Transplant arteriosclerosis is the major cause of graft organ failure after the first year of transplantation. Although its detailed pathogenesis remains unclear, clinical and laboratory studies indicate that transplant arteriosclerosis stems from a local, immune-mediated process involving interactions between the recipient's mononuclear cells, with critical roles for macrophages and B and T lymphocytes, and cells of the donor organ's vascular system. Allograft inflammatory factor (aif-1), a 17 kD protein bearing an EF hand Ca++-binding motif, is barely detectable in most normal tissues. However, its expression by cells of macrophage lineage increases markedly in both allo- and autoimmune reactions, including perivascular inflammation in transplanted hearts, experimental autoimmune neuritis, and the inflamed pancreas of prediabetic BB rats. Very little is known about the function of aif-1 in macrophage activation or its specific role in the pathogenesis of transplant arteriosclerosis or other inflammatory conditions. This proposal has three major goals: to delineate the molecular basis for the discrete disease-associated pattern of expression of aif-1, to define the role of aif-1 in macrophage biology, and to assess its importance in the pathogenesis of transplant arteriosclerosis. Molecular genetic techniques such as adenoviral transduction and gene targeting of embryonic stem cells will be used to produce macrophages with substantially different levels of aif-1 expression. Function of these cells will be tested both in vitro and in vivo. The importance of aif-1 in transplant arteriosclerosis will be assessed in allograft transplantation studies with mice lacking aif-1. This work may lead to improved longterm outcomes for organ transplantation. The genetic elements controlling aif-1 expression may be useful to direct expression of immunoregulatory gene products to sites of inflammation in transplanted organs. The functional significance of aif-1 likely resides in macrophages, or in their regulation of other inflammatory cells; how aif-1 expression affects the immune response may point to new regulatory pathways involved in the development of transplant arteriosclerosis.
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