Mouse Models for Celiac Disease

乳糜泻(CD)是一种小肠炎性疾病，每150名美国公民中就有一人受到影响。它由以下因素触发 摄入谷蛋白，这是谷类的储存蛋白质。对CD的治疗是严格的无麸质饮食。筛选- 被检测到的乳糜泻患者大多症状轻微，但可能会突然加重，伴有腹泻和吸收不良， 各种自身免疫性疾病，甚至是恶性疾病。所有的乳糜泻患者都有 并具有针对无处不在的自身抗原组织的血清抗体 转谷氨酰胺酶(TTG)。CD4T辅助1细胞介导大部分肠道炎症和tTG酶 增强面筋诱导的T细胞活化。我们的基本假设是：1.体液和CD4T细胞 TTG介导的自身免疫在CD的发病机制中起着重要作用，尤其是与 自身免疫性疾病和恶性肿瘤，2.面筋特异性CD4Th1细胞亚群在 Cd肠绒毛的炎性破坏。我们的目标是研究采用T细胞和 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 重点介绍了将tTG-/-小鼠产生的T细胞和针对tTG的抗体转移到wild型后的器官病理 和T&B细胞缺陷小鼠。将分析致病T细胞的分布和归巢，以及定位和 剖析自身抗体的作用。目的#2将研究CD4T细胞和体液免疫反应的后果 面筋反应性单个核细胞和CD4T亚群在肠道回流后对面筋的影响 同基因T和B细胞缺陷受者的细胞。口服面筋暴露与消炎痛的进一步挑战 和/或细胞因子调节有望产生模仿人类CD的模型。CD4T细胞归巢分析 肠道、CD4T细胞亚群以及预期的炎性和浸润性病变将用于 描述这种疾病的特征。面筋诱导的肠病模型将作为一种翻译工具来测试非面筋蛋白 CD的饮食治疗，如1.外源细菌Pro降解T细胞刺激性醇溶蛋白多肽 内肽酶，2.ttg抑制剂对肠道ttg活性的抑制，3.对侵袭性肠道的下调 T细胞，例如通过免疫调节细胞因子或细胞因子拮抗剂。预计结果将有所改善。 我们对CD和相关自身免疫性疾病的认识和处理。

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.