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.

父母R01奖的摘要（EY024602） 研究重新促进组织再生和免疫静止，研究表明 MSC在人类疾病中的治疗潜力。然而，基本问题仍未得到解决 考虑其免疫调节机制。该提案采用了良好的移植 鼠角膜的模型系统地研究MSC如何直接与T细胞相互作用以抑制 同种免疫。近年来 了解MSC如何调节眼部感染方面的进展。关于角膜移植， 我们和其他人表明，外源性施用MSC抑制了同种免疫力并促进 移植生存。我们实验室的报告提供了MSC的证据：（i）特别是眼表的家 角膜移植后，它们作用于（ii）限制抗原呈递细胞（APC）的成熟和 （iii）减少脱离移植物的IFNγ + T辅助1（Th1）细胞反应。此外，我们的初步数据和 来自其他小组的报告表明，移植后的MSC给予FOXP3+ 调节性T细胞（Tregs）。尽管有这些观察，MSC抑制Th1的确切机制 发电和影响尚​​不清楚。我们的初步调查表明，除了 通过APCS的间接调制，MSC对同种异体T细胞执行直接的免疫调节作用。我们 定义3个特定目的是回答以下问题：目标1：MSC的机制是什么 抑制同种反应性Th1细胞的产生？目标2：MSC抑制效应器的机制是什么 同种异体Th1细胞的功能？最终目标3：MSC如何促进耐受性的产生 - 诱发tregs？我们的初步数据暗示特定的固体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）MSC对早期T细胞负面调节 通过表面结合的分子alcAM激活，导致Th1细胞的产生减少； （2）MSC- 分泌的IL11通过拮抗IFNγ和TBET表达来抑制Th1功能。 （3）MSC偏向 通过CD80/CTLA-4相互作用将幼稚的T细胞分化为Foxp3+ Treg。主要目标 项目是定义MSC与T细胞相互作用以调节同种免疫性的分子机制。 在此拟议的补充中，我们计划应用我们对免疫调节的理解和 MSC的细胞保护功能，以促进氮芥末后眼细胞的存活 接触。在父母赠款中，我们研究了MSC在模型中如何抑制眼注射 适应性免疫学。在这里，我们将调查MSC或其分泌的免疫调节和 生长因子在囊泡诱导的损伤后提供相似的保护功能。