Chronic graft rejection is a complex and poorly understood biologic response that, unlike acute rejection, features a conspicuous and characteristic form of vascular tissue remodelling, transplant vascular sclerosis. Despite the prevalence of chronic rejection in transplant patients, little is known about its development, and it remains an untreatable condition. We have assembled a team of PIs with diverse scientific expertise to examine the basic biology of chronic rejection from several different, but overlapping perspectives. Together, these PIs can specifically address the key features of a vascular remodelling paradigm that my account for chronic graft rejection. They also provide one another with a series of unique and valuable experimental tools. Project 1 will explore the hypothesis that alloantigen-activated T cells, while not necessary for chronic rejection, can accelerate the vascular remodelling process by releasing cytokines that promote tissue growth factor production. Project 2 will evaluate the hypothesis that graft- associated alloantibodies stimulate graft-infiltrating macrophages via FcR, allowing them to avoid apoptosis and to produce pro-inflammatory cytokines that initiate local vascular remodelling. Project 3 will examine the hypothesis that peri-transplant ischemia/reperfusion injury or post-transplant alloantibody binding stimulates C5a production, which helps to initiate vascular remodelling. These projects will be assisted by three core facilities: an Administrative/Statistical Core, an Experimental Transplant Core 9001, and a Histopathology/Morphometrics Core (9002). The Administrative Core will provide organizational support, secretarial services, budget accounting, ad statistical services. 9001 will provide animal procurement and maintenance, organ or tissue transplantation, and post-transplant monitoring and care. 9002 will provide tissue sectioning, histologic and immunohistologic tissue staining, and microscopic and morphometric analyses of stained tissues. In general, this Program Project reflects the efforts of an enthusiastic and highly interactive team of investigators. They have taken advantage of their diverse scientific interests to develop several unique hypotheses and compelling preliminary data regarding the basic biology of graft vascular remodelling. They are well organized, and have strong, active support from their institution.
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