Ocular Immune Regulation by Mesenchymal Stem Cells

间充质干细胞的眼部免疫调节

基本信息

批准号：
8886060
负责人：
Sunil K Chauhan
金额：
$ 49.25万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8886060
关键词：
Adrenal Cortex Hormones Adverse effects American Anti-Inflammatory Agents Anti-inflammatory Antigens Biological Assay Bone Marrow CCL21 gene CD28 gene CD80 gene CTLA4 gene Cataract Cell Communication Cell physiology Cell surface Cells Chronic Chronic Disease Coculture Techniques Colony-Stimulating Factors Cornea Development Disease Eye Eye Injuries Frequencies Generations Glaucoma Goals Hematopoietic Hepatocyte Growth Factor High Prevalence Immature Granulocyte Immune Immune response Immune system Immunity Immunosuppressive Agents Infection Inflammation Inflammatory Injury Investigation Keratoplasty Laboratories Lead Mediating Mesenchymal Stem Cells Methodology Modeling Mus Myelogenous Myeloid Cells Myeloid Progenitor Cells Natural regeneration Patients Pharmaceutical Preparations Population Proteins Regulation Regulatory T-Lymphocyte Research Risk Series Suppressor-Effector T-Lymphocytes Testing Therapeutic Therapeutic immunosuppression Tissues Transcript Transplantation Tumor Necrosis Factor-alpha Vision adult stem cell base chemokine chemokine receptor cytokine design granulocyte immune activation in vivo macrophage mouse model novel novel therapeutics paracrine pathogen precursor cell public health relevance research study response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Patients suffering from ocular injury and inflammation are at risk for development of chronic uncontrolled immune activation and tissue injury. Many of these conditions are commonly treated with non-specific anti- inflammatory drugs such as corticosteroids, which non-discriminately suppress host immunity, including both pathogenic and regulatory cells of the immune system. There is thus a pressing need for developing more effective and safe immunomodulatory strategies which not only downregulate specific pathogenic immune cells, but importantly also promote regulatory immune cells, namely myeloid-derived suppressor cells (MDSC) and regulatory T cells (Tregs). Interestingly, non-hematopoietic bone marrow-derived mesenchymal stem cells (BM-MSC) have shown significant immunomodulatory promise. Our preliminary studies demonstrate that BM- MSC can indeed promote MDSC and Treg function, and can be used to reestablish immune quiescence in ocular inflammation. However, very little is known regarding the mechanisms by which BM-MSC promote the function of these immunoregulatory cells. We specifically hypothesize that BM-MSC (i) skew differentiation of immature myeloid progenitor cells toward MDSC and away from macrophages; and (ii) provide direct support for Treg function via both cell-to-cell contact and paracrine mechanisms. To validate these hypotheses, we propose to pursue two specific aims: In Aim 1, we will define the mechanisms by which BM-MSC promote generation of myeloid-derived suppressor cells and control ocular inflammation. We will specifically investigate i) which functional subset of MDSC is promoted by BM-MSC; and ii) determine BM-MSC-expressed factors that promote MDSC generation. In Aim 2 we plan to determine the mechanisms by which BM-MSC directly enhance regulatory T cell function. In particular, we will investigate i) how BM-MSC-secreted hepatocyte growth factor promotes Treg function; and ii) the BMMSC cell surface-expressed molecules that promote Treg function through cell-cell interactions. The methodology we propose has been designed to utilize our laboratory's expertise in immunological assays along with a well-characterized murine cornea model of transplant-induced ocular inflammation and immunity. We anticipate that delineation of the mechanisms by which BM-MSC control ocular inflammation will identify critical immunomodulatory factors which can be utilized to develop new therapeutic strategies. The overall impact of this research will be significant, given the high prevalence of ocular inflammatory disorders and the potential benefit of therapeutic strategies that promote immunoregulatory cells while also inhibiting pathogenic immune cells.

描述（由适用提供）：患有眼部损伤和感染的患者有慢性不受控制的免疫激活和组织损伤的风险。这些疾病中的许多通常都用非特异性抗炎药（例如皮质类固醇）进行治疗，皮质类固醇非歧视会抑制宿主的免疫疗法，包括免疫系统的致病性和调节性细胞。因此，迫切需要开发更有效，更安全的免疫调节策略，不仅下调了特定的病原免疫核素，而且重要的是促进了调节性免疫细胞，即髓样衍生的抑制细胞（MDSC）和调节性T细胞（Tregs）。有趣的是，非脊髓骨髓衍生的间充质干细胞（BM-MSC）表现出明显的免疫调节诺言。我们的初步研究表明，BM-MSC确实可以促进MDSC和Treg功能，并且可用于重建眼部炎症中的免疫量。但是，关于BM-MSC促进这些免疫调节细胞功能的机制知之甚少。我们特别假设BM-MSC（i）偏分化未成熟的髓样祖细胞向MDSC偏离了MDSC并远离巨噬细胞。（ii）通过细胞到细胞接触和旁分泌机制提供直接支持Treg功能。验证这些假设，我们建议追求两个具体的目标：在AIM 1中，我们将定义BM-MSC促进髓样衍生的抑制细胞并控制眼感染的机制。我们将专门研究i） MDSC的功能子集由BM-MSC促进； ii）确定促进MDSC生成的BM-MSC表达因素。在AIM 2中，我们计划确定BM-MSC直接增强调节性T细胞功能的机制。特别是，我们将研究i）BM-MSC分泌的肝细胞生长因子如何促进Treg功能； ii）BMMSC细胞表面表达的分子通过细胞 - 细胞相互作用促进Treg功能。我们提出的方法旨在利用实验室在免疫学测定方面的专业知识以及特征良好的移植引起的眼部感染和免疫组织化学的鼠角膜模型。我们预计BM-MSC控制眼感染将确定可用于开发新的治疗策略的关键免疫调节因素的机制的决定。鉴于眼部炎症性疾病的高流行以及促进免疫调节细胞的治疗策略的潜在益处，同时抑制致病性免疫力，因此这项研究的总体影响将是显着的。