This is a continuation of a project focused on the nature of the 'autoimmune' process responsible for pancreatic islet destruction and the development of diabetes in the NOD mouse. We have now turned to a study of agents which can modulate the 'autoimmune' response. We have confirmed the report of others that stimulation of the NOD immune system with CFA can delay or eliminate the development of diabetes. This effect results from some form of immune deviation; CFA treated animals show the same incidence of insulitis as untreated animals. However, following CFA stimulation of the immune system, such lesions are non-destructive (nd-) and, thus, may be qualitatively from destructive (d-) lesions that develop in the majority of female NOD mice.
The first aims of this proposal are to elucidate the mechanistic basis of the CFA effect, and to investigate whether CFA modulation of the immune system is synergistic with the use of radical scavengers to protect islet tissue from inflammatory tissue damage. The second set of aims is focused on the role NOD islets play in the activation and expression of the disease process. The experimental design is to use NOD-SCID animals reconstituted with T cells from CFA treated NOD donor animals to analyze the contribution of myelo/reticular and lymphoid elements to the regulation of diabetes precipitated by either spleen cells from diabetic animals or cloned islet reactive T cells. Cloning of T cells from either d- or nd-lesions will be carried out as previously described; d- and nd-lesions will be obtained by grafting NOD islet tissue to disease prone or CFA treated NOD animals. The contribution of NOD islets to the precipitation of disease will be studied by grafting NOD islets to SCID mice reconstituted with NOD lymphoreticular tissue. Understanding these processes is essential as we approach the use of clinical islet transplantation in the treatment of Type I diabetes; disease recurrence in the grafted tissue is a major problem requiring a solution before clinical islet grafting can be achieved without long term immune suppression. Also, understanding the disease process will allow the design of rational approaches to the prevention of type I diabetes.
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