Ocular Immune Regulation by Mesenchymal Stem Cells

这是一项竞争性更新申请，旨在进一步表征 间充质干细胞（MSC）在眼部炎症中的作用。以促进组织再生和 在免疫静止期，研究已经证明了MSC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然没有答案。 该建议采用了一种良好表征的小鼠角膜移植模型， 研究MSC如何直接与T细胞相互作用以抑制同种异体免疫。 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，但MSC抑制的确切机制仍然存在。 Th 1的产生和诱导T细胞活化尚不清楚。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。 我们定义了3个具体目标来回答以下问题：目标1： 哪种MSC抑制同种异体反应性Th 1细胞的产生？目的2：MSC通过什么机制 抑制同种异体反应性Th 1细胞的效应功能？最后目标3：MSCs如何促进 诱导耐受性的激素我们的初步数据表明， 免疫调节分子。基于这些数据，我们提出3个假设：（1）骨髓间充质干细胞负性 通过表面结合分子ALCAM调节早期T细胞活化，导致产生减少， （2）MSC分泌的IL 11通过拮抗IFNγ和Tbet表达抑制Th 1功能; (3)MSC通过CD 80/CTLA-4相互作用使幼稚T细胞向Foxp 3 + T细胞分化。的 本项目的主要目标是确定MSC直接相互作用的分子机制 来调节同种免疫。鉴于提供基于MSC的细胞的相当大的费用 在治疗中，确定介导MSC免疫调节活性的因素是研究的优先事项。它 预计完成这些全新的目标将阐明迄今未知的机制， 其中MSC调节T细胞反应，并且可以想象地提供了一个框架， 移植和其他T细胞介导的炎症性疾病的新治疗方法。

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.