Mechanisms and therapies of B7x and B7-H3 in T1D T cell co-stimulation and co-inhibition generated by the B7 family and their receptor CD28 family have key roles in regulating T lymphocyte activation and tolerance. Therefore these pathways are very attractive therapeutic targets. In addition to the long-standing pathway of B7-1/B7-2/CD28/CTLA-4, we and others have discovered several additional members of the B7/CD28 families over the last several years, including B7h/ICOS, PD- L1(B7-H1)/PD-L2(B7-DC)/PD-1, B7-H3/receptor(s), B7x(B7-H4 or B7S1)/receptor(s), and HHLA2/TMIGD2/receptors. Type 1 diabetes (T1D) is an autoimmune disease characterized by infiltration of lymphocytes into the islets of the pancreas and then breakdown of glucose homeostasis as a result of destruction of insulin-producing ? cells by T cells. The incidence of T1D has risen steadily. Little is known about the roles of B7x and B7-H3 in the regulation of T cell function in peripheral non-lymphoid organs such as the pancreas where T1D occurs. Based on our recently published work and our exciting preliminary data, we have hypothesized in this proposal that B7x and B7-H3 are coinhibitors of effector T cells in T1D and are new therapeutic targets. This hypothesis will be tested by pursuing three specific aims: 1) Specific Aim 1: Dissect the mechanisms by which B7x inhibits T1D development; 2) Specific Aim 2: Determine the physiologic roles of B7-H3 in T1D; and 3) Specific Aim 3: Assess the therapeutic efficacy in T1D by targeting the B7x and B7-H3 pathways. We have generated a number of novel tools and have assembled a multi-disciplinary team with complementary skill sets, which provides us with unique opportunities to address challenges and achieve our goals.
The proposed research is relevant to public health and NIH's mission, because our program will not only define the roles of the B7x and B7-H3 pathways in type 1 diabetes but also translate to new therapy opportunities.
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