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移植 为大约 2500 名患有恶性和非恶性疾病的儿童患者提供治疗。 目前，美国每年都会进行 HSCT。不幸的是，移植相关的并发症仍然是一个常见问题 成功结果的主要障碍，特别是移植物抗宿主病（GVHD），肺部是其目标。 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)，最近的一项研究强调了 HSCT 后发生呼吸衰竭的重要性。 2018 年 6 月 NIH 专门召开研讨会，以确定临床挑战和科学知识差距 关于儿科患者 HSCT 后肺功能障碍的机制缺乏基本了解， 因此，提供的治疗方法和生物学相关研究仍然很少。 实验室发现： (1) 可溶性 STimulation-2 (sST2)，“警报”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. J. Med, 2013；Biol Blood Marrow (2) 从机制上讲，我们已经证明由细胞病变 T 效应细胞分泌的 sST2， 隔离 IL-33，限制其对表达 ST2 跨膜分子形式的 T 细胞的利用，主要是 细胞保护性调节性 T 细胞（科学转化医学，2015）；（3）用 中和单克隆抗体（抗 ST2 mAb）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 年；《临床研究洞察杂志》，2019 年），以及 (4) 初步未发表的数据，IL-33 局部治疗或 sST2 阻断会降低供体 IFNγ 的频率 产生 T 细胞，同时增加受体 IL-9 的产生，控制产生先天性 2 型淋巴细胞 (ILC2) 这些重要的临床前和临床数据为 HSCT 后的急性肺损伤提供了基础。 以下假设：HSCT 后早期，ST2/IL-33 通路调节 IL-9 介导的 ILC2 激活， 完整性，减少 sST2 和细胞病变 T 效应细胞，并防止 IPS 的发展。 假设将通过三个具体目标进行检验：1）确认抗 ST2 的致病细胞机制 在几个实验中 HSCT 后中和抗体介导的肺部炎症调节 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 信号传导刺激 IL-9 产生的分子机制 肺受体ILC2和分泌的可溶性ST2的来源作为IL-33对ILC2保护作用的屏障。 该应用的转化研究潜力非常重要，因为这些研究将增强我们的研究能力 了解 HSCT 后警报素及其受体如何导致肺损伤，并有可能 调节这些途径并降低儿科 HSCT 受者呼吸衰竭的风险和严重程度， 从而改善结果并扩大 HSCT 以及其他新型细胞疗法的使用。