权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The role of IL-27 in iv tolerance in EAE

IL-27 在 EAE 静脉注射耐受中的作用

基本信息

批准号：
8897994
负责人：
A.M. Rostami
金额：
$ 38.75万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-08 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897994
关键词：
Address Adjuvant Animal Model Antigen-Presenting Cells Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Proteins CD4 Positive T Lymphocytes CD8B1 gene Cells Cellular Immunity Chronic Clonal Deletion Demyelinations Dendritic Cells Development Disease Dose Event Experimental Autoimmune Encephalomyelitis Galectin 1 Generations Granulocyte-Macrophage Colony-Stimulating Factor Health Human IL2RA gene ITGAM gene ITGAX gene Immune Tolerance Immune response Immune system Immunity Immunotherapy In Vitro Inflammatory Interferons Interleukin-10 Interleukin-13 Interleukin-17 Interleukin-4 Interleukins Intravenous Lead Link Microglia Multiple Sclerosis Mus Myelin Natural Killer Cells Neuraxis Nose Oral Pathway interactions Peptides Phenotype Play Polysaccharides Production Proteins Regulation Regulatory T-Lymphocyte Relapse Resistance Role Route Spleen T-Lymphocyte TNF gene Testing Th2 Cells Therapeutic Effect To autoantigen Translations Wild Type Mouse anergy autocrine base central nervous system demyelinating disorder cytokine in vivo insight interleukin-23 intravenous administration intravenous injection macrophage mast cell novel paracrine prevent receptor response

项目摘要

DESCRIPTION (provided by applicant): Intravenous (i.v.) injection of soluble antigens can induce antigen-specific tolerance in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, and effectively suppresses the disease. I.V. injected autoantigen induces tolerogenic dendritic cells (DCs), which produce IL-27, a potent immunoregulatory cytokine. While tolerance can be successfully induced in wild-type EAE mice, mice lacking IL-27 receptor are resistant, demonstrating that IL-27 plays a crucial role in tolerance induction. The central hypothesis of this proposal is that i.v. administration of autoantigen in EAE causes DCs to produce IL-27, which in turn induces tolerogenic DCs and regulatory Tr1 cells, leading to tolerance. To test this hypothesis, three specific aims are proposed: Aim 1) To study the role of IL-27 in generation of tolerogenic DCs and antigen-specific type 1 regulatory T (Tr1) cells in i.v. tolerance. We hypothesize that IL-27 plays a key role in i.v. tolerance by both paracrine (suppression of myelin-specific Th1/Th17 cells and induction of Tr1 cells) and autocrine (induction and expansion of tolerogenic DCs) mechanisms. Aim 2) To investigate the role of the galectin-1/IL-27 pathway in i.v. tolerance induction. Galectin-1 is an endogenous glycan-binding protein, produced by Tregs that can endow DCs with IL-27-dependent tolerogenic potential. We have found that MOG-reactive Tregs stimulate DCs to produce IL-27, an effect that is largely galectin-1-dependent. IL-27, in turn, can stimulate DCs to express a high level of galectin-1. Further, galectin-1 deficient mice are resistant to the induction of i.v. tolerance in EAE. In this aim we will test our hypothesis that i.v. injection of autoAg will trigger Ag-specific nTregs to preferentially form aggregates with DCs, produce galectin-1, and induce tolerogenic DCs in vivo. Aim 3) To test the effect of exogenous IL-27 on i.v. tolerance induction in EAE. Given the important role of IL- 27 in tolerance induction, we hypothesize that administration of rmIL-27 will promote development of tolerogenic/regulatory DCs and T cells upon i.v. injection of autoantigen. Hence, administration of exogenous IL-27 can enhance the therapeutic effect of i.v. tolerance, and reduce the dose of autoantigen required for maximal effect. This will decrease the likelihood of developing autoantibodies or adverse immune responses to the tolerizing autoantigen. Aims 1 and 2 study basic mechanisms of i.v. tolerance induction, while Aim 3 focuses on translation of our findings into therapy. The information gained from these studies should lead to a better understanding of the mechanisms of i.v. tolerance and provide the basis for novel immunotherapies for CNS inflammatory demyelination.

描述(申请人提供)：静脉注射(静脉注射)在多发性硬化症的动物模型实验性自身免疫性脑脊髓炎(EAE)中，注射可溶性抗原可以诱导抗原特异性耐受，并有效地抑制该疾病。静脉注射自身抗原诱导耐受树突状细胞(DC)，树突状细胞产生IL-27，一种强大的免疫调节细胞因子。虽然野生型EAE小鼠可以成功地诱导耐受，但缺乏IL-27受体的小鼠具有耐药性，表明IL-27在耐受诱导中起着至关重要的作用。这一提议的中心假设是，静脉注射。在EAE中注射自身抗原会导致DC产生IL-27，而IL-27又会诱导产生耐受性的DC和调节TR1细胞，从而导致耐受。为了验证这一假说，提出了三个特定的目标：目的1)研究IL-27在静脉注射中产生耐受树突状细胞和抗原特异性1型调节性T细胞(TR1细胞)中的作用。宽容。我们推测IL-27在静脉注射中起关键作用。耐受通过旁分泌(抑制髓鞘特异性Th1/Th17细胞和诱导TR1细胞)和自分泌(诱导和扩增产生耐受的DC)机制。目的2)探讨Galectin-1/IL-27途径在静脉注射中的作用。耐受性诱导。Galectin-1是一种内源性糖链结合蛋白，由Tregs产生，可赋予DC依赖IL-27的耐受潜能。我们发现MOG反应树突状细胞刺激DC产生IL-27，这种作用在很大程度上依赖于Galectin-1。反过来，IL-27可以刺激 DCs高水平表达Galectin-1。此外，Galectin-1缺陷小鼠对静脉注射的诱导具有抵抗力。在EAE中的耐受性。在这个目标中，我们将检验我们的假设，即静脉注射。体内注射自体抗原将触发抗原特异性nTregs优先与DC形成聚集体，产生Galectin-1，并诱导产生耐受树突状细胞。目的3)检测外源性IL-27对静脉注射的影响。诱导EAE的耐受性。鉴于IL-27在耐受诱导中的重要作用，我们假设rmIL-27的应用将促进产生耐受/调节性DC和静脉注射T细胞的发展。注射自身抗原。因此，外源性IL-27可增强静脉注射的疗效。耐受性，并减少最大效果所需的自身抗原剂量。这将降低对耐受性自身抗原产生自身抗体或不良免疫反应的可能性。目标1和目标2研究静脉注射的基本机制。目标3侧重于将我们的研究成果转化为治疗。从这些研究中获得的信息应该有助于更好地理解静脉注射的机制。并为中枢神经系统炎性脱髓鞘的新型免疫疗法提供了基础。