TH1, TH2 CELLS IN INSULIN DEPENDENT DIABETES MELLITUS

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We propose to examine the relationship between beta cell-reactive Th1 and Th2 T cells an th e development of insulin-dependent diabetes mellitus of NOD mice. Our proposal is based on the following previous observations; i) we made a transgenic NOD mouse carrying the rearranged T cell receptors (TCR) from a diabetogenic and beta cell-specific CD4+ T cell; ii) this TCR is expressed on the T cells in transgenic NOD mice, and these cells are not tolerant to the beta cell antigen; iii) the un-manipulated TCR transgenics develop a rapid and severe insulitis and falls diabetic at 4 months of age; iv) when Th1 and Th2 T cell lines re generated from these T cells and transferred in to neonatal NOD mice, only the Th1 line can transfer disease while the Th2 T cells don't despite carrying the identical TCR and infiltrating the pancreatic islets. Since in our TCR transgenic mice we have fix the variables o antigen and TCR specificity and affinity, we can conclude that Th1 T cells are the relevant antigen specific effector cell in diabetes and that Th2 cells are benign. This proposal is designed to test whether this hypothesis holds true in the spontaneous development of IDDM, and if so, can we develop methods to blunt an ongoing destructive Th1-led anti-islet response to a benign TH2. We propose to do this as follows: 1) To test whether our TCR transgenic mice deprived of certain strategic Th1 or Th2 lymphokines can develop IDDM. This will be done by breeding our TCR to mice with lymphokine or lymphokine receptor knock-out-mutations or to mice which over-express regulatory lymphokines. 2) To test the role of regulatory T cells may play in dampening the activity of diabetogenic Th1 T cells. This will be done by either introducing our transgenic T cells into environments completely devoid or enriched in other lymphoid cells. 3) To investigate the potential regulatory effects of Th2 cells on the control of IDDM and to find the means of diverting Th1 T cells to a Th2 phenotype in ongoing disease.