Chronic DTH in Human Graft Arteriosclerosis. Graft arteriosclerosis (GA) is caused by a host anti-graft immune response that reduces allograft perfusion through a combination of intimal hyperplasia, pathological vascular remodeling and abnormal vasoregulation. Resultant ischemia produces end organ failure. GA is the major cause of late cardiac allograft loss (chronic rejection). The immunopathogenesis of GA is unknown. Our original immunocytochemical studies pointed to chronic delayed type hypersensitivity (DTH) as the primary mechanism. Based on our findings, we hypothesized that alloreactive, non-cytolytic host T cells within the arterial intima directly respond to alloantigens on graft endothelial cells (EC) by secreting cytokines (e.g. IFN-gamma) that doth directly and indirectly, through activation of macrophage cytokine secretion, act on EC and vascular smooth muscle cells (VSMC) to cause the structural and functional changes that constitute GA. In this project we will ask if human EC can directly stimulate alloreactive CD4+ T cells to differentiate into effector cells that mediate DTH (known as TH1 cells); if they can recruit already differentiate TH1 cells to enter into the intima; if they can activate intimal TH1 cells to secrete IFN-gamma, and if these processes are promoted by EC injury or by EC activation with inflammatory cytokines (e.g., TNF or IL-12). We will also ask if graft EC can indirectly activate or promote the differentiation of TH1 cells (e.g., TNF or IL-12). We will also ask if graft EC can indirectly activate or promote the differentiation of TH1 cells (e.g. via dendritic cells). These experiments will use both cell culture systems (aim 1) and intact human arteries, either in organ culture or after xenotransplantation into SCID/beige mice (aim 2). We will use our intact artery culture and xenotransplant models to determine if alloreactive TH1 cells can produce structural and functional changes in the artery wall that are characteristics of GA (aim 3). We will use standard morphological approaches (e.g., histopathology, immunofluorescence/immunocytochemistry,. In situ hybridization) and supplement these methods with laser capture microscopy/reverse transcription- to analyze these experimental tissues. To validate our models, we will compare our experimental vessels with patient-derived GA specimens using these sample approaches as well as by using these same approaches as well as by using molecular expression profiling with peptide phage display, proteomics and functional genomics (aim 4). The chronic DTH hypothesis to be tested ION Project 1 is central to this PPG application and fits thematically well with the investigations of IFN-gamma actions on vascular cells proposed in Project 2. Project 1 also serves as a basis for the proposed imaging of GA pathophysiology proposed in Project 3. The experiments of Project 1 use all four scientific cores.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Yale University
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