Steroid resistance: Experimental Autoimmune Encephalomyelitis/Multiple Sclerosis

类固醇抵抗：实验性自身免疫性脑脊髓炎/多发性硬化症

基本信息

批准号：
7342891
负责人：
THOMAS G. FORSTHUBER
金额：
$ 27.86万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7342891
关键词：
Acute Adhesions Adoptive Transfer Aftercare Anti-Inflammatory Agents Anti-inflammatory Antibodies Antigen Presentation Antigens Apoptosis Autoimmune Diseases Autoimmune Responses Avidity Biological Assay CD4 Positive T Lymphocytes Cell Adhesion Molecules Cell Death Cell Survival Cells Chronic Data Dendritic Cells Dexamethasone Disease Progression Disease remission Doctor of Medicine Doctor of Philosophy Down-Regulation Experimental Autoimmune Encephalomyelitis Figs - dietary Flow Cytometry Frequencies Glucocorticoid Receptor Glucocorticoid-induced apoptosis Glucocorticoids Goals ITGAX gene Immigration Immune Immune system Immunofluorescence Immunologic Immunofluorescence Microscopy Immunosuppression In Situ In Situ Nick-End Labeling In Vitro Induction of Apoptosis Inflammatory Leucine Zippers Link Literature Macrophage-1 Antigen Measures Mediating Microglia Mifepristone Migration Inhibitory Factor Multiple Sclerosis Mus Myelin Neurons Numbers Output PTPRC gene Patients Peptides Production RU-486 Recurrent disease Relapse Reporting Research Personnel Resistance Rodent Role Site Specificity Spleen Staining method Stains Steroid Resistance Steroid therapy T-Lymphocyte Testing Therapeutic immunosuppression Time Vascular Cell Adhesion Molecule-1 annexin A5 base cell motility cell type cytokine day enzyme linked immunospot assay improved in vivo inhibitor/antagonist lymph nodes macrophage migration neutrophil phenylpyruvate tautomerase prevent programs response

项目摘要

DESCRIPTION (provided by applicant): Glucocorticoids (GC) remain the mainstay of therapy for acute MS episodes. However, it is also clear that GC fail to prevent MS relapses and disease progression, and appear to have little effect on long-term T cell responses to myelin antigens in patients. Similarly, GC treatment efficiently down-regulates EAE in rodents, but fails to prevent subsequent relapses. Importantly, GC fail to inhibit proliferation and cytokine production by T cells at inflammatory sites, which could be particularly relevant in the CMS where expression of MIF in a number of cell types including neurons could contribute to this observation. Our own preliminary data and a recent report by Powell and colleagues strongly support a link between MIF and glucocorticoids in EAE. We found that Wt mice show exacerbation of EAE and relapsing disease upon termination of Dexamethasone treatment, but not MIF-/- mice. Furthermore, EAE is substantially exacerbated in MIF-/- mice treated with the glucocorticoid receptor inhibitor Mifepristone (RU-486). Furthermore, the frequencies and functional avidity of myelin-specific T cells were decreased when MIF was neutralized in vivo with anti-MIF antibodies. Based on these results and the literature it is highly likely that MIF interferes with GC-mediated immunosuppression, induction of apoptosis, and/or migration of inflammatory cells to the CMS. This proposal will test the hypothesis that: MIF promotes EAE by counter-regulating the immunosuppressive effects of glucocorticoids on T cell and macrophage apoptosis, effector functions, and CMS migration. This hypothesis will be tested with the following specific aims: Aim 1. To determine whether MIF interferes with glucocorticoid-mediated apoptosis of encephalitogenic T cells and APCs in EAE. Aim 2. To determine whether MIF counter-regulates glucocorticoid-mediated immunosuppression of T cell effector functions in EAE. Aim 3. To determine the mechanism of MIF interference with apoptosis.

描述（由申请人提供）：糖皮质激素 (GC) 仍然是急性多发性硬化症发作的主要治疗方法。然而，同样清楚的是，GC 无法预防 MS 复发和疾病进展，并且似乎对患者髓磷脂抗原的长期 T 细胞反应影响不大。同样，GC 治疗可有效下调啮齿类动物的 EAE，但无法防止随后的复发。重要的是，GC 无法抑制炎症部位 T 细胞的增殖和细胞因子产生，这在 CMS 中尤其相关，其中 MIF 在包括神经元在内的多种细胞类型中的表达可能有助于这一观察。我们自己的初步数据以及 Powell 及其同事最近的一份报告强烈支持 MIF 与 EAE 中糖皮质激素之间的联系。我们发现，在终止地塞米松治疗后，Wt 小鼠表现出 EAE 恶化和疾病复发，但 MIF-/- 小鼠则不然。此外，用糖皮质激素受体抑制剂米非司酮 (RU-486) 治疗的 MIF-/- 小鼠中，EAE 显着加剧。此外，当用抗 MIF 抗体在体内中和 MIF 时，髓磷脂特异性 T 细胞的频率和功能亲合力会降低。根据这些结果和文献，MIF 很可能干扰 GC 介导的免疫抑制、诱导细胞凋亡和/或炎症细胞向 CMS 的迁移。该提案将检验以下假设：MIF 通过反调节糖皮质激素对 T 细胞和巨噬细胞凋亡、效应器功能和 CMS 迁移的免疫抑制作用来促进 EAE。该假设将通过以下具体目标进行检验：目标 1. 确定 MIF 是否会干扰 EAE 中糖皮质激素介导的致脑炎 T 细胞和 APC 的凋亡。目标 2. 确定 MIF 是否反调节 EAE 中糖皮质激素介导的 T 细胞效应功能免疫抑制。目的3.明确MIF干扰细胞凋亡的机制。