CNS-Specific Regulatory CD8+ T Cells in Autoimmune Demyelination

CNS 特异性调节 CD8 T 细胞在自身免疫性脱髓鞘中的作用

基本信息

批准号：
8648996
负责人：
NITIN J KARANDIKAR
金额：
$ 33.98万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8648996
关键词：
Address Adoptive Immunotherapy Affect Animal Model Antigen-Presenting Cells Antigenic Specificity Antigens Area Autoimmune Process CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Characteristics Demyelinating Diseases Demyelinations Development Disease Experimental Autoimmune Encephalomyelitis Goals Health High Prevalence Histology Human Immune Immunization Immunologics Immunology Immunotherapeutic agent Immunotherapy Inbred C3H Mice Inflammatory Intervention MHC Class I Genes Mediating Modeling Molecular Multiple Sclerosis Multiple Sclerosis Lesions Mus Neuraxis Pathogenesis Pathology Patients Peptides Play Population Process Qa-1 Antigen Regulation Regulatory T-Lymphocyte Reporting Role Site Specificity T cell response T-Lymphocyte T-Lymphocyte Subsets Therapeutic Transgenic Mice Transgenic Organisms Work arm autoreactive T cell base central nervous system demyelinating disorder copolymer cytokine cytotoxic genetic manipulation immunopathology immunoregulation innovation insight killings mouse model novel peripheral tolerance public health relevance research study trafficking treatment strategy

项目摘要

DESCRIPTION (provided by applicant): 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 may play an important role in the pathogenesis as well as regulation of autoimmune demyelination. The role of CD8+ T cells in the process of autoimmune pathology has been both understudied and controversial. While it is known that CD8+ T cells represent the predominant T cell in an MS lesion and are oligoclonally expanded at the site of pathology, the antigenic specificity of these cells and their role is not known. There is high prevalence of CNS-specific CD8+ T cells in MS patients as well as multiple models of EAE. While it makes intuitive sense that a CNS-targeted, MHC Class I-restricted CD8+ T cell response would likely have a pathogenic role in disease, our recent studies have generated the first evidence for a novel and unexpected immune suppressor role for neuroantigen-specific CD8+ T cells in EAE. We thus hypothesize that CNS-specific CD8+ T cells form an important arm of intrinsic immune regulation during autoimmune demyelinating disease. We propose that this natural process can be harnessed for the development of an effective immunotherapeutic strategy. The experiments proposed in this application will directly address the mechanisms of immune modulation by CNS-reactive CD8+ T cells, delineating their cellular, molecular and trafficking requirements. Moreover, the most potent immune suppressive subset of this population will be defined with the goal of developing a novel immunotherapeutic approach. We believe that the proposed experiments will provide greater fundamental insight into CD8+ T cell-mediated immune regulation during health and disease and will pave the way for newer intervention strategies for this and other immune-mediated diseases.

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的炎症性脱髓鞘疾病。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对其自身免疫动物模型实验性自身免疫性脑脊髓炎 (EAE) 的研究。然而，绝大多数 EAE 和 MS 的研究都集中在评估和靶向 CD4+ T 细胞反应，普遍假设这些疾病主要是 Th1/Th17 介导和 Th2/Treg 调节。其他人和我们最近的报告表明，CD8+ T 细胞可能在自身免疫性脱髓鞘的发病机制和调节中发挥重要作用。 CD8+ T 细胞在自身免疫病理过程中的作用尚未得到充分研究和争议。虽然已知 CD8+ T 细胞代表 MS 病变中的主要 T 细胞，并且在病理部位寡克隆扩增，但这些细胞的抗原特异性及其作用尚不清楚。 MS 患者以及多种 EAE 模型中 CNS 特异性 CD8+ T 细胞的患病率很高。虽然直觉上认为，针对 CNS 的 MHC I 类限制性 CD8+ T 细胞反应可能在疾病中具有致病作用，但我们最近的研究已经为神经抗原特异性 CD8+ 具有新颖且意想不到的免疫抑制作用提供了第一个证据。 EAE 中的 T 细胞。因此，我们假设 CNS 特异性 CD8+ T 细胞在自身免疫性脱髓鞘疾病期间形成内在免疫调节的重要手段。我们建议可以利用这种自然过程来开发有效的免疫治疗策略。本申请中提出的实验将直接解决 CNS 反应性 CD8+ T 细胞的免疫调节机制，描述其细胞、分子和运输要求。此外，将定义该人群中最有效的免疫抑制子集，目标是开发一种新的免疫治疗方法。我们相信，所提出的实验将为健康和疾病期间 CD8+ T 细胞介导的免疫调节提供更深入的基础见解，并将为针对这种疾病和其他免疫介导疾病的新干预策略铺平道路。