The ultimate pathologic lesion in transplant vascular sclerosis (TVS) is intimal smooth muscle cell hyperplasia. Since growth factors (e.g. IL-1 induced PDGF) produced by infiltrating intimal monocytes/ macrophages can induce the lesion, it is likely that the influx and persistence of cytokine-producing intimal macrophages is critical to the development of TVS. In this regard, recent experiments suggest that alloreactive immunoglobulin can accelerate the lesion of TVS but the mechanism of the IgG effect is unknown. Experiments from our laboratory suggest a connection between alloreactive IgG and macrophage accumulation in the intima. We present data to support the hypothesis that alloreactive IgG may both 1) promote the differentiation of monocytes into long-lived tissue macrophages by preventing apoptosis, and 2) generate the release of cytokines such as IL-1beta and MCP-1 which can drive TVS. Therefore, the long term goal of this project is to understand the role of alloreactive antibodies in preventing monocyte apoptosis, and in promoting macrophage differentiation and cytokine production in TVS. The specific goals of the study are: 1. To determine if immobilized alloreactive immunoglobulin interacts directly with monocyte Fc/gammaR to prevent monocyte apoptosis and to promote macrophage differentiation and activation. We propose to test the effect of Fc/gammaR crosslinking in vitro on the monocyte cytokine profile, markers of differentiation, and morphologic and biochemical changes characteristic of monocyte apoptosis. 2. To understand the role of lymphocyte Fc/gammaR crosslinking in monocyte/ macrophage differentiation and cytokine activation. To characterize this aspect of alloreactive antibody effects in TVS, purified lymphocytes will be studied for their ability to release soluble factors(s) that prevent monocyte apoptosis, promote differentiation of monocytes to macrophages, and modify the monocyte cytokine expression pattern in response to immobilized alloreactive IgG. 3. To determine if functioning Fc/gammaRs are necessary for alloreactive immunoglobulin to induce macrophage changes in TVS lesions in vivo. Since it has been recently shown that TVS can be induced in animals by the transfer of antidonor MHC IgG, it is important to determine the mechanisms of this IgG effect in vivo. Our combined in vivo and in vitro study of the role of Fc/gamma receptors should provide new insights into the pathogenesis and prevention of transplant vascular sclerosis.
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