Role of MAIT cells in a mouse model of spontaneous colitis

MAIT细胞在自发性结肠炎小鼠模型中的作用

• 批准号: 10300940
• 负责人: Laurent Gapin
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-22 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300940
• 关键词: Adaptive Immune System; Adult; Affect; Age; Americas; Bacteria; Blood; CRISPR/Cas technology; Cell Count; Cell physiology; Cells; Chronic; Colitis; Colon; Complex; Cues; Development; Disease; Disease Progression; Environment; Flow Cytometry; Gene Deletion; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Germ-Free; Gnotobiotic; Health; Healthcare Systems; Histology; Human; Immune; Immune response; Immune system; Immunotherapy; Inbred Strains Mice; Inbreeding; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-17; Intestines; Lamina Propria; Lead; Leukocytes; Link; Lymphocyte Count; Major Histocompatibility Complex; Modeling; Morbidity - disease rate; Mouse Strains; Mucous Membrane; Mus; Natural Immunity; Onset of illness; Organ; Other Genetics; PTPRC gene; Pathologic; Patients; Peripheral; Phenotype; Population; Population Dynamics; Predisposition; Proteins; Recombinants; Reporting; Role; T-Cell Development; T-Cell Receptor; T-Lymphocyte; TNF gene; Testing; Therapeutic Uses; Time; Tissues; United States; Vitamins; adaptive immunity; commensal microbes; cytokine; design; human disease; improved; inflammatory milieu; insight; microbiota; mouse model; novel; novel therapeutic intervention; novel therapeutics; single-cell RNA sequencing; therapeutic target; tool

Project Summary. Inflammatory bowel diseases (IBD) are chronic and cause significant morbidity. An estimated 3 million adults in the USA currently live with IBD and no cure is available. It is clear that the disease is complex with influences from host genetics, microbiota and the immune system. Therefore, further understanding of the interplay between these factors is crucial to developing novel immunotherapies. Previous mouse models of IBD are limited for studying human disease, entailing the artificial induction of IBD in susceptible mice. Newer models of spontaneous colitis are necessary to dissect the roles of novel immune players and their ability to modulate disease and serve as therapeutic targets. Mucosal-associated invariant T (MAIT) cells are a novel class of innate-like T lymphocytes, highly abundant in human blood and in mucosal tissues, including the gut. They are potently activated by bacterial-derived metabolites presented by the evolutionary conserved major histocompatibility complex class I-related molecule, MR1. To date, they have been implicated in a range of inflammatory diseases. However, their role in IBD and the possible correlations between their involvement and the course of the disease remains uncertain. Patients with IBD demonstrate significant infiltration of MAIT cells into inflamed gut tissue and display an inflammatory profile. We have identified a new inbred mouse strain with high numbers of MAIT cells in primary immune organs and peripheral tissues, including the colon, compared to other mouse strains analyzed to date. These mice spontaneously develops pathologic features of colitis that emulate the human disease. We propose to test the hypothesis that increased MAIT cell numbers in these mice affects their susceptibility to colitis. The objectives of this project are to establish the interplay of how MAIT cells, microbiota and genetics lead to the development of spontaneous colitis. In Aim1, we will assess the dynamics of MAIT cell accumulation, activation and gene expression profile of the gut leukocytes of this new mouse strain as a function of age. In Aim 2, we will examine the contributions that MAIT cells and/or the microbiota both have towards the development of colitis in this new mouse strain. These studies will open up new possibilities for understanding the potential role of MAIT cells in colitis so that it can be exploited for therapeutic usage to improve human health.

项目摘要。炎症性肠病(IBD)是一种慢性疾病，发病率很高。一个 据估计，美国目前有300万成年人患有IBD，目前还没有治愈方法。很明显，这种疾病 是复杂的，受宿主遗传学、微生物区系和免疫系统的影响。因此，进一步 了解这些因素之间的相互作用对于开发新的免疫疗法至关重要。上一首 对于研究人类疾病，IBD的小鼠模型是有限的，需要人工诱导在 易受感染的小鼠。需要更新的自发性结肠炎模型来剖析新免疫的作用 球员及其调节疾病和作为治疗目标的能力。粘膜相关不变量T (MAIT)细胞是一类新的先天类T淋巴细胞，在人类血液和粘膜中高度丰富 组织，包括肠道。它们被细菌衍生的代谢产物有效地激活，这些代谢产物由 进化保守的主要组织相容性复合体I类相关分子，MR1。到目前为止，他们已经 与一系列炎症性疾病有关。然而，它们在IBD中的作用及其可能的相关性 他们的参与和疾病的进程之间的关系仍然不确定。IBD患者表现出 大量MAIT细胞渗入发炎的肠道组织，呈炎症状态。我们有 鉴定出一种新的近交系小鼠，其初级免疫器官和外周血中有大量的MAIT细胞 组织，包括结肠，与迄今为止分析的其他小鼠品系进行比较。这些小鼠自发地 发展出类似人类疾病的结肠炎的病理特征。我们建议检验这个假设 这些小鼠体内MAIT细胞数量的增加会影响它们对结肠炎的易感性。这个项目的目标是 是建立MAIT细胞、微生物区系和遗传学如何导致 自发性结肠炎。在Aim1中，我们将评估MAIT细胞积累、激活和基因的动态 这种新品系小鼠肠道白细胞的表达谱随年龄的变化而变化。在目标2中，我们将 检查MAIT细胞和/或微生物区系在结肠炎发展中的作用 这种新的老鼠品系。这些研究将为理解MAIT的潜在作用开辟新的可能性 结肠炎中的细胞，以便它可以被开发用于治疗用途，以改善人类健康。