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.

克罗恩氏病（CD）是一种特发性炎症性肠病（IBD），是由不受控制的T-Helper产生的 （Th）对易感宿主的细胞对肠道传感器细菌的反应。而致病作用 CD患者的Th17细胞中有争议，许多研究表明肠道中的Th17细胞增加 CD的粘膜。阻断Th17细胞的签名细胞因子IL-17A在临床研究中无效。这可能 由于功能异质性和Th17细胞的动态可塑性，尤其是因为现在知道 一些Th17细胞在粘膜表面上维持稳态需要，而另一些则非常 促炎和致病性。但是，调节肠中Th17细胞复杂性的机制 粘膜是未知的。我们在此应用中的目标是确定调节炎症的机制 CD患者肠道Th17细胞的能力。在最近的一项研究中，我们发现接收器相互作用蛋白 当暴露于致病条件时，2（rip2）优选为TH17区分开的T细胞（IL-） 1β，IL-23，IL-6）。此外，在使用结肠炎TNBS模型的初步研究中，RIP2 - / - 小鼠发展了 严重的回肠炎随着回肠中Th17 T细胞的积累增加。这些Th17细胞中的许多也是 表达IFN-γ。这些IL-17A+ IFN-γ+（Th17/Th1）细胞表达CCR9，这是一种趋化因子受体，可以使它们 迁移到回肠粘膜。在体外研究中，我们观察到RIP2缺乏T细胞优先发展 进入这些高度致病的TH17/TH1。这些发现在临床上是相关的，因为RIP2的突变已经 与CD相关。我们还发现RIP2卡域可以抑制致病性TH17分化 在初步研究中，诱导常规TH17发展，因此有可能作为一种 治疗干预。因此，我们希望解决t中RIP2信号受损的假设 细胞通过促进Th17/Th1双阳性的形成和浸润引起回肠炎症 炎症T细胞。我们使用强大动物模型和体外生成TH细胞的创新方法 对肠道的反应敏感的，这将使我们能够填补TH17之间的当前知识差距 细胞生物学和CD的发病机理在宿主对肠道传感器细菌的反应中。我们 在初步研究中还发现，RIP2卡结构域可以抑制致病性TH17分化 并可能提供治疗干预的可能性。我们的假设将通过以下来解决 具体目的：1）确定T细胞固有的RIP2在致病性生成和浸润中的功能 引起回肠炎症的Th17/Th1细胞。 2）确定RIP2卡域的治疗潜力 在回肠炎症中。了解调查肠道Th17注射的机制可能导致新颖 CD患者管理中的药理干预措施和创新方法 参与。