Chronic DTH and IFN-gamma in Human Graft Arteriosclerosis. Graft arteriosclerosis (GA) is a host anti-graft immune-mediated lesion characterized by intimal expansion, vessel construction (pathological remodeling) and abnormal vasoregulation. GA is the underlying basis of chronic cardiac allograft rejection and the leading cause of allograft failure. There is currently no effective therapy or means of early diagnosis of this inexorably progressive disease. The immunopathogenetic mechanism(s) of GA is unknown. Our early immunocytochemical analysis of cardiac allograft allograft arteries suggested the presence of a chronic delayed type hypersensitivity (DTH) reaction mediated by non-cytolytic T cells within the arterial intima that appeared to be reacting to alloantigens expressed on persistent graft endothelial cells (EC). Since interactions of rodent T cells with EC are profoundly different from those that occur in humans, rodent transplant models may be of limited us in exploring immune pathogenetic mechanisms. Our more recent work has suggested that IFN-gamma, a cytokine made by T cells that mediate DTH (I.e. TH1 cells) can cause intimal expansion of human arteries. In this program project we will employ human artery cell and organ culture models as well as human arteries xenografted into SCID mice (produced by Core B) to investigate the development of anti-EC DTH and effects of chronic DTH on human vessels (Project 1) and to elucidate the mechanisms by which IFN-gamma induces intimal expansion and other changes of human arteries (Project 2). We will validate these models by comparisons to human GA specimens (analyzed by Core D) using conventional morphology (including immunofluorescence, immunocytochemistry and in situ hybridization) as well as laser capture microscopy/reverse transcription- polymerase chain reaction. These studies will be complemented with morphometry to assess both vascular remodeling and intimal chain reaction. These studies will be complemented with morphometry to assess both vascular remodeling and intimal hyperplasia (conducted by Core C) and physiological assessment of vessel function (conducted by Core C) and molecular expression profiling (via peptide phage display, SELDI/ProteinChip analysis and RNA array analysis (conducted by Project 3, Core D and Core, respectively). Finally, we will use our human artery xenografts and other models to develop new approaches for early non-invasive of GA based upon pathophysiologic processes rather than end stage structural changes (Project 3). The results of this thematically integrated program will provide a scientific basis for new and more effective approaches to address the problem of chronic allograft rejection.
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