CYTOKINE REGULATION OF REJECTION IN VIVO

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Most concepts of how allografts reject in vivo have been formulated by extrapolation from phenomena which occur in vitro. The sponge matrix allograft is a well-suited model to study the rejection process in vivo. The findings within the sponge allograft are in many ways consistent with common in vitro paradigms, such as the central role of cytokines in inducing maturation of CTL; however, some very important differences have emerged. Specifically sensitized TH and CTL are found, but T cell proliferation is virtually absent in vivo, suggesting that clonal expansion of reactive cells is not prominent. Furthermore, the most critical cytokines thought to be responsible for the expansion and maturation of specifically sensitized clones of T cells in vitro (IL-2,IL-4, IFNg) cannot be detected by bioassay. The recent discovery of TH1 and TH2 subtypes of helper T cells, capable of secreting a limited and T cell subset-specific spectrum of cytokines, may shed some light on this discrepancy, because the cytokine pattern of the sponge matrix allograft more resembles TH2 predominance than TH1. Because data on cytokine expression in the sponge matrix allograft model in vivo is very incomplete, the first aim of this proposed project is TO INVESTIGATE THE CYTOKINE ENVIRONMENT IN WHICH VARIOUS SUBSET-SPECIFIC T CELLS MATURE AND DIFFERENTIATE IN VIVO AFTER SPONGE MATRIX ALLOGRAFTING. To meet this aim, a selected group of TH1 and TH2 cytokines will be quantitated (bioassay, ELISA, messenger RNA) in the sponge allograft, and parallel studies will characterize the in vitro functions of infiltrating cells. It should then be possible to test the roles of certain cytokines in the maturation of cellular immunity in vivo. The sponge matrix is like a skin graft in that rejection takes place in the context of an acute inflammatory reactions to a wound instead of the relative isolation of an organ allograft. Therefore it is possible to analyze the influence of acute inflammation on the evolution of cellular immunity. The second aim is TO INVESTIGATE SEVERAL FACTORS PRESENT IN THE ENVIRONMENT OF THE SPONGE MATRIX ALLOGRAFT WHICH MIGHT REGULATE SUBSET- SPECIFIC T CELL FUNCTIONS. Focus will be placed on a few of many possible inflammatory factors (PGE2, TNF-a, TGF-b) which might modulate the allograft response in vivo, some of which might cause the unexpected pattern of cellular and cytokine response observed. A better understanding of the regulation of rejection in vivo will allow more rational implementation of transplantation, earlier diagnosis of rejection, and precise utilization of anti-rejection therapies.