Our interest in the phagocyte- and tumor cell-derived protein MFG-E8 continues. In accordance with our prediction and consistent with its alpha-v beta-3 integrin- and phosphatidyl serine binding activity, others have demonstrated that MFG-E8 can mediate the uptake of apoptotic cells by macrophages. We have generated several MFG-E8 mouse mutants to determine if MFG-E8 has a non-redundant role in apoptotic cell uptake in vivo and, further, to determine if MFG-E8 is involved in cross presentation of antigens that are not expressed by antigen presenting cells. Because MFG-E8 is homologous to del1, a protein expressed by endothelial cells in embryos and in tumors, we are also defining the role that MFG-E8 may play in angiogeneis and tumorigenesis. Results, to date, indicate that tumor cells produce MFG-E8 and that MFG-E8 promotes tumorigenesis in both orthotopic and transgenic models of cancer in mice (melanoma, non-melanoma skin cancer and pancreatic beta-cell cancer). In addition, ongoing experiments suggest that MFG-E8 may be a relevant therapeutic target in cancer. The other project area that is being actively pursued in the laboratory involves testing the feasibility of using T cell receptor proteins expressed by clonal T cell malignancies as tumor antigens in vaccines. DNA-based (genetic vaccination) strategies are being emphasized because of concerns regarding the practicality of patient-specific therapies. A reproducible model involving subcutaneous growth of T cell lymphomas in mice has been established in the laboratory. cDNAs encoding T cell receptor alpha and beta chains from this murine T cell lymphoma have been cloned and sequenced, and several candidate vaccines have been generated. We have determined that several candidate vaccines have activity. In the course of these studies, we identified a novel adjuvant strategy that dramatically increases the efficacy of TCR-based vaccines. Because we anticipate that this adjuvant strategy will be generally applicable and well tolerated, incorporation into human vaccine trials may be feasible. Collaborative studies of dendritic cells and their products in experimental cutaneous leishmaniasis are also ongoing, and results continue to inform our understanding of dendritic cell function in this murine model of an important human disease. It is anticipated that these insights will promote development of a vaccine that will attenuate the burden of this world-wide health problem.
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