IFN-gamma in Human Graft Arteriosclerosis is the major limitation of cardiac transplantation and is characterized by pathological remodeling and dysfunction of coronary arteries, termed graft arteriosclerosis (GA). The pathogenesis of GA is poorly understood, but is likely immune- mediated and may result from chronic delayed type hypersensitivity (DTH) responses by recipient T cells to donor vascular antigens. Activated T cells induced DTH through secretion of cytokines, such as interferon-gamma (IFN-gamma). Paradoxically, IFN-gamma is generally thought to have an anti-proliferative effect on vascular smooth muscle cells (VSMCs) and considered to function as a pro-arteriosclerotic agent solely because of its immunomodulatory effects on vascular cells and infiltrating leukocytes. However, we have recently reported that IFN- gamma elicits arteriosclerosis in the absence of leukocytes. Our observations have led us to hypothesize that IFN-gamma acts directly on VSMCs to potential platelet-derived growth factor (PDGF)-BB induced mitogenesis through interactions involving growth factor receptors and STAT proteins. To test our hypothesis with the experiments planned in this project, we have formed productive collaborations with other investigators of the program application and together we have developed novel models of GA by establishing methods to transplant human and pig coronary arteries to immunodeficient mouse hosts and by defining conditions for the long-term organ culture of human and pig coronary arteries. We will use these approaches to elucidate the effects of IFN- gamma on vascular tissues in vivo and in vitro.
The aims of our application are: (1) to test the hypothesis that IFN-gamma growth stimulatory signals to VSMCs are mediated by STAT3 and are enhanced by PDGF-BB; (2) to test the hypothesis that IFN-gamma growth inhibitory signals to VSMCs are mediated by STAT1 and are diminished by PDGF-BB; (3) to test the hypothesis that IFN-gamma induced proliferation of VSMCs is independent of IFN-gamma effects on endothelial cells; and (4) to validate our model by confirming that the expression of certain IFN gamma-dependent gene products correlates with the presence and degree of GA in human cardiac allografts the outcomes of these studies will provider considerable new information about the role of IFN-gamma in GA. Our experimental work performed in conjunction with Cores B and C will provide a mechanistic extension to the studiers of Project 1. The reagents we characterize in conjunction with Cores D and E will be applied in imaging studies by Project 3. The comparisons between experimental and clinical specimens in conjunction with Project 3, Cores D and E will validate our models. Our findings may ultimately have diagnostic, prognostic, and therapeutic clinical utility.
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