TRANSGENIC MODELS OF AUTOIMMUNE GASTRITIS

区分自我与非自我（外来）的能力是免疫反应的标志之一。诸如自身免疫性胃炎（AIG）的疾病已被归因于T细胞对组织特异性自身蛋白的耐受性的正常状态的破坏。实验性AIG可以由与壁细胞特异性抗原H +/K+-ATP酶反应的T细胞启动。定位于胃壁细胞的抗原的这种识别可以解释AIG中对壁细胞的损伤，但它不能解释作为人和鼠疾病的标志的酶原细胞的损失或粘液细胞和过度增殖细胞的获得。我们现在已经产生了一种新的实验模型，以测试我们的假设，这是一个次要的非抗原特异性噬菌体的免疫介质，导致显着的组织特异性组织病理学变化的特征AIG。该模型利用转基因小鼠，其仅在胃壁细胞群的一个子集中表达人生长激素（hGH），并且在功能上耐受该hGH转基因报告基因。我们现在证明，这种耐受性可以通过用hGH免疫来消除，从而导致抗原特异性T细胞增殖，抗体产生和胃的酶原腺中上皮结构的改变。这种新型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异性免疫识别事件与非抗原特异性事件。在该授权申请中，我们提出：1）通过利用T细胞介导的抗自身（转基因）免疫应答在转基因小鼠中建立AIG的淋巴细胞转移模型;以及2）定义T细胞在组织特异性胃上皮损伤中的直接或间接作用中至关重要的细胞和分子机制。这些研究将导致自身免疫性胃肠道疾病的明确定义的人工模型，并将导致对人类胃炎性疾病的组织特异性发病机制的细胞和分子事件的更详细的理解。

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.