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）等疾病被认为是由于t细胞对组织特异性自身蛋白的正常耐受状态的破坏。实验性AIG可由t细胞对壁细胞特异性抗原h +/K+- atp酶反应而引发。这种抗原定位于胃壁细胞的识别可以解释AIG中壁细胞的损伤，但它不能解释酶原细胞的损失或粘液细胞和超增殖细胞的增加，这是人和鼠疾病的标志。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，即它是免疫介质的次级非抗原特异性噬菌体，导致AIG特征的显著组织特异性组织病理学变化。该模型使用转基因小鼠，这些小鼠仅在胃的胃壁细胞群的一个亚群中表达人类生长激素（hGH），并且对这种hGH转基因报告基因具有功能耐受性。我们现在证明，这种耐受性可以通过hGH免疫消除，导致抗原特异性T细胞增殖，抗体产生，并改变胃酶原腺的上皮结构。这种胃肠道自身免疫性疾病的新模型非常适合研究t细胞的贡献在多大程度上是由于特异性免疫识别事件而不是非抗原特异性事件。在本课题中，我们提出：1)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；2)明确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。这些研究将产生一个定义良好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症性疾病组织特异性发病机制的细胞和分子事件的更详细的了解。

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.