Immunotherapeutic Regulatory CD8 T cells in Autoimmune Demyelinating Disease

自身免疫性脱髓鞘疾病中的免疫治疗调节性 CD8 T 细胞

基本信息

批准号：
9483533
负责人：
NITIN J KARANDIKAR
金额：
--
依托单位：
IOWA CITY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9483533
关键词：
Address Adoptive Immunotherapy Adoptive Transfer Affect Animal Model Anti-inflammatory Antigenic Specificity Antigens Area Autoantigens Autoimmune Diseases Autoimmune Process CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Characteristics Chronic Country Data Demyelinating Diseases Demyelinations Dendritic Cells Development Disease Exhibits Experimental Autoimmune Encephalomyelitis Experimental Models Goals Histology Human ITGAX gene Immune Immunization Immunologics Immunology Immunotherapeutic agent Immunotherapy In Vitro Inbred C3H Mice Inflammatory Interferon Type II Intervention Intuition MHC Class I Genes Mediating Modeling Molecular Morbidity - disease rate Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Neuraxis Organ Pathogenesis Pathogenicity Pathology Peripheral Pharmaceutical Preparations Phenotype Play Population Process Regulation Regulatory T-Lymphocyte Relapse Reporting Role SJL Mouse Site T cell response T-Lymphocyte Therapeutic Therapeutic Effect Transgenic Organisms Veterans Work arm autoreactive T cell autoreactivity base central nervous system demyelinating disorder copolymer 1 cytotoxic experimental study immunopathology immunoregulation in vivo innovation insight mouse model neuroinflammation novel perforin response trafficking treatment strategy

项目摘要

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS). A great deal of our understanding about the immunologic processes that underlie MS derives from studies in its autoimmune animal model, experimental autoimmune encephalomyelitis (EAE). However, the vast majority of studies in EAE and MS have focused on evaluating and targeting CD4+ T cell responses, with the general assumption that these diseases are predominantly Th1/Th17-mediated and Th2/Treg-modulated. Recent reports from others and us indicate that CD8+ T cells play a role in the pathogenesis as well as regulation of autoimmune demyelination. Our recent studies in MS and EAE have provided evidence for a novel and unexpected disease suppressive role for CNS-specific CD8+ T cells and also demonstrated the requirement of CD8+ T cells in mediating effects of glatiramer acetate (GA) immunotherapy. Based on our data, we hypothesize that a subset of autoantigen-specific or GA-induced CD8 T cells form an important arm of immune regulation during autoimmune demyelinating disease. We propose that this process can be harnessed for the development of an effective immunotherapeutic strategy. The experiments proposed in this application will utilize EAE models to address the fundamental cellular and molecular mechanisms of immune modulation by intrinsic and therapeutic CD8 T cells. In addition, the most potent immune suppressive subset of these populations will be defined with the goal of developing a novel adoptive immunotherapeutic approach. We believe that the proposed experiments will provide greater fundamental insights into CD8 T cell-mediated immune regulation and pave the way for newer intervention strategies for this and other immune-mediated diseases.

多发性硬化症（MS）是中枢神经系统（CNS）的炎症性脱髓鞘疾病。一个我们对MS基础的免疫过程的理解很大自身免疫动物模型，实验性自身免疫性脑脊髓炎（EAE）。但是，绝大多数在EAE和MS中的研究重点是评估和靶向CD4+ T细胞反应，一般假设这些疾病主要是TH1/TH17介导的，并且Th2/Treg调节。最近的来自他人和美国的报告表明，CD8+ T细胞在发病机理以及调节中起作用自身免疫性脱髓鞘。我们最近在MS和EAE的研究为小说提供了证据 CNS特异性CD8+ T细胞的意外疾病抑制作用，也证明了 CD8+ T细胞的需求在乙酸盐（GA）免疫疗法的介导作用中。基于我们的数据，我们假设自身抗原特异性或GA诱导的CD8 T细胞的子集形成自身免疫性脱髓鞘疾病期间免疫调节的重要部门。我们提出这一点可以利用过程来制定有效的免疫治疗策略。这本应用程序中提出的实验将利用EAE模型来解决基本的细胞和固有和治疗性CD8 T细胞免疫调节的分子机制。另外，最多这些人群的有效免疫抑制子集将以开发新颖的目的定义收养免疫治疗方法。我们认为拟议的实验将提供更大的对CD8 T细胞介导的免疫调节的基本见解，并为新干预铺平道路该策略和其他免疫介导的疾病。