TRANSGENIC MODELS OF AUTOIMMUNE GASTRITIS

区分自我和非我(异类)的能力是免疫反应的标志之一。自身免疫性胃炎(AIG)等疾病被归因于T细胞对组织特异性自身蛋白的正常耐受状态的崩溃。实验性AIG可由壁细胞特异性抗原-H/K-ATPase反应的T细胞启动。这种定位于胃壁细胞的抗原识别可以解释AIG对壁细胞的损害，但不能解释人类和小鼠疾病的标志--酶原细胞的丧失或粘液细胞和过度增殖细胞的增加。我们现在已经建立了一个新的AIG实验模型来验证我们的假设，即它是一个次级的非抗原特异性免疫介质噬菌体，导致了AIG显著的组织特异性组织病理学变化。该模型利用转基因小鼠，这些转基因小鼠仅在胃的胃壁细胞亚群中表达人生长激素(HGH)，并且对这种hGH转基因报告具有功能耐受性。我们现在证明，这种耐受性可以通过hGH免疫来消除，导致抗原特异性T细胞增殖、抗体产生和胃产酶腺体上皮结构改变。这种新的胃肠道自身免疫性疾病模型非常适合于研究T细胞的贡献在多大程度上是由于特定的免疫识别事件而不是非抗原特异性事件。在这项赠款申请中，我们建议：1)利用T细胞介导的抗自身(转基因)免疫反应，在转基因小鼠中建立AIG的淋巴细胞转移模型；2)确定T细胞在组织特异性胃上皮损伤中直接或间接作用的关键细胞和分子机制。这些研究将导致一个明确的自身免疫性胃肠道疾病的人工模型，并将导致对人类胃炎性疾病组织特异性发病机制下的细胞和分子事件有更详细的了解。

The ability to discriminate self from non-self (foreign) is one of the hallmarks of the immune response. Diseases such as autoimmune gastritis (AIG) have been attributed to a breakdown of the normal state of T-cell tolerance to tissue-specific self proteins. Experimental AIG can be initiated by T-cells reactive to the parietal cell-specific antigen-H+/K+-ATPase. This recognition of antigens localized to the gastric parietal cell can explain the damage to the parietal cells in AIG, but it does not provide any explanation for the loss of zymogenic cells or the gain of mucous cells and hyperproliferative cells which are a hallmark of both human and murine disease. We have now generated a novel experimental model of AIG to test our hypothesis that it is a secondary non-antigen specific phage of immune mediators which leads to the striking tissue-specific histopathologic changes that characterize AIG. This model utilizes transgenic mice which express human growth hormone (hGH) exclusively in a subset of the gastric parietal cell population of the stomach and are functionally tolerant to this hGH transgenic reporter. We now demonstrate that this tolerance can be ablated by immunization with hGH, resulting in antigen-specific T cell proliferation, antibody production, and altered epithelial architecture in the zymogenic glands of the stomach. This novel model of gastrointestinal autoimmune disease is ideally suited to investigate to what extent the contribution of T-cells is due to specific immune recognition events versus non antigen-specific events. In this grant application, we propose to: 1) establish a lymphocyte transfer model of AIG in a transgenic mouse by utilizing a T-cell mediated anti-self (transgene) immune response; and 2) define the cellular and molecular mechanisms critical in the direct or indirect effects of T-cells in tissue- specific gastric epithelial damage. These studies should result in a well- defined artificial model of autoimmune gastrointestinal disease, and will lead to a more detailed understanding of the cellular and molecular events underlying the tissue-specific pathogenesis of human gastric inflammatory disease.