LIVER EXPRESSED MHC ANTIGENS

哺乳动物肝脏长期以来一直被认为具有免疫特权组织的特性：它在实质肝细胞上表达低水平的表面I类MHC抗原，并在MHC不匹配的移植受体中诱导供体特异性同种异体耐受。 鉴于小鼠中H-2K、D基因和人中HLA-A、-B、-C基因的高组成性转录，以及鉴于肝脏通过CTL介导的I类限制性免疫应答清除细胞内肝病原体的能力，表面I类MHC蛋白的抑制展示是矛盾的。本申请试图定义在正常、细胞因子处理（IFN γ、TNF α）和病原体（单核细胞增生李斯特菌、用于肝基因治疗的重组腺病毒）感染的小鼠的肝细胞中表达的全套I类基因，并探索I类抗原加工途径在其表达中的作用。 我们将我们的研究限制在C57 BL/6小鼠及其H-2Kb，Db缺陷突变体，这将有助于优化检测稀有Ib类产品的条件。本研究结果将为阐明Ib类蛋白在肝实质组织中表达的异质性提供信息。 此外，对肝细胞中I类抗原加工机制的组分的调节表达的研究将有助于理解I类介导的针对模型肝营养病原体的应答中涉及的机制。 这些知识对于肝移植、肝脏机会性感染和肝脏基因治疗的临床研究具有重要意义。

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.