We have previously demonstrated that the predisposition for diabetes can be transferred by bone marrow cells from diabetes-prone (dp) BB/W rats to congenic diabetes-resistant (dr) BB/W recipients. We have also devised two quantitative adoptive transfer systems for studying the developmental potential of prothymocytes in histocompatible strains of rats. The first system uses the standard intravenous route of injection. The second system uses a novel intrathymic route of injection that allows the selective regeneration of thymocytes and T cells by prothymocytes in the absence of other lymphohemopoietic cell development; and can be used to study the developmental potential of intrathymic, as well as prethymic precursors. We now propose to use these two assay systems to conduct reciprocal prothymocyte cross-transfer, mixing (competition) and thymus grafting experiments between dp BB/W, dr BB/W and WF strain rats in order to determine the cellular and/or environmental bases for the genetic predisposition or resistance of these rat strains to diabetes. Further experiments using established secondary adoptive transfer systems will be conducted in order to associate the developmental abnormalities of prothymocytes with the generation of functional T cell subsets important in the pathogenesis of diabetes. For these studies, donor- and host-origin thymocytes and T cells will be separated from the chimeras according to their RT-7 alloantigenic phenotypes, and tested for their ability to induce or prevent diabetes in naive recipients. When taken together, these experiments should permit the abnormalities responsible for the predisposition to diabetes in BB/W rats to be localized to: 1) a primary defect in BB/W prethymic or intrathymic precursors; 2) a microenvironmental defect in the thymus; 3) an abnormality in accessory cells (macrophages) or other lymphohemopoietic cell lineages; 4) an extrathymic (but otherwise uncharacterized) cellular or environmental defect; 5) a combination of the above.
Showing the most recent 10 out of 87 publications
