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.

母公司R 01奖励总结（EY 024602） 以促进组织再生和免疫静止而闻名，研究表明 MSC在人类疾病中的治疗潜力。尽管如此，一些根本性的问题仍然没有答案 关于他们的免疫调节机制。这项提案采用了一种特征鲜明的移植方法， 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几个实验室的工作取得了重大进展。 了解MSC如何调节眼部炎症的进展。关于角膜移植， 我们和其他人已经表明，外源性施用MSC抑制同种异体免疫，并促进同种异体免疫。 移植物存活率来自我们实验室的报告提供了证据表明，MSC：（i）特异性地归巢于眼表 在角膜移植后，它们起到（ii）限制抗原呈递细胞（APC）成熟的作用，和 (iii)减少移植物破坏性IFNγ +辅助性T细胞-1（Th 1）反应。此外，我们的初步数据和 来自其他组的报告表明，移植后施用MSC诱导Foxp 3 + 调节性T细胞（Tcells）。尽管有这些观察结果，MSC抑制Th 1的确切机制 产生和诱导TdR是未知的。我们的初步调查显示，除了 通过APC的间接调节，MSC对同种异体反应性T细胞发挥直接的免疫调节作用。我们 定义3个具体目标来回答以下问题：目标1：MSC通过什么机制 抑制同种异体反应性Th 1细胞的产生？目的2：MSCs抑制效应细胞增殖的机制是什么？ 同种异体反应性Th 1细胞的功能最后，目标3：MSCs如何促进耐受性的产生- 诱发甲状腺激素？我们的初步数据表明，特异性可溶性和表面结合的免疫调节 分子。基于这些数据，我们提出了3个假设：（1）MSCs负性调节早期T细胞 通过表面结合分子ALCAM激活，导致Th 1细胞生成减少;（2）MSC- 分泌的IL 11通过拮抗IFNγ和Tbet表达抑制Th 1功能;（3）MSC使IFN γ和Tbet的表达发生偏移， 通过CD 80/CTLA-4相互作用，幼稚T细胞向Foxp 3 + T细胞分化。主要目标 该项目旨在确定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，我们计划运用我们的理解免疫调节和 骨髓间充质干细胞的细胞保护功能促进氮芥后眼细胞的存活 exposure.在母基金中，我们研究了MSC如何在一个模型中抑制眼部炎症。 适应性免疫在这里，我们将研究是否MSC或其分泌的免疫调节和免疫调节因子， 生长因子在发泡剂诱导的损伤后提供类似的保护功能。