CELLULAR PATHOLOGY OF GRAFT VERSUS HOST DISEASE

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DESCRIPTION: (Adapted from the applicant's abstract) - GVHD is a major impediment to successful allogeneic bone marrow transplantation for establishing remission from leukemias and non-Hodgkin's lymphomas. This competing renewal is a continuation of research initiated in l995 devoted to understanding mechanisms that underlie the cellular pathology of GVHD. During previous cycles, a relevant murine model for human GVHD has been developed and characterized. An in vivo bioassay for GVHD-like cytotoxicity in human skin also has been described. The investigators have learned that tissue injury in cutaneous acute GVHD has at least three phases: i) Allostimulation whereby donor T cells are activated via antigen binding to CD4 surface molecules associated with the T-cell receptor-CD3 complex; ii) homing of activated donor cells to specific organs as a result of expression of adhesion molecules by cytokine-activated microvascular endothelial cells; and iii) cytotoxicity involving selective apoptosis of specific subpopulations of target cells. Allostimulation, homing, and cytotoxic phases, respectively, involve direct interactions between T cells and antigen presenting cells, T cells and endothelial cells, and T cells and target keratinocytes. Such interactions are potential targets for therapeutic intervention. The investigators have successfully inhibited experimental murine GVHD by use of synthetic peptides designed specifically to mimic the CDR3 region of the D1 immunoglobulin domain of the murine and human CD4 molecule. They hypothesize that the efficacy of this approach lies in blunted induction of T-cell allostimulation and cytotoxic capacity as well as inhibition of T-cell homing to specific target tissues. They now plan to explore mechanisms whereby murine CD4-CDR3 peptide abrogates target cell apoptosis in GVHD. A novel synthetic peptide that mimics the FceRIa molecule on mast cells and that appears also to inhibit this disease will be studied. In addition, they will evaluate peptide administration protocols in experimental GVHD to assess the practical utility of this novel therapeutic approach. Finally, they will evaluate mechanisms of immunomodulatory strategies, including the CD4-CDR3 peptide, to inhibit human cutaneous cytotoxicity in an in vivo chimeric model relevant to human disease. These data should expand present understanding of key early events that result in potentially lethal tissue damage in acute GVHD, and assist in evaluating synthetic peptides as relevant therapeutic strategies for human disease.