IL-23/Th17 pathways and Inflammatory Bowel Disease

IL-23/Th17 通路与炎症性肠病

• 批准号: 8535918
• 负责人: CLARA ABRAHAM
• 金额: $ 41.52万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-11 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535918
• 关键词: Address; Affect; Amino Acids; Ankylosing spondylitis; Antigen-Presenting Cells; Attenuated; CCR6 gene; CD8B1 gene; Cell Communication; Cell Differentiation process; Cells; Crohn' s disease; Cytoplasmic Tail; Dendritic Cells; Dinoprostone; Disease; Disease susceptibility; Figs - dietary; Genetic Polymorphism; Homeostasis; Human; Immune response; Immunoprecipitation; Individual; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-17; Intestines; Laboratories; Lead; Ligands; Maintenance; Mediating; Modeling; Mus; Outcome; Pathway interactions; Patients; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Play; Population; Psoriasis; Risk; Role; STAT3 gene; Secondary to; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; T-Lymphocyte; Testing; Toll-like receptors; Ulcerative Colitis; chemokine receptor; genetic association; genome wide association study; in vivo; interleukin-22; interleukin-23; monocyte; mouse model; response

DESCRIPTION (provided by applicant): The critical role of the IL-23/Th17 pathway in mediating the intestinal inflammation observed in inflammatory bowel disease (IBD) has been demonstrated through expression studies in patients with IBD, experimental mouse models of IBD and genetic association studies. A number of independent polymorphisms in IL23R have been identified to confer both risk and protection from developing ulcerative colitis and Crohn's disease, as well as other inflammatory disorders such as ankylosing spondylitis and psoriasis. The most significant of these genetic associations is the R381Q single nucleotide polymorphism (SNP) which results in an amino acid change in the proximal IL23R cytoplasmic tail. This polymorphism leads to a 2-3-fold decreased risk of developing IBD, such that it is enriched in healthy individuals. Studies in our laboratory have identified functional consequences of the R381Q IL23R SNP in both human CD4+ and CD8+ T cells; R381Q IL23R individuals have decreased circulating IL-17- and IL-22- producing CD4+ and CD8+ T cells ex vivo and decreased STAT3 activation to IL-23 stimulation. We hypothesize that this is due to a combination of decreased Th17 and Tc17 cell differentiation and expansion secondary to decreased signaling through R381Q IL23R. This proposal will utilize combined approaches with cells transfected with IL23R polymorphisms and ex vivo cells from individuals with IL23R polymorphisms to define changes in T cell expansion and differentiation, identify altered T cell signaling pathways and determine the compound effects of antigen presenting cell:T cell interactions that ultimately contribute to the decrease in circulating Th17 and Tc17 cells. Addressing these responses in primary human cells is critical to understanding the complexity of the IL-23/Th17 pathway in human immune responses.

描述（由申请人提供）：IL-23/Th17 通路在介导炎症性肠病 (IBD) 中观察到的肠道炎症中的关键作用已通过 IBD 患者、IBD 实验小鼠模型和遗传关联的表达研究得到证实研究。 IL23R 中的许多独立多态性已被确定可赋予患溃疡性结肠炎和克罗恩病以及其他炎症性疾病（如强直性脊柱炎和牛皮癣）的风险和保护作用。这些遗传关联中最重要的是 R381Q 单核苷酸多态性 (SNP)，它导致近端 IL23R 胞质尾部的氨基酸变化。这种多态性导致患 IBD 的风险降低 2-3 倍，因此它在健康个体中丰富。我们实验室的研究已经确定了 R381Q IL23R SNP 在人类 CD4+ 和 CD8+ T 细胞中的功能后果； R381Q IL23R 个体体外循环中产生 IL-17 和 IL-22 的 CD4+ 和 CD8+ T 细胞减少，并减少 STAT3 对 IL-23 刺激的激活。我们假设这是由于 R381Q IL23R 信号传导减少继发的 Th17 和 Tc17 细胞分化和扩增减少所致。该提案将利用转染 IL23R 多态性的细胞和来自具有 IL23R 多态性的个体的离体细胞的组合方法来定义 T 细胞扩增和分化的变化，识别改变的 T 细胞信号传导途径并确定抗原呈递细胞：T 细胞相互作用的复合效应最终导致循环 Th17 和 Tc17 细胞减少。解决原代人类细胞中的这些反应对于了解人类免疫反应中 IL-23/Th17 途径的复杂性至关重要。