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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：
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
项目类别：
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

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 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的研究集中在评估和靶向CD 4 + T细胞应答，假设这些疾病主要是Th 1/Th 17介导的和Th 2/Treg调节的。最近来自其他人和我们的报告表明，CD 8 + T细胞在发病机制以及调节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。