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

描述（由申请人提供）：历史上，IL-9已被证明是Th 2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。该提议的一个关键发现是Th 17产生比任何其他分化的T细胞更大量的IL-9，IL-9对Th 17发挥自分泌作用，并且IL-9有助于Th 17炎性疾病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，并保证重新探索这种细胞因子作为Th 17驱动的炎症介质。因此，R21的具体目标是1。重新探讨IL-9对T细胞功能的自分泌和旁分泌作用。似乎Th 17产生IL-9和IL-9 R KO Th 17具有钝化的分化。因此，我们将定义IL-9在体外和体内对Th 17分化和功能的自分泌作用。由于Th 17产生如此高水平的IL-9，并且IL-9是有效的MC生长和分化因子，我们将定量IL-9对Th 17同源和非同源与MC相互作用的旁分泌作用。2.确定Th 17-IL-9-肥大细胞轴是否存在以及是否介导炎症？Th 17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）的发生发展中起着重要作用。此外，MC还参与促进疾病的发展。我们的目的是将Th 17产生IL-9作为MC激活的关键因素与EAE的发展联系起来。 公共卫生相关性：我们描述了IL 9在介导炎症性疾病中的新功能。鉴于抗IL 9目前处于临床开发中，这些研究开辟了使用抗IL 9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.