CD27/CD27 LIGAND AND T CELL RESPONSES

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CD27, a cell-surface antigen, with homology to tumor necrosis factor (TNF) receptor family of molecules is found on a majority of T cells and has been suggested to play a role in T cell activation and generation of cytotoxic T lymphocytes(CTL). Although elevated levels of soluble CD27 have been demonstrated in serum from patients with rheumatoid arthritis and other autoimmune disease, the exact role of this T cell activation antigen in T cell immune responses is still poorly understood. We intend to establish an in vivo murine model that effectively neutralizes the CD27/CD27 ligand (CD27L) interaction by the injection of an adenoviral vector encoding an inhibitor molecule, i.e. a fusion protein formed by joining the extracellular domain of the murine CD27 receptor to a murine IgG heavy chain (CD27-Fc). In order to determine the effects of the neutralization of CD27/CD27L interaction in vivo on CTL, a comparison of the generation of CTL by primary and secondary intraperitoneal injection of P815 (H-2d) tumor cells into B6 (H-2b) control mice and mice infected with the adenovirus containing the CD27-Fc construct will be performed. To further assess the immunologic importance of the CD27/CD27L system, evaluation of antigen specific T cell responses and delayed type hypersensitivity (DTH) responses will be assessed and compared in mice infected with the adenovirus containing the CD27-Fc inhibitor and control mice. CTL play an important role in murine graft versus host disease (GVHD). The importance of the CD27/CD27L system in the evolution of murine GVHD will similarly be assessed by comparing control and adenovirus infected animals in 2 models of GVHD, one that induces bile duct damage and portal inflammation and simulates lesions in primary biliary cirrhosis utilizing B6->B6 X BM1 mice; the other inducing extensive colonic inflammatory lesions similar to those detected in human Crohn's disease utilizing DBA/2 ->B6D2F1 mice. All of these studies should better delineate the role of CD27/CD27L interaction in the evolution of T cell immune responses and their contribution to the pathogenesis of GVHD. Finally, the role of TNFR(receptor)/TNF interaction in the evolution of similar immunologic responses is surprisingly still not well understood. Comparable assessments of the TNF system in generation of CTL, contribution to the development of DTH and to GVHD will be performed in mice in which TNFR/TNF interactions are neutralized by injection of the adenovirus vector encoding the inhibitor TNFR-Fc, a murine model that was developed and is already being used in our laboratory.