Mouse Models for Celiac Disease

乳糜泻（cd）是一种小肠炎症性疾病，影响1的150个美国公民。它是由 谷蛋白是谷物的储藏蛋白。治疗cd是严格的无麸质饮食。筛选- 检测到的乳糜泻大多具有轻微症状，但可能发展为腹泻和吸收不良的突然恶化， 各种自身免疫性疾病或甚至恶性肿瘤作为保持不治疗的结果。所有乳糜泻患者都患有 HLA II类分子DQ 2（或DQ 8），并具有针对普遍存在的自身抗原组织的血清抗体 转氨酶（tTG）。CD 4+辅助性T细胞1介导了大部分肠道炎症和tTG酶 增强谷蛋白诱导的T细胞活化。我们的基本假设是1。体液和CD 4 + T细胞 tTG介导的自身免疫在cd的发病机制中起重要作用，特别是相关的 自身免疫性疾病和恶性肿瘤，2.谷蛋白特异性的CD 4 + Thelper 1细胞亚群有助于 CD肠绒毛的炎性破坏。我们的目标是研究过继性T细胞的小鼠模型， 免疫球蛋白转移允许解剖导致CD及其并发症的免疫过程。目标#l 重点关注在tTG-/-小鼠中产生的tTG的T细胞和抗体转移到野生型后的器官病理学 和T & B细胞缺陷小鼠。将分析病原性T细胞的概况和归巢，并将其定位和归巢。 剖析自身抗体的作用。目标2将研究CD 4 + T细胞和体液免疫应答的后果 谷蛋白反应性单核细胞和CD 4 + T细胞亚群在肠道重建后针对谷蛋白 在同基因T和B细胞缺陷的接受者中。口服暴露于麸质并进一步用吲哚美辛激发 和/或细胞因子调节预期产生模拟人CD的模型。CD 4 + T细胞归巢分析 肠道、CD 4 + T细胞亚群以及预期的炎症和浸润性病变将用于 描述疾病。谷蛋白诱导的肠病模型将被开发为一种翻译工具，以测试非 CD的饮食疗法，例如1.外源细菌脯氨酰降解T细胞刺激性麦醇溶蛋白肽 内肽酶，2.通过tTG抑制剂抑制肠tTG活性，和3.下调侵袭性肠 T细胞，例如通过免疫调节细胞因子或通过细胞因子拮抗剂。预计结果将有所改善 我们对CD和相关自身免疫性疾病的理解和管理。

Celiac disease (cd) is a small intestinal inflammatory disorder that affects 1 out of 150 US citizens. It is triggered by consumption of gluten which is the storage protein of cereals. Treatment of cd is a strictly gluten-free diet. Screening- detected celiacs mostly have mild symptoms, but may develop a sudden exacerbation with diarrhoea and malabsorption, various autoimmune disorders or even malignancy as a consequence of remaining untreated. All celiac patients bear the HLA class II molecules DQ2 (or DQ8) and have serum antibodies directed to the ubiquitous self antigen tissue transglutaminase (tTG). CD4+ T helper 1 cells mediate most of the intestinal inflammation and the enzyme tTG potentiates the gluten-induced T cell activation. Our underlying hypotheses are that 1. the humoral and CD4+ T cell mediated autoimmunity to tTG plays an important role in the pathogenesis of cd, in particular of the associated autoimmune disorders and malignancies, 2. subpopulations ofgluten specific CD4+ Thelper 1 cells are instrumental in the inflammatory destruction of the intestinal villi of cd. Our goal is to study mouse models of adoptive T cell and immunoglobulin transfer that allow dissection of the immune processes that lead to cd and its complications. Aim#l focuses on the organ pathology after transfer of T cells and antibodies to tTG, generated in tTG-/- mice, intowildtype and T & B cell deficient mice. The profile and homing of pathogenic T cells will be analyzed, and the localization and role of autoantibodies dissected. Aim#2 will study the consequences of CD4+ T cells and the humoral immune response directed at gluten after intestinal repopulation with gluten-reactive mononuclear cells and subpopulations of CD4+ T cells in syngeneic T and B cell deficient recipients. Oral exposure to gluten and further challenge with indomethacin and/or cytokine modulation is expected to generate models that mimick human cd. Analysis of CD4+ T cell homingto the intestine, of CD4+ T cell subsets, and of the expected inflammatory and infiltrative lesions will be used to characterize the disease. The model of gluten-induced enteropathy will be developed as a translational tool to test non- dietary therapies for cd, such as 1. degradation of T cell stimulatory gliadin peptides by exogenous bacterial prolyl endopeptidases, 2. inhibition of intestinal tTG activity by tTG-inhibitors, and 3. downregulation of aggressiveintestinal T cells, e.g. by immunomodulatory cytokines or by cytokine antagonists. It is anticipated that the results will improve our understanding and management of cd and related autoimmune diseases.