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The Role of IL-II in the development of autoimmune response in multiple sclerosis

IL-II 在多发性硬化症自身免疫反应发展中的作用

基本信息

批准号：
10221496
负责人：
Silva Markovic-Plese
金额：
$ 39万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-11 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221496
关键词：
Animal Disease Models Animals Antigens Attenuated Autoimmune Responses Biological Markers Biopsy Specimen Blood Circulation Blood specimen Brain CCR6 gene CD4 Positive T Lymphocytes Cell Adhesion Molecules Cell Differentiation process Cells Cerebrospinal Fluid Clinical Clinical Data Demyelinating Diseases Development Disease Disease remission Endothelial Cells Endothelium Event Exhibits Experimental Autoimmune Encephalomyelitis Flare Flow Cytometry Gene Expression Profile Gene Expression Profiling Human Immunohistochemistry In Vitro Inflammatory Inflammatory Infiltrate Integrin alpha4beta1 Intercellular adhesion molecule 1 Interleukin-11 Interleukin-17 Knockout Mice Lesion Magnetic Resonance Imaging Mediating Migration Assay Modeling Molecular Monoclonal Antibodies Multiple Sclerosis Multiple Sclerosis Lesions Mus Neuraxis Pathogenesis Pathogenicity Patients Peripheral Phase Phenotype Population Relapse Relapsing-Remitting Multiple Sclerosis Role Serum Severity of illness Signal Pathway Source Specificity Spinal Cord Suggestion Syndrome T-Cell Receptor T-Lymphocyte Subsets Testing Therapeutic Therapeutic Effect Up-Regulation base cytokine disability disabling disease early detection biomarkers experimental study immunomodulatory therapies in vivo interleukin-11 receptor migration multiple sclerosis patient novel therapeutic intervention polarized cell pre-clinical prevent response therapeutic biomarker therapeutic target transcriptome transcriptome sequencing young adult

项目摘要

Multiple sclerosis (MS), a central nervous system (CNS) inflammatory demyelinating disease, is a leading cause of disability in the young adult population. While dramatic progress has been made in our understanding of the disease pathogenesis, the initial disease-triggering events remain poorly understood. Since immunomodulatory therapies are most effective when administered early in the course of the disease, we are seeking biomarkers of the clinically isolated syndrome (CIS) suggestive of MS, the earliest phase of the disease. Our preliminary studies have identified IL-11, a new Th17 cell-polarizing cytokine, as the most significantly increased cytokine in the serum and cerebrospinal fluid (CSF) of CIS patients, whose serum levels are increased during clinical exacerbations of the disease. CD4+ cells are the main source of IL-11 in the peripheral circulation. The percentage of IL- 11+CD4+ cells is increased in the peripheral circulation of CIS patients in comparison to matched healthy controls (HCs), and they significantly accumulate in the CSF and the active brain MS lesions in comparison to matched blood samples. Animal studies have confirmed the causal role of IL-11 in the exacerbation of relapsing remitting (RR) experimental autoimmune encephalomyelitis (EAE), since IL- 11 administration worsened clinical course and induced increased numbers of IL-17A+CD4+ cells in the central nervous system (CNS) inflammatory infiltrates. Our central hypothesis is that IL-11 induces CD4+ cell migratory capacity and encephalitogenicity, mediated via up-regulation of CCR6, ICAM-1 and VLA-4, which mediate CD4+ cells trans-endothelial migration. We propose that IL-11+CD4+ cells, which are also expanded in the presence of IL-11, may represent a pathogenic cell subset, whose transcriptional profiling and T cell receptor (TCR)Vb repertoire will elucidate their function and antigen specificity. aIL-11R mAb treatment of RRAEA will provide pre-clinical data and identify markers of therapeutic effect for this new therapeutic approach. The objective of this study is (1) to identify the molecular mechanisms involved in IL-11-induced migration of CD4+ cell subsets to the CNS in CIS patients, (2) to characterize the phenotype, transcriptional profile and TCRVb repertoire of CSF- enriched IL-11+CD4+ cells in CIS patients, and (3) to examine the potential of IL-11 to induce encephalitogenic CD4+ cells capable of passively transferring disease, and to determine the therapeutic effect of aIL-11R mAb in RREAE, an animal model of the disease. The results are expected to provide biomarkers of early autoimmune response in CIS patients and to identify selective therapeutic targets for this disabling disease.

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