Our previous studies, as well as those of others, have found that NOD mice develop spontaneous splenic Th1 cell responses to GAD and its peptide determinants, which then spread intra-molecularly and inter-molecularly to other beta-cell autoantigens during the process of T1DM. Treatment of young NOD mice with single beta-cell antigen primes Th2 responses and the induced Th2 responses spread to other unrelated beta cell antigens, which is associated with the inhibition of disease progression. However, little is known about the role of antigen presenting cells (APC) in the determinant spreading of T cell autoimmunity in NOD mice. B cells are likely to be good candidates for mediating determinant spreading of T cell autoimmunity as B cells can concentrate antigen by capturing antigen via its antigen receptor, efficiently process and present antigen to T cells. Recent studies have showed that Ig mu-/- NOD mice fail to develop diabetes, and showed only minor insulitis. In addition, our preliminary studies have showed that NOD/scid mice that received naive T and B cells isolated from young NOD mice (TB NOD/scid mice), but not NOD/scid mice that received naive T cell alone (T NOD/scid mice), develop spontaneous T cell autoimmune responses and T1DM. Ig mu-/- NOD mice reconstituted with syngeneic bone marrow cells and mature B cells isolated from young NOD mice (Ig mu-/- BMB NOD mice), but not with bone marrow cells alone cells (Ig mu-/- BM NOD mice), display spontaneous T cell responses to beta cell antigens and become diabetic. We hypothesize that B cells are a necessary component for determinant spreading of T cell autoimmunity to beta cell antigens during the natural process of T1DM and following antigen-based immunotherapy. In this proposal, we will examine the role of B cells in determinant spreading of Th1 and Th2 immunity during spontaneous development of T1DM and following antigen-based immunotherapy in the TB NOD/scid and T NOD/scid mice and in the Ig mu-/- BMB NOD and Ig mu-/- BM NOD mice. These studies will address fundamental questions concerning the role of B cells in T cell autoimmunity and may provide a basis to develop novel immunotherapies for the intervention of human IDDM.
