Stem cell-derived regulatory T cells for therapeutic use in arthritis

干细胞衍生的调节性 T 细胞用于治疗关节炎

• 批准号: 9281649
• 负责人: Jianxun Jim Song
• 金额: $ 38.45万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9281649
• 关键词: Adoptive Transfer; Animal Model; Antigens; Apoptosis Inhibitor; Arthritis; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Cycle Progression; Cell Therapy; Chaperonin 60; Cytotoxic T-Lymphocytes; Data; Development; Differentiation Antigens; FLT3LG gene; FOXP3 gene; Foundations; Functional disorder; Gene Expression Profile; Genes; Goals; Harvest; Hematopoietic; Hematopoietic stem cells; Human; Immunologic Surveillance; Immunosuppression; In Vitro; Interleukin-2; Interleukin-7; Knowledge; Laboratories; Lead; Ligands; Lymphoid Tissue; Manuscripts; Mus; Organ; Patients; Phenotype; Pluripotent Stem Cells; Property; Publishing; Receptor Cell; Regulation; Regulatory T-Lymphocyte; Research; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Source; Specificity; Stem cells; Synovial Membrane; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic Uses; Tissues; Transduction Gene; autoimmune arthritis; autoreactive T cell; cell type; embryonic stem cell; forkhead protein; human pluripotent stem cell; in vivo; induced pluripotent stem cell; innovation; insight; mouse model; notch protein; novel; programs; survivin; transcription factor

PROJECT SUMMARY CD4+ regulatory T cells (Tregs) are essential for normal immune surveillance, and their dysfunction can lead the development of autoimmune diseases, such as rheumatoid arthritis. Pluripotent stem cells (PSCs) can be utilized to obtain a renewable source of healthy Tregs to treat autoimmune arthritis as they have the ability to produce almost all cell types in the body, including Tregs. However, the right conditions for the development of antigen (Ag)-specific Tregs from PSCs (i.e., PSC-Tregs) have not been fully defined, especially the signaling mechanisms that direct differentiation of such Tregs. Ag-specific PSC-Tregs can be tissue-associated and infiltrate to local inflamed tissue (e.g., synovium) to suppress autoimmune responses after adoptive transfer, thereby avoiding potential overall immunosuppression from non-specific Tregs. The long-term goal of our research program is to develop and optimize strategies for utilizing PSCs as a source of highly reactive Tregs for cell-based therapies. The objective of this application is to determine the mechanisms underlying the Ag- specific PSC-Treg treatments that aim to modulate tolerance in autoimmune arthritis. The central hypothesis is that auto Ag-specific PSC-Tregs are tissue-associated Tregs, which accumulate in inflamed synovium and suppress the autoimmunity after adoptive transfer and act as excellent candidates for cell-based therapies. Guided by published results and preliminary data from the applicant's laboratory, this hypothesis will be tested by pursuing three specific aims: 1) to define the fundamental properties of auto Ag-specific PSC-Tregs that relate to suppressive activity; 2) to determine the signaling mechanisms that direct the differentiation of auto Ag-specific PSC-Tregs; and 3) to study cell-based therapies of autoimmune arthritis using auto Ag-specific PSC- Tregs. Under the first aim, in vitro and in vivo approaches, which have been established as feasible in the applicant's laboratory, will be used. The fundamental properties of auto Ag-specific PSC-Tregs with regard to phenotype, specificity and function will be defined. Under the second aim, gene expression profile and intracellular signaling pathways will be studied to determine the critical roles of Notch-Hes1, Notch-Runx1 and Notch-survivin signaling during the development of auto Ag-specific PSC-Tregs. Under the third aim, well- characterized animal models will be used to optimize cell-based therapies of autoimmune arthritis using auto Ag-specific mouse or human PSC-Tregs. The approach is innovative, because the concept of auto Ag-specific PSC-Tregs for cell-based therapies in autoimmune arthritis has not been previously explored. The proposed research is significant, because it will provide the foundation for developing tissue-associated PSC-Tregs that will reduce overall immunosuppression after adoptive transfer by accumulating inflamed synovium and drive forward the use of therapeutic PSC-Tregs for cell-based therapies in autoimmune arthritis.

项目摘要 CD4+调节性T细胞（Tregs）对于正常的免疫监视至关重要，它们的功能障碍可以导致 自身免疫性疾病的发展，例如类风湿关节炎。多能干细胞（PSC）可以是 被用来获得可再生的健康Treg来治疗自身免疫性关节炎，因为它们有能力 生产体内几乎所有细胞类型，包括Treg。但是，开发的正确条件 来自PSC的抗原（Ag）特异性Treg（即PSC-Tregs）尚未完全定义，尤其是信号传导 直接分化此类Treg的机制。 Ag特异性的PSC-Treg可以与组织相关，并且 浸润到局部发炎组织（例如，滑膜）以抑制过继转移后的自身免疫反应， 从而避免了非特异性Treg的潜在总体免疫抑制。我们的长期目标 研究计划是开发和优化利用PSC作为高反应性Treg的策略 基于细胞的疗法。该应用的目的是确定Ag-的基础机制 旨在调节自身免疫性关节炎的耐受性的特定PSC-Treg治疗方法。中心假设是 自动Ag特异性的PSC-Treg是组织相关的Treg，它们积累在发炎的滑膜和 抑制收养转移后的自身免疫，并充当基于细胞的疗法的出色候选者。 在已发布的结果和申请人实验室的初步数据的指导下，该假设将进行检验 通过追求三个具体目标：1）定义自动AG特异性PSC-Tregs的基本属性 与抑制活动有关； 2）确定指导自动分化的信号传导机制 Ag特异性PSC-Tregs; 3）使用自动Ag特异性PSC-研究基于细胞的自身免疫性关节炎的疗法 Tregs。在第一个目标下，体外和体内方法已确定为可行的 申请人的实验室将被使用。自动Ag特异性PSC-Treg的基本特性 表型，特异性和功能将被定义。在第二个目标下，基因表达谱和 将研究细胞内信号通路，以确定Notch-Hes1，Notch-Runx1和 自动Ag特异性PSC-Tregs开发过程中Notch-Survivin信号传导。在第三个目标下， 特征动物模型将用于使用自动免疫关节炎优化基于细胞的疗法 Ag特异性小鼠或人类PSC-Treg。这种方法具有创新性，因为自动Ag特定的概念 以前尚未探讨用于自身免疫性关节炎的基于细胞的PSC-Tregs。提议 研究很重要，因为它将为发展与组织相关的PSC-Treg提供基础 通过累积发炎的滑膜和驱动器，将在收养转移后减少总体免疫抑制 将治疗性PSC-Treg用于自身免疫性关节炎的基于细胞的疗法。