The goal of the proposed research is to identify a receptor for human PECAM-1 that can potentially be targeted by therapeutics to treat human graft rejection. This application proposes to screen an array of more than 2000 human surface proteins using PECAM-1 as a probe. The array was very recently developed by Dr. Lieping Chen, a colleague at Yale University School of Medicine and a collaborator on this project. It represents a very powerful resource not previously available to identify human receptors/counter- receptors. Human endothelial cells (EC) act as antigen presenting cells and affect the recruitment of T cells, an event relevant not only for graft rejection, but potentially or a wide range of human pathologies in which an immune component is implicated (e.g., autoimmune diseases and atherosclerosis). Interestingly, only a small subset of T cells found in the peripheral blood of normal individuals, namely effector memory T cells, are recruited by a distinct mechanism when their TCR is activated by polyclonal TCR- stimulating reagents presented on the surface of the EC. These findings coincide with an emerging paradigm that antigen-specific (or graft-specific) T cells serve as pioneers in an immune reaction. In this paradigm, a small number of antigen-specific T cells are recruited to the site of infection (or a graft) and condition the site via inflammatory cytokines (TNF and IFN-?) for a cascade of other immune cells. PECAM-1 on the EC is necessary for the recruitment of EM CD4+ T cells in a model mimicking antigen-specific transendothelial migration, yet none of the known receptors for PECAM-1 are expressed on EM CD4+ T cells. This receptor, by controlling antigen (graft) - specific recruitment of EM CD4+ T cells, is a potentially effective target for therapeutics. This application proposes to identify that receptor using Dr. Chen's new array.
Alloimmune reactions are a major cause of human graft failure, characterized by a destruction of the graft vasculature. We have found that human endothelial cells, when presenting antigen to T cells under conditions like that of flowing blood, induce their activation and recruitment by a unique mechanism. These studies will illuminate the molecular mechanisms underlying antigen-driven recruitment of T cells and may lead to the development of specific therapies to ameliorate allograft rejection.
