: CR associated with fibrosis is a major cause of allograft failure since the advent of immunosuppressive drugs that block acute rejection. The hypothesis to be tested here is that CR is driven by T cells that are stimulated by donor antigen peptides presented by APC of the recipient at a time when surgery related inflammation has waned. It is further proposed that this environment causes donor antigen peptide specific T cells to differentiate into type 2 lymphokine (IL-4, IL-5, IL-6, IL-10) producing cells. These lymphokines are proposed to directly or indirectly cause fibrosis within the graft. This hypothesis will be tested using a novel C57BL/6 (B6) Tg mouse line that expresses ovalbumin (OVA) on all cells of the body. Preliminary results show that skin grafts from OVA B6 donors are acutely rejected by B6 recipients in a T cell dependent fashion. In the first aim, an attempt will be made to identify conditions that convert this process into CR by treating recipients with cyclosporine A to allow OVA B6 skin grafts to survive the period of surgery related inflammation, by forcing antigen presentation by recipient APC by removing MHC molecules from OVA B6 donors, and by grafting OVA B6 tracheas that undergo CR naturally. In the second aim, the conditions that result in CR will be used to determine which T lymphocyte subset is responsible and whether or not these cells produce type 2 lymphokines. This approach will be strengthened by the use of adoptive transfer of OVA reactive TCR transgenic CD4 and CD8 T cells to physically track the location and function of specific T cells during CR. The experiments proposed in the third aim will rely on IL-4 deficient recipients and IL-12 administration to test a causal relationship between type 2 lymphokine production by graft antigen specific T cells and the subsequent fibrosis that impairs graft function. It is hoped that an improved understanding of the immunological processes that underlie CR will lead to therapies aimed at graft antigen specific tolerance or treatment of fibrosis.
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