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（CNS-CD8）。根据我们的数据，我们假设CNS-CD8的特定功能和表型子集构成重要的，并且自身免疫性脱髓鞘疾病期间免疫调节的可剥削部门。我们提出这一点可以利用有效的免疫治疗方法来利用过程。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免疫调节的分子机制（IFNγ及其受体，运输和细胞毒性，抑制在病理部位）通过这些自动调节的CD8 T细胞，并定义潜在的和可增强的免疫 CNS-CD8的抑制子集。此外，一种新型的疫苗接种策略，可靠地参与抗病 CNS-CD8也将作为原理证明进行研究。我们相信，可实现的结果提出的实验将为CD8 T细胞介导的免疫调节提供更多的基本见解并为MS和其他免疫介导的疾病的新干预策略铺平道路。