Role of Rip2 in the Generation of Pathogenic Th17/Th1 T-cells and Ileitis

Rip2 在致病性 Th17/Th1 T 细胞生成和回肠炎中的作用

• 批准号: 10312819
• 负责人: Timothy Robert Crother
• 金额: $ 25.05万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-07 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312819
• 关键词: Address; Affect; Animal Model; CCR9 gene; Cell Differentiation process; Cells; Cellular biology; Clinical Research; Colitis; Colonic inflammation; Crohn' s disease; Data; Development; Disease; Exposure to; Future; Generations; Helper-Inducer T-Lymphocyte; Heterogeneity; Ileitis; Immune; Immune response; Immunology; Impairment; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interferon Type II; Interleukin-1 beta; Interleukin-17; Interleukin-6; Intervention; Intestinal Mucosa; Intestines; Knowledge; Lead; Maintenance; Mediating; Modeling; Molecular; Mucous Membrane; Mutation; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmacology; Play; Population; Public Health; Receptor-Interacting Serine/Threonine Protein Kinase 2; Regulation; Role; Signal Transduction; Surface; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Tertiary Protein Structure; Testing; Th1 Cells; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Transforming Growth Factor beta; Ulcerative Colitis; cell motility; chemokine receptor; chronic inflammatory disease; clinically relevant; commensal bacteria; cytokine; effector T cell; ileum; improved; in vivo; innate immune pathways; innovation; insight; interleukin-23; migration; mouse Ripk2 protein; neoplastic; novel; novel therapeutics; response

Crohn’s disease (CD), a form of idiopathic inflammatory bowel diseases (IBD), results from uncontrolled T-helper (Th) cell responses to intestinal commensal bacteria in genetically susceptible hosts. While the pathogenic role of Th17 cells in CD patients is controversial, many studies have shown an increase in Th17 cells in intestinal mucosa of CD. Blocking IL-17A, a signature cytokine of Th17 cells, was not effective in clinical studies. This may be due to functional heterogeneity and dynamic plasticity of Th17 cells, especially as it is now understood that some Th17 cells are required for homeostatic maintenance at mucosal surfaces, while others are extremely proinflammatory and pathogenic. However, the mechanism regulating the complexity of Th17 cells in intestinal mucosa is unknown. Our objective in this application is to determine the mechanisms regulating the inflammatory capacity of intestinal Th17 cells in patients with CD. In a recent study we found that receptor-interacting protein 2 (Rip2) deficient T cells preferentially differentiated towards Th17 when exposed to pathogenic conditions (IL- 1β, IL-23, IL-6). Additionally, in a preliminary study using the TNBS model of colitis, Rip2-/- mice developed a severe ileitis with an increased accumulation of Th17 T-cells in the ileum. Many of these Th17 cells were also expressing IFN-γ. These IL-17A+ IFN-γ+ (Th17/Th1) cells express CCR9, a chemokine receptor that allows them to migrate to the ileal mucosa. In in vitro studies we observed that RIP2 deficient T-cells preferentially develop into these highly pathogenic Th17/Th1. These findings are clinically relevant as mutations of Rip2 have been associated with CD. We have also found that the Rip2 CARD domain can inhibit pathogenic Th17 differentiation and in preliminary studies, induce conventional Th17 development, thus potentially offering the possibility as a therapeutic intervention. Therefore, we wish to address the hypothesize that impaired Rip2 signaling in T cells causes ileal inflammation by promoting the formation and infiltration of Th17/Th1 double positive inflammatory T-cells. Our innovative approaches using robust animal models and in vitro generation of Th cells that are responsive to intestinal commensal bacteria will allow us to fill the current knowledge gap between Th17 cell biology and the pathogenesis of CD in the context of host response to intestinal commensal bacteria. We have also found in preliminary studies that the Rip2 CARD domain can inhibit pathogenic Th17 differentiation and may offer the possibility as therapeutic intervention. Our hypothesis will be addressed via the following Specific Aims: 1) Determine the function of T cell intrinsic Rip2 in the generation and infiltration of pathogenic Th17/Th1 cells that cause ileal inflammation. 2) Determine the therapeutic potential of the Rip2 CARD Domain in ileal inflammation. Understanding the mechanisms regulating intestinal Th17 inflammation may lead to novel pharmacological interventions and innovative approaches in the management of CD patients with ileal involvement.

克罗恩病（CD）是一种特发性炎症性肠病（IBD），由不受控制的T辅助细胞（Th） (Th)在遗传易感宿主中对肠道寄生菌的细胞反应。虽然致病作用 Th 17细胞在CD患者中的表达是有争议的，许多研究表明， CD粘膜阻断IL-17 A（Th 17细胞的标志性细胞因子）在临床研究中无效。这可能 这可能是由于Th 17细胞的功能异质性和动态可塑性，特别是现在已经理解， 一些Th 17细胞是维持粘膜表面稳态所必需的，而另一些则是非常重要的。 促炎性和致病性。然而，调节肠道Th 17细胞复杂性的机制， 粘膜未知。我们在本申请中的目的是确定调节炎性细胞因子的机制。 CD患者肠道Th 17细胞的能力。在最近的一项研究中，我们发现受体相互作用蛋白 2（Rip 2）缺陷型T细胞在暴露于致病性条件时优先向Th 17分化（IL-2）。 1β、IL-23、IL-6）。此外，在一项使用TNBS结肠炎模型的初步研究中，Rip 2-/-小鼠产生了一种新的结肠炎模型。 严重回肠炎伴回肠中Th 17 T细胞积累增加。这些Th 17细胞中的许多也是 表达IFN-γ。这些IL-17 A + IFN-γ+（Th 17/Th 1）细胞表达CCR 9，CCR 9是一种趋化因子受体， 迁移到回肠粘膜。在体外研究中，我们观察到RIP 2缺陷型T细胞优先发育为 转化为高致病性的Th 17/Th 1。这些发现具有临床相关性，因为Rip 2的突变已被发现。 与CD有关我们还发现Rip 2 CARD结构域可以抑制致病性Th 17分化 并在初步研究中，诱导常规Th 17的发展，从而潜在地提供了作为 治疗干预因此，我们希望解决以下假设：T细胞中受损的Rip 2信号传导 细胞通过促进Th 17/Th 1双阳性细胞的形成和浸润引起回肠炎症 炎性T细胞我们的创新方法使用强大的动物模型和体外产生Th细胞 这些对肠道细菌有反应的细胞将使我们能够填补目前Th 17 细胞生物学和CD的发病机制在宿主对肠道寄生菌的反应的背景下。我们 在初步研究中还发现Rip 2 CARD结构域可以抑制致病性Th 17分化 并可能提供作为治疗干预的可能性。我们的假设将通过以下方式来解决 具体目的：1）确定T细胞内在Rip 2在致病性T细胞增殖和浸润中的作用。 Th 17/Th 1细胞引起回肠炎症。2)确定Rip 2 CARD结构域的治疗潜力 回肠炎症了解调节肠道Th 17炎症的机制可能会导致新的 药物干预和创新方法在治疗CD患者回肠 参与。