The Th17-IL-9 mast cell axis in inflammatory disease

描述(申请人提供)：历史上，IL-9被证明是一种由Th2产生的细胞因子，其功能主要归因于调节肥大细胞(MC)的生长和分化。这一提议的一个关键发现是，Th17产生的IL-9比任何其他分化的T细胞产生的IL-9多得多，IL-9对Th17发挥自分泌作用，IL-9导致Th17炎症性疾病EAE。这些发现从根本上挑战了对这种细胞因子的概念性理解，并需要重新探索这种细胞因子作为Th17驱动的炎症的媒介。因此，该R21的具体目的是：1.重新探讨IL-9对T细胞功能的自分泌和旁分泌作用。Th17细胞产生IL-9，IL-9R KO Th17细胞分化迟钝。因此，我们将确定IL-9在体外和体内对Th17分化和功能的自分泌作用。由于Th17产生如此高水平的IL-9，而IL-9是一种强有力的MC生长和分化因子，我们将量化IL-9在Th17与MC的同源和非同源相互作用中的旁分泌作用。2.确定Th17-IL-9-肥大细胞轴是否存在，是否参与炎症反应？众所周知，Th17在中枢神经系统炎症性疾病--实验性自身免疫性脑脊髓炎(EAE)的发生发展中起中心作用。此外，MC在促进疾病的发展方面也有牵连。我们的意图是将Th17产生IL-9作为MC激活导致EAE发生的关键因素联系起来。 公共卫生相关性：我们描述了IL9在调节炎症性疾病中的一种新功能。鉴于目前抗IL9抗体正处于临床开发阶段，这些研究开启了使用抗IL9抗体治疗自身免疫性疾病的令人兴奋的可能性。

DESCRIPTION (provided by applicant): Historically, IL-9 has been shown to be a Th2-produced cytokine whose function was mostly attributed to regulating the growth and differentiation of mast cells (MC). A key finding of this proposal is that Th17 produce far greater amounts of IL-9 then do any other differentiated T cells, that IL-9 exerts autocrine effects on Th17, and IL-9 contributes to the Th17 inflammatory disease EAE. These findings fundamentally challenge the conceptual understanding of this cytokine and warrant a re-exploration of this cytokine as a mediator of Th17-driven inflammation. Therefore, the specific aims of this R21 are 1. Re-explore the autocrine and paracrine effects of IL-9 on T cell function. It appears that Th17 produce IL9 and IL-9R KO Th17 have blunted differentiation. As such, we will define the autocrine effects of IL-9 in vitro and in vivo on Th17 differentiation and function. Because Th17 produce such high levels of IL-9 and IL-9 is a potent MC growth and differentiation factor, we will quantify the paracrine effects of IL-9 on Th17 cognate and non- cognate interactions with MC. 2. Determine if the Th17-IL-9-Mast cell axis exists and if it mediates inflammation? It is well established that Th17 are central to the development of the CNS inflammatory disease, experimental autoimmune encephalomyelitis (EAE). Furthermore, MC have been implicated in facilitating disease development. It is our intent to causally link the production of IL-9 by Th17 as a critical factor in MC activation leading to the development of EAE. PUBLIC HEALTH RELEVANCE: We describe a new function of IL9 in mediating inflammatory diseases. Given that anti-IL9 is currently in clinical development, these studies open up the exciting possibilities of using anti-IL9 in the treatment of autoimmune disease.