Non-obese diabetic (NOD) mice spontaneously develop diabetes resembling human IDDM. In both humans and NOD mice, susceptibility to diabetes is strongly associated with genes of the major histocompatibility complex (MHC). Since MHC class II molecules function as restriction elements for antigen presented by CD4(+) T cells and because monoclonal antibodies (mabs) reactive with CD4(+) T cells block disease progression in the mouse, it is possible that a selected subset of CD4(+) T lymphocytes expressing a unique T cell receptor (TCR) element(s) might be involved in early inductive events which lead to islet inflammation (insulitis) with resultant beta cell destruction and hyperglycemia. The hypothesis underlying this project application is that in experimental, as well as human IDDM, CD4(+) T cells expressing a limited and highly homologous set of V region gene segments might be involved in the early induction of insulitis. This hypothesis will be examined using a novel animal source, the NOD/scid/scid mouse, developed in the Jackson Laboratories and provided to us collaboratively by Dr. Leonard Schultz from the Jackson Laboratory. By adoptive transfer of selected subsets of T cells either from NOD mice or from crosses of TCR transgenic mice with NOD mice which bear the NOD MHC and T cell receptor Vbeta gene products (which have been implicated in disease pathogenesis) with or without a corresponding T cell receptor Valpha transgene, we will be able to ask what role selected subsets of T cells bearing limited T cell receptors will play in insulitis and resultant beta cell destruction. In addition, we will be able to ask questions about immunotherapy in this model. First, can lymphocytes, previously demonstrated to cause insulitis in NOD mice and confirmed by NOD/scid/scid transfers, be rendered anergic and maintain the state of anergy in the NOD/scid/scid animal? Secondly, can lymphocytes, transferred into a NOD/scid/scid animal, be rendered anergic? Finally, if CD4(+) cells transfer only insulitis, can subsequent beta cell destruction be mediated by the adoptive transfer of CD8(+) lymphocytes or are additional cell types involved in mediating beta cell destruction? These experiments rely upon technology currently ongoing in our laboratory and, in part, utilize animals provided to us collaboratively as described in the text of this project. It is our expectation that we will be able to identify those T cells involved in NOD insulitis, to demonstrate whether this is an oligoclonal or monoclonal population and, finally, to attempt to identify those lymphocytes involved in beta cell destruction.
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