Regulatory role of CD90+ stromal cells in Th1/Th17 activity in Crohn's Disease

CD90 基质细胞对克罗恩病 Th1/Th17 活性的调节作用

• 批准号: 9079462
• 负责人: Iryna V Pinchuk
• 金额: $ 34.51万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9079462
• 关键词: Acute; Address; Adult; Animal Model; Antigen-Presenting Cells; Apoptosis; Bone Marrow; CD4 Positive T Lymphocytes; Cell Proliferation; Cell physiology; Cells; Chronic; Coculture Techniques; Colitis; Crohn' s disease; Data; Development; Disease; Disease model; Epigenetic Process; Equilibrium; Fibroblasts; Gene Expression; Generations; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Immune; Immune response; Immunosuppressive Agents; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Intestines; Knockout Mice; Knowledge; Laboratories; Lamina Propria; Lead; Ligands; Mediating; Mesenchymal Stem Cells; MicroRNAs; Mission; Modeling; Modification; Mucositis; Mus; Myofibroblast; Natural Immunity; Onset of illness; PDCD1LG1 gene; Pathologic Processes; Pathway interactions; Peripheral; Phenotype; Play; Process; Property; Public Health; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Research Priority; Role; Sampling; Signal Transduction; Signaling Molecule; Stromal Cells; T-Lymphocyte; TLR4 gene; Testing; Tissues; Toll-like receptors; Up-Regulation; adaptive immunity; base; cell type; combat; cytokine; early onset; economic impact; effective therapy; immunoregulation; in vivo; innovation; insight; microbial; mouse model; new therapeutic target; novel; novel therapeutics; prevent; receptor; response; restoration; signal processing; socioeconomics

DESCRIPTION (provided by applicant): The immunopathogenesis of Crohn's Disease (CD) is characterized by defective immunoregulation of innate and adaptive immune responses toward intestinal microflora, leading to uncontrolled inflammatory T helper cell (Th)1 and Th17 responses via a yet unknown mechanism. Although the proinflammatory activation of professional antigen presenting cells (APCs) thorough MyD88-dependent toll like receptors (TLRs) has been proposed as the mechanism, abrogation of pathogenic responses of professional APCs leads only to a strong improvement, but not full restoration, of the intestinal balance in animal models of CD. This incomplete response raises the question: what role do non-professional APCs such as CD90+ stromal cells, an abundant cell type in the gut lamina propria, plays in these processes? Our objective is to identify how TLR-dependent and independent signaling processes in human intestinal colonic mucosal CD90+ stromal cells (myofibroblasts/fibroblasts, CMFs) are involved in the regulation of Th1/Th17 intestinal balance, and determine how these processes are disrupted in CD. Our central hypothesis is that a switch in the CD90+ (myo)fibroblast function from immunosuppressive (IL-6lowPD-L1+) toward inflammatory (IL-6highPD-L1low) is a key process in the persistence of the Th1/Th17 responses in CD. The rationale for this hypothesis is that normal (N-) CD90+ CMFs suppress undesirable Th1 type acute inflammation mediated via PD-L1 (Programmed cell death 1 ligand 1) and stimulate the generation of CD4+ regulatory T cells. In contrast, our data suggest that CD-CMFs display a fundamentally altered phenotype: they have low expression of Th1 suppressive molecule PD-L1, reduced ability to generate CD4+ regulatory T cells and upregulated basal and TLR inducible IL-6 secretion, aTh17 promoting cytokine. Our initial in vivo data with use of fibroblast-specific MyD88 conditional knockout mice also support the importance of CMFs in the regulation of the Th1/Th17 responses. We will test our hypothesis by addressing the following specific aims: (1) Define role of the proinflammatory activation of human CD-CMFs in the regulation of Th1/Th17 responses; (2) Elucidate mechanism(s) responsible for the inflammatory (PD- L1lowIL-6high) activation of CD-CMFs; (3) Determine the pathophysiological role CMF inflammatory activation to the development of CD murine colitis. This project is highly significant to the integrative global research priorities in IBD: it will elucidate previously unexplored interactions between innate and adaptive immune components contributing to the initiation and progression of CD. We expect to provide key mechanistic insights into the role of CMFs in regulation of the Th1/Th17 responses during CD immunopathogenesis. As a translational project, we expect to identify new therapeutic targets for effective treatments of CD.

描述（由申请人提供）：克罗恩病（CD）的免疫发病机制的特征在于对肠道微生物菌群的先天性和适应性免疫应答的免疫调节缺陷，通过一种未知的机制导致不受控制的炎性T辅助细胞（Th）1和Th 17应答。尽管已经提出通过MyD 88依赖性Toll样受体（TLR）的专职抗原呈递细胞（APC）的促炎性活化为机制，但是专职APC的致病性应答的消除仅导致CD动物模型中肠道平衡的强烈改善，而不是完全恢复。这种不完全的反应提出了一个问题：非专业的APC，如CD 90+基质细胞，在肠道固有层中丰富的细胞类型，在这些过程中发挥什么作用？我们的目标是确定如何TLR依赖性和独立的信号转导过程中的人肠结肠粘膜CD 90+基质细胞（肌成纤维细胞/成纤维细胞，CMFs）参与调节Th 1/Th 17肠道平衡，并确定这些过程是如何在CD中断。我们的中心假设是，CD 90+（肌）成纤维细胞功能从免疫抑制（IL-6低PD-L1+）向炎症（IL-6高PD-L1低）的转变是CD中Th 1/Th 17应答持续存在的关键过程。该假设的基本原理是正常（N-）CD 90 + CMF抑制通过PD-L1（程序性细胞死亡1配体1）介导的不良Th 1型急性炎症，并刺激CD 4+调节性T细胞的产生。相反，我们的数据表明，CD-CMFs显示出根本改变的表型：它们具有Th 1抑制分子PD-L1的低表达，产生CD 4+调节性T细胞的能力降低，并且上调基础和TLR诱导的IL-6分泌，aTh 17促进细胞因子。我们使用成纤维细胞特异性MyD 88条件性敲除小鼠的初步体内数据也支持CMF在调节Th 1/Th 17应答中的重要性。我们将通过解决以下具体目标来验证我们的假设：（1）确定人CD-CMF的促炎性激活在调节Th 1/Th 17应答中的作用;（2）阐明CD-CMF的炎性（PD-L1低IL-6高）激活的机制;（3）确定CMF炎性激活对CD小鼠结肠炎发展的病理生理作用。这个项目意义重大 IBD的综合性全球研究优先事项：它将阐明先天性和适应性免疫成分之间的相互作用，有助于CD的启动和进展。我们希望提供关键的机制的见解CMFs的作用，在CD免疫发病机制的调节Th 1/Th 17反应。作为一个转化项目，我们希望确定新的治疗靶点，以有效治疗CD。