It is noted that the orthotopic liver transplant model in mice results in virtually 100 percent tolerance and survival of recipients without need for immunosuppression and also results in transfer of dendritic cells systemically within the recipient. Progenitor dendritic cells are deficient in MHC Class II and stimulatory molecule expression and allostimulatory activity and can also prolong allograft survival in certain circumstances. These immunosuppressive properties of progenitor dendritic cells are controlled by both cytokines and by matrix interactions. Therefore the applicant hypothesizes that regulation of the expression of cell surface MHC antigens and T cell costimulatory molecules on dendritic cells determines their potential to induce tolerance and immunity.
Three specific aims are proposed: I. Determine how cytokines and matrix proteins alter the phenotype and function of liver dendritic cells. II. Define the cellular and molecular mechanisms by which alterations in dendritic cell phenotype and function alter T cell responses in vitro. III. Establish the in vivo relevance of alterations in dendritic cell expression of co-stimulatory molecules by extending their observation that dendritic progenitors promote the survival of organ allografts.
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