Although tremendous progress has been made in clinical organ transplantation over the past decade, there is still room for improvement in both graft survival and quality of life. Since T lymphocytes are important regulators and effectors in the immune response to organ transplants, the underlying hypothesis of the studies proposed here is that a better understanding of the events involved in T lymphocyte activation and differentiation will help to define new diagnostic reagents and therapeutic approaches to the treatment of transplant rejection. During the past five years this grant supported the identification and characterization of four novel genes and protein products expressed """"""""late"""""""" (3-5 days) after T cell activation. The focus of this renewal application is the identification and characterization of the transcriptional factors involved in the regulation of expression of these genes. Specifically, we propose to: (1) Determine the genomic organization of three late T cell activation associated genes, 519/520, RANTES, and Tactile; (2) Characterize the regulatory regions for these genes; (3) Identify, clone, and characterize novel DNA binding proteins regulating expression of these genes; and (4) Investigate the role of these specific cis-acting regulatory sequences and trans-acting regulatory proteins by examining human transplant tissues and performing cell lineage ablation experiments in transgenic mice. Identification of transcriptional activators specific for late T cell activation will be an important step toward the eventual goal of designing new technologies to interrupt T lymphocyte mediated disease in general and organ transplant rejection in particular.
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