Ocular Immune Regulation by Mesenchymal Stem Cells

家长R01奖摘要(EY024602) 以促进组织再生和免疫平静而闻名，研究表明 骨髓间充质干细胞在人类疾病中的治疗潜力。然而，根本问题仍然没有得到回答。 关于它们的免疫调节机制。这项提议采用了一种很有特色的移植 建立小鼠角膜模型，系统研究MSCs如何直接与T细胞相互作用抑制 同种异体豁免。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Th1的确切机制 产生和诱导树突状细胞的情况尚不清楚。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3个具体目标以回答以下问题：目标1：MSCs通过什么机制 抑制同种异体反应性Th1细胞的生成？目的2：间充质干细胞抑制效应器的机制是什么 同种异体反应性Th1细胞的功能？最后目标3：MSCs如何促进耐受性的产生- 引诱特雷格？我们的初步数据涉及特定的可溶性和表面结合的免疫调节 分子。基于这些数据，我们提出了3个假说：(1)MSCs对早期T细胞的负性调节 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IL-11通过拮抗干扰素γ和Tbet的表达抑制Th1功能； CD80/CTLA-4相互作用诱导幼稚T细胞向Foxp3+Tregs分化这样做的主要目的 该项目旨在确定MSCs与T细胞相互作用以调节同种异体免疫的分子机制。 在这份拟议的补充材料中，我们计划将我们对免疫调节和 间充质干细胞在氮芥酸诱导眼细胞存活中的细胞保护作用 曝光。在父母资助中，我们研究了骨髓间充质干细胞如何抑制眼部炎症。 适应性免疫。在这里，我们将研究MSCs或其分泌的免疫调节和 生长因子在发泡剂诱导的损伤后也具有类似的保护作用。

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.