The Role of IL-11 in Development of Th17-mediated Autoimmune Response in EAE

IL-11 在 EAE 中 Th17 介导的自身免疫反应发展中的作用

• 批准号: 8693109
• 负责人: Silva Markovic-Plese
• 金额: $ 7.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693109
• 关键词: Active Immunization; Adoptive Cell Transfers; Adoptive Transfer; Aggressive Clinical Course; Animal Disease Models; Animal Model; Animals; Ants; Autoimmune Diseases; Autoimmune Responses; Automobile Driving; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Clinical; Consensus; Data; Demyelinating Diseases; Development; Disease; Disease remission; Disease susceptibility; Dose; Effectiveness; Experimental Autoimmune Encephalomyelitis; Goals; Human; In Vitro; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Interleukin-11; Measures; Mediating; Memory; Molecular; Mus; Onset of illness; Patients; Peptides; Phase; Play; Prevention; Proteins; Proteolipids; Regulation; Relapse; Relapsing-Remitting Multiple Sclerosis; Research; Role; SJL Mouse; Serum; Signal Transduction; Sorting - Cell Movement; Source; Spleen; Syndrome; System; T cell differentiation; Testing; Therapeutic; Time; Transgenic Mice; base; cytokine; in vivo; lymph nodes; nervous system disorder; new therapeutic target; oligodendrocyte-myelin glycoprotein; polarized cell; public health relevance; response; therapeutic target

DESCRIPTION (provided by applicant): The involvement of Th17-cells in the development of the autoimmune response in relapsing remitting multiple sclerosis (RRMS) is well documented. However, there is still no consensus regarding the cytokines required for the differentiation of human Th17-cells. Our preliminary studies have identified IL- 11 as a new Th17-promoting cytokine. Furthermore, we found that IL-11 is the most significantly increased cytokine in the serum and cerebrospinal fluid (CSF) of patients with clinically isolated syndrome (CIS) suggestive of MS. Although we have also demonstrated an increase in the IL-11 serum and CSF levels in patients with clinically definitive RRMS in comparison to healthy controls (HCs), and significantly higher serum IL-11 levels during the clinical exacerbations in comparison to the remissions, those results still do not confirm a causative role of this cytokine in the development of the inflammatory CNS disease. The rationale for our proposed research is that the in-vivo animal model of the disease will allow us to directly characterize the role of IL-11 in the development of the autoimmune response. Based on preliminary results, our central hypothesis is that IL-11 may play a critical role in the regulation of Th17-cells, which represent a pathogeni cell subset driving the autoimmune response in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our long-term goal is to characterize the molecular mechanisms through which IL-11 initiates, augments and perpetuates the autoimmune response in RRMS. We will pursue the following specific aims: 1. Characterize the role of IL-11 in the development of the Th17-mediated autoimmune response in EAE. The study will: 1.A. Identify to what extent IL-11 induces the development of RR EAE. 1.B. Determine the effectiveness of anti-IL-11 mAb in the prevention and suppression of the clinical and histopathological parameters of RR EAE. 2. Determine the effect of IL-11-mediated Th17-cell differentiation and expansion on the development of encephalitogenic Th17-cells. More specifically, we will: 2.A. Determine the effect of IL-11-mediated na¿ve CD4+ T-cell differentiation in the Th17-cell passive transfer EAE. 2.B. Identify the effect of IL-11-mediated Th17 memory cell expansion in adoptive transfer EAE. The proposed in-vivo animal studies are expected to characterize the role of IL-11 in the development of the Th17-cell- mediated CNS inflammatory disease, and to provide results that will justify selective targeting of IL-11 in the treatment for RRMS.

描述(由申请人提供)：Th17细胞参与复发缓解性多发性硬化症(RRMS)自身免疫反应的发展是有很好的文献记载的。然而，关于人类Th17-细胞分化所需的细胞因子仍未达成共识。我们的初步研究证实IL-11是一种新的Th17促进细胞因子。此外，我们还发现，IL-11是临床隔离综合征(CIS)患者血清和脑脊液(CSF)中最显著的细胞因子，提示MS。尽管我们也证实了临床明确的RRMS患者血清和脑脊液中IL-11水平高于健康对照组(HCS)，并且在临床加重期与缓解期相比，血清IL-11水平显著升高，但这些结果仍不能证实这种细胞因子在RRMS发生发展中的致病作用。 炎症性中枢神经系统疾病。我们提出的研究的基本原理是，这种疾病的体内动物模型将使我们能够直接表征IL-11在自身免疫反应发展中的作用。根据初步结果，我们的中心假设是IL-11可能在Th17-细胞的调节中发挥关键作用，Th17-细胞是推动实验性自身免疫性脑脊髓炎(EAE)自身免疫反应的一个致病细胞亚群。我们的长期目标是表征IL-11启动、增强和维持RRMS自身免疫反应的分子机制。我们将追求以下具体目标：1.研究IL-11在Th17介导的EAE自身免疫反应中的作用。本研究将：1.明确IL-11在多大程度上诱导RR EAE的发生。1.确定抗IL-11单抗预防和抑制RR型EAE的临床和组织病理学指标的有效性。2.检测IL-11介导的Th17-细胞分化和扩增对脑源性Th17-细胞发育的影响。更具体地说，我们将：2.A.确定IL-11介导的NA和CD4+T细胞分化在Th17细胞被动转移EAE中的作用。2.确定IL-11介导的Th17记忆细胞扩增在过继转移EAE中的作用。拟议的体内动物研究有望确定IL-11在Th17细胞介导的中枢神经系统炎症性疾病发展中的作用，并提供证明在RRMS治疗中选择性靶向IL-11的结果。