Regulation of IDDM by AIM 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 associations 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-1beta, IL-6 and IL-12 in macrophages and dendritic cells (DCs). Based on these findings, 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 of the disease. Specific Aims 1 and 2 are focused on establishing the propriety of the hypothesis by generating transgenic NOD mice that overproduce AIM in the islets, expecting disease acceleration (aim 1), testing the impact of the cytokines downstream of AIM on the disease acceleration by inducing them in macrophages or DCs in young NOD mice via the Tet-inducible transgenic system (aim 2-1), and assessing whether the expression of the cytokines in the absence of AIM may restore the disease in NOD mice on AIM-/- background (aim 2-2). 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 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-/- by using the cells. Our proposed studies will clarify the precise picture of 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 the 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.