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

基本信息

批准号：
9176564
负责人：
Jianxun Jim Song
金额：
$ 37.74万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9176564
关键词：
Adoptive Transfer Animal Model Antigens 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 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 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 cell type embryonic stem cell in vivo induced pluripotent stem cell innovation insight mouse model notch protein novel programs survivin transcription factor

项目摘要

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.

项目概要 CD4+ 调节性 T 细胞 (Treg) 对于正常的免疫监视至关重要，它们的功能障碍可能导致自身免疫性疾病的发展，例如类风湿性关节炎。多能干细胞 (PSC) 可用于获得健康 Tregs 的可再生来源来治疗自身免疫性关节炎，因为它们有能力产生体内几乎所有类型的细胞，包括 Tregs。然而，发展的适当条件 PSC 中的抗原 (Ag) 特异性 Tregs（即 PSC-Tregs）尚未完全定义，尤其是信号传导指导此类 Tregs 分化的机制。 Ag 特异性 PSC-Treg 可以是组织相关的，渗透到局部发炎组织（例如滑膜）以抑制过继转移后的自身免疫反应，从而避免非特异性 Tregs 潜在的整体免疫抑制。我们的长期目标研究计划的目的是开发和优化利用 PSC 作为高反应性 Tregs 来源的策略基于细胞的疗法。本申请的目的是确定 Ag- 的潜在机制。旨在调节自身免疫性关节炎耐受性的特定 PSC-Treg 治疗。中心假设是自身 Ag 特异性 PSC-Treg 是组织相关性 Tregs，它们在发炎的滑膜中积聚，抑制过继转移后的自身免疫，是基于细胞的疗法的优秀候选者。根据已发表的结果和申请人实验室的初步数据，该假设将得到检验通过追求三个具体目标：1）定义汽车 Ag 特异性 PSC-Treg 的基本特性，与抑制活动有关； 2）确定指导汽车分化的信号机制 Ag 特异性 PSC-Treg； 3) 使用自身Ag特异性PSC-研究基于细胞的自身免疫性关节炎疗法特雷格。在第一个目标下，体外和体内方法已在将使用申请人的实验室。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 和自身 Ag 特异性 PSC-Treg 发育过程中的 Notch-survivin 信号传导。在第三个目标下，好吧—— 特征化的动物模型将用于优化基于细胞的自身免疫性关节炎疗法 Ag 特异性小鼠或人 PSC-Treg。该方法具有创新性，因为汽车特有的概念此前尚未探索过 PSC-Tregs 用于自身免疫性关节炎细胞治疗的方法。拟议的研究意义重大，因为它将为开发组织相关的 PSC-Treg 奠定基础通过积累发炎的滑膜和驱动力，将减少过继移植后的整体免疫抑制推进治疗性 PSC-Tregs 在自身免疫性关节炎细胞疗法中的应用。