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型先天淋巴细胞在儿科患者造血干细胞移植（HSCT）后急性肺损伤的调节中

• 批准号: 10392134
• 负责人: Sophie Paczesny
• 金额: $ 62.56万
• 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/10392134
• 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; Data; Detection; Development; Disease; Educational workshop; Effector Cell; Endothelium; Epithelial; Epithelial Cells; 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; 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.

异基因造血干细胞移植（HSCT）是目前唯一的治疗性细胞移植。 治疗许多患有恶性和非恶性疾病的儿科患者。约2500名儿童 HSCT目前在美国每年进行一次。不幸的是，移植相关的并发症仍然是一个严重的问题。 移植物抗宿主病（GVHD）是成功结局的主要障碍。肺是一个目标， 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)往往是致命的。HSCT后发生呼吸衰竭的重要性最近被一项研究强调， 2018年6月专门召开NIH研讨会，以确定临床挑战和科学知识差距 关于儿科患者HSCT后肺功能障碍。缺乏基本的机械理解， 因此仍然缺乏所提供的治疗和生物学相关研究。帕琴斯尼酒店 实验室发现：（1）可溶性STimulation-2（sST 2），白细胞介素-33（IL-33）诱饵 受体，作为GVHD和IPS风险的生物标志物（N. Engl.医学杂志，2013;生物学血液骨髓 移植（2）从机制上讲，我们已经证明，由致细胞病变的T效应细胞分泌的sST 2， 隔离IL-33，限制其对表达ST 2的跨膜分子形式的T细胞的可用性， 细胞保护性调节性T细胞（Science Translational Medicine，2015）;（3）用免疫抑制剂阻断sST 2， 中和性单克隆抗体（抗ST 2 mAb）或小分子化合物降低GVHD严重性， 死亡率（Science Translational Medicine，2015; Journal of Clinical Investigation Insights，2019），以及（4）在 初步未发表的数据，IL-33局部治疗或sST 2阻断可降低供体IFNγ的频率， 产生T细胞，同时增加受体IL-9产生先天性淋巴样细胞2型（ILC 2）， HSCT后急性肺损伤这一重要的临床前和临床数据为以下研究提供了基础： 以下假设：HSCT后早期，ST 2/IL-33通路调节IL-9介导的ILC 2活化， 完整性，减少sST 2和致细胞病变的T效应细胞，并防止IPS的发展。我们的新 本研究将从三个方面对这一假说进行检验：1）确认抗ST 2抗体的致病细胞机制 中和抗体介导的HSCT后肺部炎症调节在几个实验中 IPS模型; 2）建立IL 9-ILC 2对诱导细胞保护性调节性T细胞的作用;和3）阐明 内源性IL-33/膜ST 2信号传导刺激IL-9产生的分子机制， 肺受体ILC 2s和分泌源可溶性ST 2作为IL-33对ILC 2s的保护作用的屏障。 这一应用的转化研究潜力是重要的，因为这些研究将提高我们的 了解HSCT后alarmins及其受体如何促进肺损伤， 调节这些途径，降低儿科HSCT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。