Ocular Immune Regulation by Mesenchymal Stem Cells

间充质干细胞的眼部免疫调节

• 批准号: 10219739
• 负责人: Sunil K Chauhan
• 金额: $ 12.5万
• 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/10219739
• 关键词: ALCAM gene; Antigen-Presenting Cells; Autoimmune Diseases; Award; Binding; CD80 gene; CTLA4 gene; Cell Maturation; Cells; Cornea; Data; Data Reporting; Eye Injuries; FOXP3 gene; Generations; Graft Survival; Growth Factor; Home; Immune; Immunity; Inflammation; Inflammatory; Injury; Interferon Type II; Interleukin-11; Investigation; Keratoplasty; Knowledge; Laboratories; Mechlorethamine; Mesenchymal Stem Cells; Modeling; Molecular; Mustard Gas; Parents; Pathologic; Regulatory T-Lymphocyte; Reporting; Surface; T-Cell Activation; T-Lymphocyte; Therapeutic; Tissue Grafts; Transplantation; Vesicants; Work; adaptive immunity; base; experimental study; human disease; immunoregulation; improved; isoimmunity; mouse model; ocular surface; parent grant; response; therapeutic target; tissue regeneration; tissue repair; transplant model

Summary of Parent R01 Award (EY024602) 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. Principal objective of this project is to define the molecular mechanism by which MSCs interact with T cells to regulate alloimmunity. In this proposed supplement, we plan to apply our understanding of the immunomodulatory and cytoprotective functions of MSCs to promote the survival of ocular cells following nitrogen mustard exposure. In the parent grant, we investigate how MSCs suppress ocular inflammation in a model of adaptive immunity. Here, we will investigate whether MSCs or their secreted immunoregulatory and growth factors provide similar protective functions following vesicant-induced injury.

家长 R01 奖摘要 (EY024602) 以促进组织再生和免疫静止而闻名，研究表明 间充质干细胞在人类疾病中的治疗潜力。然而，基本问题仍未得到解答 关于它们的免疫调节机制。该提案采用了特征良好的移植 小鼠角膜模型系统地研究 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，MSC 抑制 Th1 的确切机制 Tregs 的产生和诱导尚不清楚。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 3 个具体目标来回答以下问题： 目标 1：MSC 的作用机制是什么 抑制同种反应性 Th1 细胞的产生？目标2：MSCs抑制效应子的机制是什么 同种异体反应性Th1细胞的功能？最后目标3：间充质干细胞如何促进耐受性的产生—— 诱导Tregs？我们的初步数据表明特定的可溶性和表面结合的免疫调节 分子。基于这些数据，我们提出3个假设：（1）MSC负向调节早期T细胞 通过表面结合分子 ALCAM 激活，导致 Th1 细胞生成减少； (2) MSC- 分泌的IL11通过拮抗IFNγ和Tbet表达来抑制Th1功能； (3) MSC 扭曲 幼稚 T 细胞通过 CD80/CTLA-4 相互作用向 Foxp3+ Tregs 分化。本次活动的主要目标 该项目的目的是确定 MSC 与 T 细胞相互作用以调节同种免疫的分子机制。 在这个拟议的补充中，我们计划应用我们对免疫调节和免疫调节的理解。 间充质干细胞的细胞保护功能促进氮芥后眼细胞的存活 接触。在母基金中，我们研究了 MSC 如何在模型中抑制眼部炎症 适应性免疫。在这里，我们将研究 MSC 或其分泌的免疫调节和 生长因子在疱疹引起的损伤后提供类似的保护功能。