Ocular Immune Regulation by Mesenchymal Stem Cells

间充质干细胞的眼部免疫调节

• 批准号: 9248361
• 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
• 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/9248361
• 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 secretion; Cell surface; Cells; Chronic; Chronic Disease; Coculture Techniques; Colony-Stimulating Factors; Cornea; Development; Disease; Eye; Eye Injuries; FOXP3 gene; Frequencies; Generations; Glaucoma; Goals; HGF gene; High Prevalence; Immature Granulocyte; Immune; Immune response; Immune system; Immunity; Immunology procedure; Immunosuppressive Agents; Infection; Inflammation; Inflammatory; Injury; Interleukin-1 beta; Investigation; Keratoplasty; Laboratories; Lead; Mediating; Mesenchymal Stem Cells; Methodology; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Natural regeneration; Pathogenicity; Patients; Pharmaceutical Preparations; Population; Proteins; Regulatory T-Lymphocyte; Research; Risk; Series; Standardization; Suppressor-Effector T-Lymphocytes; TNF gene; Testing; Therapeutic; Therapeutic immunosuppression; Tissues; Transcript; Transplantation; Vision; adult stem cell; base; chemokine; chemokine receptor; cytokine; design; experimental study; granulocyte; immune activation; immunoregulation; in vivo; macrophage; monocyte; mouse model; novel; novel therapeutic intervention; novel therapeutics; paracrine; pathogen; precursor cell; public health relevance; response; treatment strategy

 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(申请人提供)：患有眼部损伤和炎症的患者有发展为慢性失控免疫激活和组织损伤的风险。其中许多疾病通常使用非特异性抗炎药物治疗，如皮质类固醇，这些药物不分青红皂白地抑制宿主免疫，包括免疫系统的致病细胞和调节细胞。因此，迫切需要开发更有效和更安全的免疫调节策略，不仅下调特定的致病免疫细胞，而且重要的是促进调节性免疫细胞，即髓系来源的抑制细胞(MDSC)和调节性T细胞(Tregs)。有趣的是，非造血性骨髓间充质干细胞(BM-MSC)已显示出显著的免疫调节前景。我们的初步研究表明，BM-MSC确实能促进MDSC和Treg功能，并可用于重建眼部炎症的免疫静止。然而，关于BM-MSC促进这些免疫调节细胞功能的机制还知之甚少。我们特别假设BM-MSC(I)未成熟的髓系祖细胞向MDSC和远离巨噬细胞的偏向分化；(Ii)通过细胞间接触和旁分泌机制为Treg功能提供直接支持。为了验证这些假设，我们建议追求两个特定的目标：在目标1中，我们将确定BM-MSC促进髓系来源的抑制细胞的产生和控制眼部炎症的机制。我们将具体调查i)哪一项 BM-MSC促进MDSC的功能亚群；ii)确定BM-MSC表达的促进MDSC生成的因子。在目标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；以及ii)BMMSC细胞表面表达的通过细胞间相互作用促进Treg功能的分子。我们提出的方法旨在利用我们实验室在免疫学分析方面的专业知识，以及具有良好特征的移植诱导的眼部炎症和免疫的小鼠角膜模型。我们预计，对BM-MSC控制眼部炎症的机制的描述将确定关键的免疫调节因素，这些因素可用于开发新的治疗策略。鉴于眼部炎症性疾病的高患病率，以及促进免疫调节细胞同时抑制致病免疫细胞的治疗策略的潜在好处，这项研究的总体影响将是显著的。