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

• 批准号: 9338988
• 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
• 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/9338988
• 关键词: Address; Adoptive Immunotherapy; Adoptive Transfer; Affect; Animal Model; Anti-Inflammatory Agents; 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; Pathology processes; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Population; Process; Regulation; Regulatory T-Lymphocyte; Relapse; Reporting; Role; SJL Mouse; Site; 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

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) 是一种中枢神经系统 (CNS) 炎症性脱髓鞘疾病。一个 我们对多发性硬化症背后的免疫过程的大部分了解都来自于其研究 自身免疫动物模型，实验性自身免疫性脑脊髓炎（EAE）。然而，绝大多数 EAE 和 MS 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 介导的和 Th2/Treg 调节的。最近的 其他人和我们的报告表明 CD8+ T 细胞在发病机制以及调节中发挥作用 自身免疫性脱髓鞘。我们最近在 MS 和 EAE 方面的研究为一种新颖且有效的方法提供了证据。 CNS 特异性 CD8+ T 细胞具有意想不到的疾病抑制作用，并且还证明了 CD8+ T 细胞在醋酸格拉替雷 (GA) 免疫治疗介导作用中的需求。基于 根据我们的数据，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手段。我们建议这 可以利用该过程来开发有效的免疫治疗策略。这 本申请中提出的实验将利用 EAE 模型来解决基本的细胞和 内在和治疗性 CD8 T 细胞免疫调节的分子机制。此外，最 这些人群的有效免疫抑制子集将被定义，目标是开发一种新的 过继免疫治疗方法。我们相信所提出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，为新的干预措施铺平道路 针对这种疾病和其他免疫介导疾病的策略。