The role of IL-27 in iv tolerance in EAE

描述（由申请人提供）：静脉注射可溶性抗原可诱导实验性自身免疫性脑脊髓炎（EAE）（多发性硬化症动物模型）的抗原特异性耐受性，并有效抑制该疾病。静脉注射自身抗原诱导耐受性树突状细胞（dc），产生IL-27，一种有效的免疫调节细胞因子。虽然野生型EAE小鼠可以成功诱导耐受性，但缺乏IL-27受体的小鼠具有耐药性，这表明IL-27在诱导耐受性中起着至关重要的作用。该建议的中心假设是，在EAE中静脉注射自身抗原导致dc产生IL-27， IL-27反过来诱导耐受性dc和调节性Tr1细胞，导致耐受性。为了验证这一假设，我们提出了三个特定的目的：目的1)研究IL-27在耐受性dc和抗原特异性1型调节性T （Tr1）细胞产生中的作用。我们假设IL-27通过旁分泌（抑制髓磷脂特异性Th1/Th17细胞和诱导Tr1细胞）和自分泌（诱导和扩大耐受性dc）机制在静脉耐受性中发挥关键作用。目的2)探讨半乳糖凝集素-1/IL-27通路在静脉耐受诱导中的作用。半乳糖凝集素-1是一种内源性的聚糖结合蛋白，由treg产生，可以赋予dc具有il -27依赖性的耐受性。我们发现mog反应性Tregs刺激dc产生IL-27，这种作用主要依赖于半乳糖凝集素-1。反过来，IL-27可以刺激

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.