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

IL-33诱导产生IL-9的2型先天淋巴细胞在调节儿科患者造血干细胞移植（HSCT）后急性肺损伤中的作用

• 批准号: 10540768
• 负责人: Sophie Paczesny
• 金额: $ 56.43万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540768
• 关键词: Acute Lung Injury; Allogenic; Alveolar; Binding; Biological; Biological Markers; Blood; Bone Marrow Transplantation; Cell Therapy; Cells; Childhood; Chimera organism; Clinical; Clinical Data; Clinical Trials; Correlative Study; Cytoprotection; Data; Detection; Development; Disease; Educational workshop; Effector Cell; Endothelium; Epithelial Cells; Epithelium; Equilibrium; Eragrostis; Frequencies; Functional disorder; Genetic; Hematology; Hematopoietic; Hematopoietic Stem Cell Transplantation; IL9 gene; Idiopathic pneumonia syndrome; Incidence; Inflammation; Interferon Type II; Interleukin-9; Interleukins; Journals; Knowledge; Laboratories; Life; Lung; Lymphoid Cell; Malignant - descriptor; Mediating; Membrane; Minor; Modeling; Molecular; Monoclonal Antibodies; Multiple Organ Failure; Non-Malignant; Outcome; PTPRC gene; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Plasma; Population; Pre-Clinical Model; Procedures; Production; Proteome; Regimen; Regulation; Regulatory T-Lymphocyte; Residual state; Respiratory Failure; Risk; Risk Reduction; Role; Severities; Severity of illness; Signal Transduction; Source; Stromal Cells; T-Lymphocyte; Testing; Therapeutic; Translating; Translational Research; Transplant Recipients; Transplantation; United States National Institutes of Health; cell type; clinical investigation; curative treatments; effector T cell; experimental study; graft vs host disease; improved; improved outcome; insight; lung injury; mortality; neutralizing antibody; neutralizing monoclonal antibodies; new therapeutic target; novel; novel strategies; pediatric patients; pre-clinical; prevent; prophylactic; protective effect; radioresistant; receptor; response; risk stratification; small molecule; success; translational medicine

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.

项目摘要：同种异体造血干细胞移植（HSCT）是唯一的治愈性细胞 许多恶性和非恶性疾病的儿科患者的治疗。大约2500个小儿 不幸的是，目前在美国每年每年进行HSCT，与移植有关的并发症仍然是 成功结局的主要障碍，尤其是移植物与宿主病（GVHD）。肺是 GVHD导致非感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，A 2018年6月，美国国立卫生研究院（NIH）专门召集了旨在确定临床挑战和科学知识差距 关于小儿患者HSCT后肺部功能障碍。缺乏机械基本理解， 因此，提供的疗法和生物相关性研究仍然很少。 Paczesny 实验室发现：（1）可溶性刺激-2（SST2），“ Alarmin”白介素33（IL-33）诱饵 受体，作为GVHD和IPS风险的生物标志物（N.Engl。J.Med，2013年； Biol Blood Marrow 移植。 2018）; （2）从机械上讲，我们已经表明，由细胞病T效应细胞分泌的SST2， 隔离IL-33，将其可用性限制为表达跨膜分子形式的T细胞，主要是 细胞保护调节T细胞（科学转化医学，2015年）； （3）SST2桶 中和单克隆抗体（抗ST2 mAb）或小分子化合物降低了GVHD严重程度和 死亡率（科学转化医学，2015年；临床研究杂志，2019年），（4） 初步未发表的数据，IL-33局部治疗或SST2的封锁降低供体IFNγ的频率 产生T细胞，同时增加受体IL-9的产生先天淋巴样细胞2型（ILC2） HSCT后急性肺损伤。大量的临床前和临床数据为 以下假设：HSCT之后，ST2/IL-33途径调节IL-9介导的ILC2S激活和 完整性，降低SST2和细胞性T效应细胞，并防止IPS的发展。我们的新 假设将以三个特定目的进行检验：1）确认抗ST2的病原性细胞机制 在几种实验中，HSCT后，中和抗体介导的肺部炎症调节调节 IPS模型； 2）确定IL9-ILC2在诱导的细胞保护调节T细胞上的作用； 3）阐明 内源性IL-33/膜ST2信号传导的分子机制，该信号通过刺激IL-9的产生 肺接受者ILC2和分泌固体ST2的来源是IL-33对ILC2的受保护作用的障碍。 该应用的翻译研究潜力很重要，因为这些研究将增强我们的 了解HSCT后，警报蛋白及其接收者如何造成肺损伤，并有可能 调节这些途径，并降低小儿HSCT接受者呼吸衰竭的风险和严重程度， 从而改善结果并扩展HSCT以及其他新型细胞疗法的使用。