Regulation of IDDM by Proinflammatory and Th1-cytokines

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DESCRIPTION (provided by applicant): Insulin-dependent diabetes mellitus (IDDM) is characterized by the infiltration of T-lymphocytes into the islets of Langerhans of the pancreas (insulitis), followed by selective destruction of insulin-secreting beta cells leading to overt diabetes. Preliminarily, we observed the important association of IDDM with AIM factor (a secretion molecule we initially identified as an apoptosis inhibitory factor), which are: (1) AIM [-/-] mice backcrossed to non-obese diabetes (NOD) background showed complete prevention of IDDM; (2) AIM is expressed by infiltrating macrophages in the pancreatic islets from the very early stage of the disease; (3) AIM strongly induces TNF-alpha, IL-1 beta, IL-6 and IL-12 in macrophages and dendritic cells (DCs). Based on these, a hypothesis has emerged that AIM may accelerate IDDM by inducing pro-inflammatory- and type I- cytokines in initially infiltrating macrophages and DCs in the islets at the onset stage of the disease. The Specific Aim 1 and 2 are focused on establishing the propriety of the hypothesis by adding back the AIM expression in macrophages in AIM-null NOD mice expecting the disease recurrence (aim 1), and testing the impact of the cytokines downstream of AIM signaling on the disease acceleration by assessing whether the induction of the cytokines in macrophages and DCs via the Tet-inducible transgenic system may overcome the disease prevention in AIM-null NOD mice (aim 2). In addition, our recent result that AIM mediates Toll-signaling to induce the cytokines provoked an idea that the putative AIM-receptor may be a TolI/IL-1 receptor family member. In the Specific Aim 3, we will purify and characterize the AIM-receptor by expression screening of a cDNA library generated from macrophage cells. We also plan to create knockout mice of the AIM-receptor by disrupting the gene in the NOD-derived ES cells, as we generated AIM[-/-]/-NOD by using the cells. Our proposed studies will clarify the precise picture of the IDDM pathogenesis in the context of AIM, in particular, during the early stage of the disease, and thus will contribute to development of a new therapy via suppression of AIM. In addition, identification of AIM-receptor will shed light on the precise molecular machinery of AIM functions, as well as a new aspect of physiological function of the Toll-family.