IL-33 induced-lL-9 producing type 2 innate lymphoid cells in the regulation of acute lung injury after hematopoietic stem cell transplantation (HSCT) in pediatric patients

项目摘要：异基因造血干细胞移植(HSCT)是唯一可治愈的细胞。 治疗多种儿科恶性和非恶性疾病。大约2500名儿科医生 目前在美国每年都要进行造血干细胞移植。不幸的是，与移植相关的并发症仍然是 取得成功的主要障碍，特别是移植物抗宿主病(GVHD)。肺为本病靶子 GVHD导致非传染性急性肺损伤和呼吸衰竭称为特发性肺炎综合征 (IPS)，通常是致命的。最近一项研究强调了造血干细胞移植后发生呼吸衰竭的重要性。 2018年6月专门召开了NIH研讨会，以确定临床挑战和科学知识差距 关于儿童HSCT后肺功能障碍的研究。缺乏机械性的基本认识， 因此，提供的治疗方法和生物学相关研究仍然很少。The Paczesny 实验室已发现：(1)可溶性刺激因子-2(Sst2)，白介素33(IL-33)的诱饵 受体，作为GVHD和IPS风险的生物标记物(N.Engl.《J.Med》，2013；《Biol Hour Marrow》 移植。2018年)；(2)从机制上讲，我们已经证明了由细胞病变T效应细胞分泌的Sst2， 隔离IL-33，限制其对表达跨膜ST2分子形式的T细胞的可用性，主要是 细胞保护性调节性T细胞(科学转化医学，2015)；(3)用一种药物阻断Sst2 中和单抗(抗ST2单抗)或小分子化合物可降低GVHD的严重程度和 死亡率(《科学转化医学》，2015；《临床调查洞察》杂志，2019年)，和(4) 未发表的初步数据，IL-33局部治疗或阻断Sst2降低供者干扰素γ的频率 在增加受体IL-9产生固有淋巴样细胞2型(ILC2s)的同时产生T细胞 HSCT后急性肺损伤。这一重要的临床前和临床数据为 假设：HSCT后早期，ST2/IL-33通路调节IL-9介导的ILC2s的激活和 减少Sst2和细胞病变T效应细胞，阻止IPS的发展。我们的新产品 假设将以三个特定的目的进行检验：1)确认抗ST2的致病细胞机制 中和抗体介导的几种实验性HSCT后肺部炎症的调节 建立iPS模型；2)建立IL9-ILC2在诱导细胞保护性调节性T细胞中的作用；3)阐明 内源性IL-33/膜ST2信号途径刺激IL-9产生的分子机制 肺受体ILC2s和来源分泌的可溶性ST2作为IL-33的屏障对ILC2s具有保护作用。 这一应用程序的翻译研究潜力很大，因为这些研究将增强我们的 HSCT后Alarmins及其受体在肺损伤中的作用 调节这些通路，降低儿童HSCT受者呼吸衰竭的风险和严重程度， 从而改善结果并扩大HSCT和其他新的细胞疗法的使用。

PROJECT SUMMARY: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative cellular therapy for many pediatric patients with malignant and non-malignant disorders. Approximately 2500 pediatric HSCT are currently performed annually in the U.S. Unfortunately, transplant-related complications remain a major barrier to successful outcomes particularly graft-versus-host disease (GVHD). The lung is a target of GVHD leading to noninfectious acute lung injury and respiratory failure called idiopathic pneumonia syndrome (IPS), often fatal. The significance of respiratory failure occurring after HSCT was recently underscored by a June 2018 NIH workshop specifically convened to identify clinical challenges and scientific knowledge gaps regarding pulmonary dysfunction after HSCT in pediatric patients. Mechanistic basic understanding is lacking, and thus there remains a paucity of therapies and biological correlative studies offered. The Paczesny laboratory has discovered that: (1) soluble STimulation-2 (sST2), the “alarmin” interleukin-33 (IL-33) decoy receptor, as a biomarker for risk of GVHD as well as of IPS (N. Engl. J. Med, 2013; Biol Blood Marrow Transplant. 2018); (2) Mechanistically, we have shown that sST2, secreted by cytopathic T effector cells, sequesters IL-33, limiting its availability to T cells expressing the transmembrane molecule form of ST2, mostly cytoprotective regulatory T cells (Science Translational Medicine, 2015); (3) blockade of sST2 with a neutralizing monoclonal antibody (anti-ST2 mAb) or small molecule compounds reduced GVHD severity and mortality (Science Translational Medicine, 2015; Journal of Clinical Investigation Insights, 2019), and (4) In preliminary unpublished data, IL-33 local treatment or blockade of sST2 decrease frequencies of donor IFNγ producing T cells while increasing recipient IL-9 producing innate lymphoid cells type 2 (ILC2s) that controls acute lung injury after HSCT. This significant body of preclinical and clinical data provides the basis for the following hypothesis: Early after HSCT, the ST2/IL-33 pathway regulate IL-9-mediated ILC2s activation and integrity, decreasing sST2 and cytopathic T effector cells, and preventing the development of IPS. Our new hypothesis will be tested with three specific aims: 1) Confirm the pathogenic cellular mechanisms of anti-ST2 neutralizing antibody mediated regulation of inflammation in the lung following HSCT in several experimental IPS models; 2) Establish the role of IL9-ILC2s on inducing cytoprotective regulatory T cells; and 3) Elucidate the molecular mechanisms of endogenous IL-33/membrane ST2 signaling that stimulates IL-9 production by lung recipient ILC2s and the source of secreted soluble ST2 as a barrier to IL-33 protective effect on ILC2s. The translational research potential of this application is significant as these studies will enhance our understanding of how alarmins and their receptors after HSCT contribute to lung injury with the potential to modulate these pathways and reduce the risk and severity of respiratory failure in pediatric HSCT recipients, and thereby improve outcomes and extend the use of HSCT as well as other novel cellular therapies.