Ocular Immune Regulation by Mesenchymal Stem Cells

间充质干细胞的眼部免疫调节

• 批准号: 10396435
• 负责人: Sunil K Chauhan
• 金额: $ 47.77万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396435
• 关键词: ALCAM gene; Activated-Leukocyte Cell Adhesion Molecule; Allografting; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; B-Lymphocytes; Binding; Biological Assay; CD80 gene; CTLA4 gene; Cell Maturation; Cell Therapy; Cells; Cornea; Data; Data Reporting; Development; Disease; Endothelial Cells; FOXP3 gene; Frequencies; Generations; Goals; Graft Survival; Graft Tolerance; Helper-Inducer T-Lymphocyte; Home; Immune; Immunity; In Vitro; Inflammation; Inflammatory; Interferon Type II; Interleukin-11; Investigation; Keratoplasty; Knockout Mice; Laboratories; Lymphoid Tissue; Mediating; Mesenchymal Stem Cells; Molecular; Mus; Pathogenicity; Regulatory T-Lymphocyte; Reporter; Reporting; Research; Research Priority; Series; Site; Surface; T cell regulation; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; TNFSF5 gene; Therapeutic; Tissue Donors; Tissue Grafts; Transplant Recipients; Transplantation; Transplantation Tolerance; Work; base; cell injury; design; draining lymph node; enzyme linked immunospot assay; experimental study; graft function; human disease; immunoregulation; improved; isoimmunity; mouse model; novel; novel therapeutic intervention; ocular surface; receptor; reconstitution; response; stem cell differentiation; therapeutic target; tissue regeneration; transplant model; transplantation therapy

This is a competitive renewal application to further characterize the immunoregulatory function of mesenchymal stem cells (MSCs) in ocular inflammation. Renowned for promoting tissue regeneration and immune quiescence, studies have demonstrated the therapeutic potential of MSCs in human disease. Nevertheless, fundamental questions remain unanswered regarding their immunomodulatory mechanisms. This proposal employs a well-characterized transplant model of the murine cornea to systematically investigate how MSCs directly interact with T cells to suppress alloimmunity. Over recent years the work of several laboratories, including our own, has made substantial progress in understanding how MSCs regulate ocular inflammation. With respect to corneal transplantation, we and others have shown that exogenous administration of MSCs suppresses alloimmunity and promotes graft survival. Reports from our lab provide evidence that MSCs: (i) specifically home to the ocular surface following corneal transplantation, where they act to (ii) limit antigen-presenting cell (APC) maturation, and (iii) decrease graft-destroying IFNγ + T helper-1 (Th1) cell responses. Moreover, our preliminary data and reports from other groups indicate that administration of MSCs following transplantation induces Foxp3+ regulatory T cells (Tregs). Despite these observations, the exact mechanisms by which MSCs suppress Th1 generation and induce Tregs are not known. Our preliminary investigations indicate that, in addition to indirect modulation via APCs, MSCs exert a direct immunomodulatory effect on alloreactive T cells. We define 3 specific aims to answer the following questions: Aim 1: What are the mechanisms by which MSCs inhibit generation of alloreactive Th1 cells? Aim 2: What are the mechanisms by which MSCs inhibit effector function of alloreactive Th1 cells? And finally Aim 3: How do MSCs promote the generation of tolerance-inducing Tregs? Our preliminary data implicate specific soluble and surface-bound immunoregulatory molecules. Based on these data, we propose 3 hypotheses: (1) MSCs negatively regulate early T cell activation via the surface-bound molecule ALCAM, resulting in decreased generation of Th1 cells; (2) MSC-secreted IL11 suppresses Th1 function by antagonizing IFNγ and Tbet expression; and (3) MSCs skew the differentiation of naïve T cells toward Foxp3+ Tregs via CD80/CTLA-4 interaction. The principal objective of this project is to define the molecular mechanisms by which MSCs directly interact with T cells to regulate alloimmunity. Given the considerable expense of delivering MSC-based cell therapies, identifying the factors that mediate the immunoregulatory activity of MSCs is a research priority. It is anticipated that completion of these entirely novel aims will elucidate as-yet-unknown mechanisms by which MSCs regulate T cell responses, and may conceivably provide a framework for the development of new therapeutic approaches in transplantation and other T cell-mediated inflammatory disorders.

这是一项竞争性更新应用，旨在进一步表征免疫调节功能 间充质干细胞（MSC）在眼部炎症中的作用。以促进组织再生和 免疫静止，研究证明了间充质干细胞在人类疾病中的治疗潜力。 然而，关于其免疫调节机制的基本问题仍未得到解答。 该提案采用了特征良好的小鼠角膜移植模型来系统地 研究 MSC 如何直接与 T 细胞相互作用以抑制同种免疫。 近年来，包括我们自己在内的多个实验室的工作取得了实质性进展 在理解间充质干细胞如何调节眼部炎症方面取得了进展。在角膜移植方面， 我们和其他人已经证明，外源性施用 MSC 会抑制同种免疫并促进 移植物存活。我们实验室的报告提供证据表明 MSC：(i) 特别驻留在眼表 角膜移植后，它们的作用是 (ii) 限制抗原呈递细胞 (APC) 成熟，以及 (iii) 减少破坏移植物的 IFNγ + T 辅助细胞 1 (Th1) 细胞反应。此外，我们的初步数据和 其他小组的报告表明，移植后给予 MSC 会诱导 Foxp3+ 调节性 T 细胞 (Treg)。尽管有这些观察结果，间充质干细胞抑制的确切机制 Th1 的产生和诱导 Tregs 尚不清楚。我们的初步调查表明，除了 通过 APC 间接调节，MSC 对同种异体反应性 T 细胞发挥直接免疫调节作用。 我们定义了 3 个具体目标来回答以下问题： 目标 1：其机制是什么 哪些 MSC 抑制同种异体反应性 Th1 细胞的产生？目标2：MSCs通过什么机制 抑制同种反应性 Th1 细胞的效应功能？最后目标 3：MSC 如何促进一代 诱导耐受的Tregs？我们的初步数据表明特定的可溶性和表面结合 免疫调节分子。基于这些数据，我们提出 3 个假设：（1）MSCs 负作用 通过表面结合分子 ALCAM 调节早期 T 细胞激活，从而减少 T 细胞生成 Th1细胞； (2) MSC分泌的IL11通过拮抗IFNγ和Tbet表达来抑制Th1功能；和 (3) MSC 通过 CD80/CTLA-4 相互作用使初始 T 细胞向 Foxp3+ Tregs 分化。这 该项目的主要目标是确定间充质干细胞直接相互作用的分子机制 与T细胞一起调节同种免疫。鉴于交付基于 MSC 的细胞的费用相当高 治疗中，确定介导 MSC 免疫调节活性的因素是研究的重点。它 预计这些全新目标的完成将通过以下方式阐明迄今未知的机制： MSCs 调节 T 细胞反应，并且可能为 T 细胞的发展提供框架 移植和其他 T 细胞介导的炎症性疾病的新治疗方法。