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Mouse Models for Celiac Disease

乳糜泻小鼠模型

基本信息

批准号：
7229848
负责人：
DETLEF SCHUPPAN
金额：
$ 24.76万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2007-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7229848
关键词：
Acids Adoptive Transfer Affect Animal Model Antibodies Antigens Apoptosis Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Barley Binding CD4 Positive T Lymphocytes Celiac Disease Cells Cellular Immunity Cereals Chemicals Chemosensitization Class Consumption Data Development Diarrhea Diet Disease Disease model Dissection Down-Regulation Endopeptidases Enzymes Epitopes Exposure to Gliadin Glutamine Gluten Goals Histology Homing Human Hyperplasia Immune Immune response Immunoglobulin A Immunoglobulins Inbred NOD Mice Indomethacin Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Intestinal Diseases Intestines Lamina Propria Lead Lesion Link Malabsorption Syndromes Malignant Neoplasms Mediating Modeling Monitor Mononuclear Mus Oral Organ Pathogenesis Pathology Patients Peptide Hydrolases Peptides Play Population Process Proteins Research Personnel Role Rye cereal Screening procedure Serum Speed Symptoms T-Cell Activation T-Cell Lymphoma T-Lymphocyte T-Lymphocyte Subsets Testing Tissues Transglutaminases Ursidae Family Villous Atrophy Villus Wheat base cytokine deamidation improved in vivo inhibitor/antagonist intestinal villi meprin A mouse model programs prolyl oligopeptidase research study response tool

项目摘要

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.

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存蛋白。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，并进行定位和定位。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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gliadin-primed CD4+CD45RBlowCD25- T cells drive gluten-dependent small intestinal damage after adoptive transfer into lymphopenic mice.

DOI：
10.1136/gut.2009.186361
发表时间：
2009-12
期刊：
Gut
影响因子：
24.5
作者：
Freitag TL;Rietdijk S;Junker Y;Popov Y;Bhan AK;Kelly CP;Terhorst C;Schuppan D
通讯作者：
Schuppan D

Turning swords into plowshares: transglutaminase to detoxify gluten.

化剑为犁：转谷氨酰胺酶解麸质。