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: 10447061
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447061
• 关键词: Address; Adoptive Immunotherapy; Adoptive Transfer; Affect; American; Animal Model; Anti-Inflammatory Agents; Antigen Targeting; Antigenic Specificity; Antigens; Area; Attenuated; Autoimmune; Autoimmune Diseases; Automobile Driving; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CNS Demyelinating Autoimmune Diseases; Cells; Characteristics; Chronic; Data; Demyelinating Diseases; Demyelinations; Dendritic Cells; Development; Disease; Dissection; Exhibits; Experimental Autoimmune Encephalomyelitis; Experimental Models; Goals; Granzyme; Histology; ITGAX gene; Immune; Immunization; Immunologics; Immunology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infection; Inflammatory; Interferon Type II; Intervention; Listeria monocytogenes; MHC Class I Genes; Mediating; Modeling; Molecular; Morbidity - disease rate; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Neuraxis; Organ; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Peripheral; Phenotype; Play; Population; Process; Production; Publishing; Recurrent disease; Regulation; Regulatory T-Lymphocyte; Relapse; Reporting; Role; SJL Mouse; Signal Transduction; Site; T cell response; T-Lymphocyte; Therapeutic; Time; Veterans; Work; arm; autoreactive T cell; autoreactivity; base; central nervous system demyelinating disorder; cytotoxic; cytotoxicity; experimental study; immunopathology; immunoregulation; in vivo; innovation; insight; mouse model; multiple sclerosis treatment; neuroinflammation; novel; novel strategies; perforin; prevent; receptor; trafficking; treatment strategy; vaccination 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 studies in MS and EAE have provided evidence for a novel and unexpected disease suppressive role for CNS-specific CD8+ T cells (CNS-CD8). Based on our data, we hypothesize that specific functional and phenotypic subsets of CNS-CD8 form an important and exploitable arm of immune regulation during autoimmune demyelinating disease. We propose that this process can be harnessed for the development of effective immunotherapeutic approaches. The experiments proposed in this application will utilize EAE models to address the fundamental cellular and molecular mechanisms of immune modulation (IFNγ and its receptor, trafficking and cytotoxicity, suppression at the site of pathology) by these autoregulatory CD8 T cells, and to define a potent and enhanceable immune suppressive subset of CNS-CD8. Further, a novel vaccination strategy that reliably engages disease-reversing CNS-CD8 will also be investigated as a proof of principle. We believe that achievable results from the proposed experiments will provide greater fundamental insights into CD8 T cell-mediated immune regulation and pave the way for newer intervention strategies for MS and other immune-mediated diseases.

多发性硬化（MS）是中枢神经系统（CNS）的炎性脱髓鞘疾病。一 我们对MS基础免疫过程的大量理解来自于其 实验性自身免疫性脑脊髓炎（EAE）。但绝大多数 EAE和MS的研究重点是评估和靶向CD 4 + T细胞反应，总体而言， 假设这些疾病主要是Th 1/Th 17介导的和Th 2/Treg调节的。最近 其他人和我们的报告表明，CD 8 + T细胞在发病机制和调节中发挥作用 自身免疫性脱髓鞘我们在MS和EAE中的研究为一种新的， CNS特异性CD 8 + T细胞（CNS-CD 8）的意外疾病抑制作用。根据我们的数据， 假设CNS-CD 8特异性功能和表型亚群形成了一个重要且 自身免疫性脱髓鞘疾病期间免疫调节的可利用的手臂。我们建议， 可以利用这一过程来开发有效的免疫方法。的 本申请中提出的实验将利用EAE模型来解决基本的细胞和 免疫调节的分子机制（IFNγ及其受体、转运和细胞毒性、抑制 在病理部位）通过这些自身调节性CD 8 T细胞，并定义一种有效的和可增强的免疫 CNS-CD 8的抑制性子集。此外，一种新的疫苗接种策略，可靠地从事疾病逆转 CNS-CD 8也将作为原则证明进行调查。我们认为， 拟议的实验将为CD 8 T细胞介导的免疫调节提供更深入的基础见解 并为MS和其他免疫介导疾病的新干预策略铺平道路。