Chronic DTH and IFN-gamma in Human Graft Arteriosclerosis

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DESCRIPTION (provided by applicant): The overall goals of this PPG remain largely unchanged, namely to elucidate the pathogenesis graft arteriosclerosis (GA), the major cause of late cardiac allograft failure, in order to develop new strategies to prevent, treat and diagnose this condition. GA is a rapidly progressive stenosis of graft conduit arteries that results in ischemic graft failure. Our general hypothesis is that GA is caused by IFN-gamma, a cytokine made predominantly by certain subsets of T cells. Project by J.S. Pober, project leader, will investigate features of graft endothelial cells that lead to selective recruitment, differentiation and/or activation of host T cells which make IFN-gamma and NO, mediators of GA. Project by Pober will also develop new immunodeficient mouse models for analysis of human GA, exploiting advances in hematopoietic stem cell transplantation and tissue engineering of blood vessels. Project by Min, will investigate how IFN-gamma, acting through SOCS-1, may combine with TNF to produce endothelial dysfunction, an early event in GA. Project by G. Tellides, will investigate how IFN-gamma can cause proliferation and/or death of vascular smooth muscle cells, key processes in vessel remodeling and stenosis. Project by Tellides will also evaluate the contributions of innate immunity and PPAR- gamma signaling to these processes. Project by J.R. Bender, will explore the relationships between IFN-gamma, VEGF and integrin expression and activation in the pathogenesis of GA. Project by Bender will also identify targets and reagents for noninvasive imaging early processes in GA. The Administrative Core (J.S. Pober, core leader) will administer the PPG. The Microsurgery Core (G. Tellides, core leader) will produce immunodeficient mice bearing human xenogeneic or mouse allogeneic arterial segments, models central to this PPG. The Microsurgery Core will also explore the use of immunodeficient rats as the basis for developing a new model for human GA. The Morphometry and Physiology Core (W.C. Sessa, core leader) will provide state-of-the-art analytic tools to evaluate transplanted blood vessel segments. The Apheresis Core (E.L. Snyder, core leader) will conduct leukaphereses of adult human volunteers, providing human lymphocytes and hematopoietic stem cells, crucial reagents for the proposed experiments. If successful, the integrated efforts of the four projects and four cores will not only produce new insights into human GA, but will also increase our understanding of related human arteriopathies such as atherosclerosis and post-procedure restenosis.