Mammalian liver has been long known to exhibit properties of immunologically privileged tissue: it expresses low levels of surface class I MHC antigens on parenchymal hepatocytes and induces donor-specific allotolerance in MHC mismatched transplant recipients. The suppressed display of surface class I MHC proteins is paradoxical in view of the high constitutive transcription of H-2K, D genes in mice and HLA-A, -B, -C in human, and in view of the liver s ability to clear intracellular hepatic pathogens via CTL-mediated, class I-restricted immune responses. This application seeks to define a full set of class I genes expressed in hepatocytes of normal, cytokine treated (IFNgamma, TNFalpha) and pathogen (Listeria monocytogens, recombinant adenovirus used for liver gene therapy) infected mice and to explore the role of class I antigen processing pathway in their expression. We will restrict our studies to C57BL/6 mice and its H-2Kb,Db-deficient mutant, which will serve to optimize the conditions for detection of rare class Ib products. The results of the proposed research will provide information about the heterogeneity of distince class Ib proteins expressed in parenchymal tissue of liver. Furthermore, the studies of the regulated expression of the components of class I antigen- processing machinery in liver cells will contribute to the understanding of the mechanisms involved in class I-mediated responses against model hepatotrophic pathogens. This knowledge is relevant for clinical research addressing liver transplantation, opportunistic infections of liver and liver gene therapy.
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