This proposal addresses the molecular mechanisms of transplant arteriosclerosis in long term survival of heart transplantation. Transplant arteriosclerosis is characterized by widespread, often obliterative intimal thickening which is rich in macrophages and smooth muscle cells. The applicants propose to study the function of three macrophage derived molecules and determine if they are essential components of the immune response that mediates intimal smooth muscle in transplant arteriosclerosis. First, they plan to establish a temporal pattern of expression of these genes in Lewis to F344 rat cardiac allografts at distinct stages of transplant arteriosclerosis. They will also evaluate the effect of various immunosuppressive drugs on this expression. Second, they will identify cytokines that regulate the expression of these three genes in macrophages. They propose to generate recombinant versions of these three genes and a panel of antibodies against the gene products. They will use both of these to evaluate the activity of the three gene products in chemotaxis assays and adhesive properties of cardiac allografts. Third, they will explore manipulations that modulate levels of the macrophage derived proteins to determine if they will ameliorate arteriosclerosis. They propose to develop a model of transplant arteriosclerosis in """"""""gene knockout"""""""" mice with which to study the arteriosclerotic development in recipients that are deficient in the factors that have isolated.
