B cell-T cell crosstalk in celiac disease

乳糜泻中的 B 细胞-T 细胞串扰

基本信息

批准号：
10670373
负责人：
Valerie Abadie
金额：
$ 42.75万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670373
关键词：
Address Adherence Affect Antibodies Antibody Formation Antigen Presentation Antigen-Presenting Cells Antigens Autoantibodies Autoimmune Diseases Automobile Driving B cell therapy B-Cell Activation B-Lymphocytes CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Case Study Celiac Disease Cells Cellular Immunity Chronic Clinical Complex Data Development Disease Enzymes Epithelial Cells Exposure to Functional disorder Gene Expression Profile Genetic Transcription Gluten Gluten-free diet HLA-DQ2 HLA-DQ8 antigen Immune Immune System Diseases Immunoglobulin-Secreting Cells Immunology Impairment Individual Inflammation Inflammatory Inflammatory Bowel Diseases Intervention Intestinal Mucosa Intestines Knowledge Laboratories Lamina Propria Mediating Modeling Monitor Mucous Membrane Mus Pathogenesis Pathway interactions Patients Peptide antibodies Peptides Peyer&apos s Patches Phenotype Plasma Cells Play Population Predisposition Production Proliferating Property Research Proposals Role Severity of illness Small Intestines Small intestine mucous membrane Stress T cell response T memory cell T-Cell Activation T-Lymphocyte Testing Therapeutic Time Tissues Transgenic Mice Villous Atrophy cell mediated immune response cytokine cytotoxic deamidation dietary effective therapy effector T cell immunopathology in vivo innovation insight intestinal epithelium intraepithelial mesenteric lymph node mouse model novel therapeutics oral tolerance persistent symptom prevent programs response stem therapeutic target therapeutically effective tositumomab transcriptome sequencing transglutaminase 2 uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Celiac disease (CeD) is a complex intestinal inflammatory disorder that is triggered by dietary gluten and develops in genetically susceptible individuals expressing HLA-DQ2 or HLA-DQ8 molecules. 1% of the worldwide population is affected by this disease for which the only effective treatment is a lifelong and restrictive gluten-free diet (GFD). Yet, persistent symptoms and enteropathy remain commonplace even among CeD patients that adhere to a GFD. This stresses the need to develop non-dietary interventions for CeD. The development of new therapies has however proven challenging because of our incomplete understanding of the immune mechanisms underlying CeD pathogenesis and the lack of a suitable mouse model. CeD is characterized by the loss of oral tolerance to gluten manifested by HLA-DQ2 or HLA-DQ8- restricted anti-gluten inflammatory CD4 T cells in the small intestinal mucosa and by a massive expansion of cytotoxic intraepithelial CD8+ lymphocytes (IE-CTLs) that are involved in the killing of intestinal epithelial cells. These observations have led to the general idea that CeD is primarily a T cell-mediated immune disorder. We hypothesize, however, that B cells also play a critical role. This hypothesis stems from several observations. First, CeD is characterized by a considerable expansion of plasma cells in the mucosa of CeD patients as well as the development of anti-deamidated gluten peptides (DGP) antibodies and autoantibodies against the enzyme tissue transglutaminase 2 (TG2). Second, the main model to explain the production of anti-DGP and anti-TG2 antibodies is that gluten-specific CD4+ T cells provide help to B cells suggesting that B cells could act as antigen-presenting cells for T cells and promote the amplification of the anti-gluten CD4 T cell response. Finally, several case reports on patients having CeD associated with another autoimmune disease suggest that B cell depletion therapy can provide clinical benefit in CeD, and we have demonstrated that B cell depletion significantly reduces intestinal tissue damage in our mouse model of CeD. The objective of this application is to characterize in vivo the role of B cells in amplifying the anti-gluten T cell response and allow it to reach a sufficient magnitude to promote tissue destruction. This project is innovative as it employs unique mouse models of CeD allowing to manipulate B lymphocytes, gluten-specific T cells, the gluten antigen, and the CeD predisposing HLA molecule to 1) assess the contribution of B cells as antigen-presenting to the activation and amplification of the anti-gluten CD4+ T cell response, and 2) assess the role of B cells and antibodies in the activation of IE-CTLs and tissue destruction. The knowledge gained from this study will provide unprecedented insights into the mechanisms by which B cell-mediated immunity contribute to the pathogenesis of CeD and will assess for the first time the therapeutic potential of B cell depletion therapy in an experimental mouse model of CeD.

项目概要/摘要乳糜泻 (CeD) 是一种复杂的肠道炎症性疾病，由膳食麸质和在表达 HLA-DQ2 或 HLA-DQ8 分子的遗传易感个体中发生。 1%的全世界人口都受到这种疾病的影响，唯一有效的治疗方法是终身治疗限制性无麸质饮食（GFD）。然而，即使是持续的症状和肠病仍然很常见坚持 GFD 的 CeD 患者。这强调需要制定非饮食干预措施行政长官。然而，由于我们的不完整，新疗法的开发被证明具有挑战性。了解 CeD 发病机制的免疫机制以及缺乏合适的小鼠模型。 CeD 的特点是对麸质的口服耐受性丧失，表现为 HLA-DQ2 或 HLA-DQ8- 限制小肠粘膜中的抗麸质炎症 CD4 T 细胞，并通过大量扩增细胞毒性上皮内 CD8+ 淋巴细胞 (IE-CTL) 参与杀伤肠上皮细胞。这些观察结果得出了这样一个普遍观点：CeD 主要是一种 T 细胞介导的免疫疾病。我们然而，假设 B 细胞也发挥着关键作用。这一假设源于多项观察。首先，CeD 的特点是 CeD 患者粘膜中的浆细胞也大量扩增随着抗脱酰胺麸质肽（DGP）抗体和自身抗体的开发组织转谷氨酰胺酶 2 (TG2)。二、主要模型讲解抗DGP的制作及抗 TG2 抗体是麸质特异性 CD4+ T 细胞为 B 细胞提供帮助，表明 B 细胞可以发挥作用作为 T 细胞的抗原呈递细胞，促进抗谷蛋白 CD4 T 细胞反应的放大。最后，一些关于患有与另一种自身免疫性疾病相关的 CeD 的患者的病例报告表明 B 细胞耗竭疗法可以为 CeD 提供临床益处，并且我们已经证明 B 细胞在我们的 CeD 小鼠模型中，消耗显着减少了肠道组织损伤。此举的目的应用是表征体内 B 细胞在放大抗麸质 T 细胞反应中的作用，并使其达到足够的程度以促进组织破坏。该项目具有创新性，因为它采用了独特的 CeD 小鼠模型允许操纵 B 淋巴细胞、麸质特异性 T 细胞、麸质抗原和 CeD 易感 HLA 分子 1) 评估 B 细胞作为抗原呈递对抗谷蛋白 CD4+ T 细胞反应的激活和放大，以及 2) 评估 B 细胞和抗体激活 IE-CTL 和组织破坏。从这项研究中获得的知识将对 B 细胞介导的免疫促进免疫的机制提供了前所未有的见解 CeD 的发病机制，并将首次评估 B 细胞耗竭疗法的治疗潜力 CeD实验小鼠模型。