Ocular Immune Regulation by Mesenchymal Stem Cells

这是一个竞争性的更新申请，以进一步表征免疫调节功能 间充质干细胞(MSCs)与眼部炎症以促进组织再生和 免疫静止期，研究证实了间充质干细胞在人类疾病中的治疗潜力。 然而，关于它们的免疫调节机制，基本的问题仍然没有得到回答。 这项提案使用了一种具有良好特性的小鼠角膜移植模型，以系统地 研究MSCs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。 骨髓间充质干细胞调控眼部炎症的研究进展。关于角膜移植， 我们和其他人已经证明，外源性给予MSCs抑制同种异体免疫并促进 移植物存活率。我们实验室的报告提供的证据表明：(I)特别是在眼表 角膜移植后，它们的作用是(Ii)限制抗原提呈细胞(APC)的成熟，以及 (Iii)减少破坏移植物的干扰素γ+T辅助细胞-1(Th1)细胞反应。此外，我们的初步数据和 来自其他组织的报告表明，移植后给予MSCs可诱导Foxp3+ 调节性T细胞(Treg)。尽管有这些观察，间充质干细胞抑制的确切机制 Th1代和诱导Tregs尚不清楚。我们的初步调查表明，除了 通过APC的间接调节，MSCs对同种异体反应性T细胞具有直接的免疫调节作用。 我们定义了三个具体的目标来回答以下问题：目标1：通过什么机制 哪些MSCs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 抑制同种异体反应性Th1细胞的效应功能？最终目标3：MSCs如何促进新一代 关于诱导耐受性的树吗？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，我们提出了3个假设：(1)骨髓间充质干细胞为负性 通过表面结合分子alcam调节早期T细胞激活，导致减少产生 (2)骨髓间充质干细胞分泌的IL-11通过拮抗干扰素γ和Tbet的表达而抑制Th1细胞的功能； (3)MSCs通过CD80/CTLA-4相互作用使原始T细胞向Foxp3+Tregs分化。这个 该项目的主要目标是确定MSCs直接相互作用的分子机制。 用T细胞来调节同种异体免疫。考虑到交付基于MSC的小区的可观成本 在治疗方面，确定介导MSCs免疫调节活性的因素是一项优先研究任务。它 预计完成这些全新的目标将阐明目前尚不清楚的机制 其中MSCs调节T细胞反应，可以想象的是提供了一个框架，以发展 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.