Research Plan: In specific immune reactions, such as allograft rejection, endothelial cells participate in the recruitment and activation of lymphocytes. However, little is known about the regulation and specificity of the antigen presenting abilities of endothelium. The realization that CD4+ T cells are the principal controlling elements of all immune reactions, has focused attention on how these cells interact with endothelium. CD4+ T cells consist of distinct subsets, characterized by the ability to secrete non-Overlapping sets of cytokines. Subset- specific actiVation of T cells by endothelium may reflect variable expression of endothelial cell surface adhesion and costimulatory molecules, and thus may determine the cytokine-dependent effector phase of an immune reaction. The overall objective of this research proposal is to determine mechanisms whereby endothelial cells may regulate the quality and evolution of cell mediated immune reactions, such as allograft rejection.
The specific aims of this proposal are 1) to analyze the role of endothelial cell surface costimulatory molecules in selective T cell subset activation, 2) to analyze the ability of endothelial cells to mediate the selective adhesion and transmigration of naive, recently activated, and memory T cells, and to determine mechanisms whereby antigen-specific """"""""memory"""""""" T cells migrate to sites of immune inflammation, and 3) to analyze the patterns and Junction of endothelial cell interactions with lymphocytes in vivo in a model of human allograft rejection using human to mouse skin transplants. This research proposal is unique in that it involves a detailed analysis of antigen-specific (pathophysiologic) interactions between endothelial cells and T cells, in both human and murine models. The studies will utilize cultured murine and human endothelial cells, cloned antigen specific T cell lines as well as T cells from T cell receptor transgenic mice to analyze true unprimed naive and """"""""pure"""""""" antigen-specific memory T cell responses. The proposed studies will provide valuable information regarding the specificity and consequences of lymphocyte-endothelial cell interactions. Such knowledge may provide the basis for developing new therapeutic agents to modulate selective T cell activation in pathologic processes such as acute and chronic allograft rejection.
| Melter, M; McMahon, G; Fang, J et al. (1999) Current understanding of chemokine involvement in allograft transplantation. Pediatr Transplant 3:10-21 |
| Denton, M D; Geehan, C S; Alexander, S I et al. (1999) Endothelial cells modify the costimulatory capacity of transmigrating leukocytes and promote CD28-mediated CD4(+) T cell alloactivation. J Exp Med 190:555-66 |
| Reul, R M; Fang, J C; Denton, M D et al. (1997) CD40 and CD40 ligand (CD154) are coexpressed on microvessels in vivo in human cardiac allograft rejection. Transplantation 64:1765-74 |
| Briscoe, D M; Henault, L E; Geehan, C et al. (1997) Human endothelial cell costimulation of T cell IFN-gamma production. J Immunol 159:3247-56 |
