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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：
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
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/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

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.