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，每 150 名美国公民中就有 1 人患有乳糜泻。它是由麸质的消耗，麸质是谷物的储存蛋白。 CD 的治疗是严格的无麸质饮食。筛选- 检测到的乳糜泻大多症状较轻，但可能会突然加重，伴有腹泻和吸收不良，由于不治疗而导致各种自身免疫性疾病甚至恶性肿瘤。所有乳糜泻患者都承受 HLA II 类分子 DQ2（或 DQ8），并具有针对普遍存在的自身抗原组织的血清抗体转谷氨酰胺酶（tTG）。 CD4+ T 辅助细胞 1 细胞介导大部分肠道炎症和 tTG 酶增强麸质诱导的 T 细胞活化。我们的基本假设是 1. 体液和 CD4+ T 细胞 tTG 介导的自身免疫在 cd 的发病机制中起着重要作用，特别是相关的自身免疫性疾病和恶性肿瘤，2. 麸质特异性 CD4+ Thelper 1 细胞亚群有助于 CD小肠绒毛的炎症破坏。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可以剖析导致克罗恩病及其并发症的免疫过程。目标#l 重点关注将 tTG-/- 小鼠中产生的 T 细胞和 tTG 抗体转移至野生型后的器官病理学和T&B细胞缺陷小鼠。将分析致病性 T 细胞的概况和归巢，以及定位和定位剖析自身抗体的作用。 Aim#2 将研究 CD4+ T 细胞和体液免疫反应的后果在用麸质反应性单核细胞和 CD4+ T 亚群进行肠道再填充后针对麸质同基因 T 和 B 细胞缺陷受体中的细胞。口服麸质并进一步接受吲哚美辛挑战和/或细胞因子调节有望产生模仿人类CD的模型。 CD4+ T 细胞归巢分析肠道、CD4+ 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的特征。麸质诱发的肠病模型将被开发为测试非麸质肠病的转化工具。 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. tTG 抑制剂抑制肠道 tTG 活性，3. 下调侵袭性肠道 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。预计结果会有所改善我们对克罗恩病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。