Allograft inflammatory factor-1 and immune tolerance

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Allograft inflammatory factor-1 and immune tolerance Solid organ transplantation is the ultimate therapeutic approach for many end-stage diseases, but its long-term success is often limited by chronic immune rejection. In heart transplantation, this low-grade rejection manifests as cardiac allograft vasculopathy (CAV). The lesions of CAV characteristically show concentric vascular intimal hyperplasia composed of smooth muscle-like cells and associated extracellular matrix; this intimal expansion develops diffusely throughout the vasculature of transplanted organs, eventually limiting their arterial conduit function and causing graft ischemia and failure. Allograft inflammatory factor-1 (AIF1), a 17kDa EF hand-bearing protein, is strongly expressed in peri-arterial macrophages in transplanted hearts, and is also upregulated in multiple autoimmune conditions. In preclinical studies, forced expression of AIF1 in non-transplant models of vascular injury increases neointimal and atherosclerotic lesion size, suggesting that AIF1 acts as a driver of vascular obstruction. AIF1 deficiency, on the other hand, limits disease activity in experimental autoimmune encephalomyelitis (EAE) and in collagen-induced arthritis, models for multiple sclerosis and rheumatoid arthritis, respectively. These findings suggest that expression of AIF1 promotes inflammation and contributes to the pathogenesis of autoimmune inflammatory processes. How AIF1 induction and accumulation after transplantation affects CAV and donor organ survival is unknown. AIF1 has been characterized as a cytoplasmic protein that acts as a scaffold for pro- inflammatory signaling. It is associated most closely with actin bundling, which plausibly relates to AIF1-based cytoskeletal effects on macrophage migration and phagocytosis, but the precise basis for broader AIF1-dependent effects on cell function and inflammation remains nebulous. In recent studies, we identified novel interactions of AIF1 with proteins that have established links to immune regulation. Our goals with the proposed studies are to ascertain the nature of these molecular interactions and how they affect immune cell phenotypes, and to test if AIF1 expression is necessary for the allogeneic response that causes CAV and transplant failure.