Inflammatory mechanisms responsible for the development of multiple organ dysfunction in pediatric patients following allogeneic blood and marrow transplantation (BMT).

炎症机制导致儿童患者在同种异体血液和骨髓移植（BMT）后出现多器官功能障碍。

• 批准号: 10554332
• 负责人: KENNETH R COOKE
• 金额: $ 40.07万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554332
• 关键词: ANGPT1 gene; Adhesiveness; Adolescent and Young Adult; Agonist; Allogenic; Angiopoietin-2; Binding Proteins; Biological; Biological Markers; Blood; Blood Vessels; Blood capillaries; Bone Marrow Transplantation; Cell Adhesion Molecules; Cell Therapy; Cell physiology; Cell surface; Cells; Cessation of life; Child; Childhood; Clinical; Clinical Data; Clinical Trials; Cytotoxic Chemotherapy; Data; Development; Disease; E-Selectin; Educational workshop; Endothelial Cells; Equilibrium; Etanercept; Evaluation; Functional disorder; Funding; Human; Idiopathic pneumonia syndrome; Immunologics; Incidence; Inflammation; Inflammatory; Injury; Interleukin-6; Knowledge; Lead; Life; Ligands; Link; Liver diseases; Lung; Malignant - descriptor; Mediating; Multiple Organ Failure; Mus; National Heart, Lung, and Blood Institute; National Institute of Child Health and Human Development; Non-Malignant; Onset of illness; Organ; Outcome; P-Selectin; Pathway interactions; Patients; Peptides; Plasma; Procedures; Production; Proteins; Proteomics; Pulmonary Inflammation; Research; Respiratory Failure; Risk Reduction; Role; Sampling; Selectins; Severities; TIE-2 Receptor; TNF gene; Testing; Translational Research; Transplant Recipients; Transplantation; United States National Institutes of Health; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Cell; Veno-Occlusive Disease; Work; antagonist; cell injury; chemokine; curative treatments; cytokine; dimer; experimental study; graft vs host disease; improved; improved outcome; insight; lumican; lung injury; novel strategies; pediatric patients; pre-clinical; predicting response; receptor; vascular injury

Allogeneic blood and marrow transplantation (allo-BMT) is the only curative therapy for many pediatric patients with malignant and non-malignant disorders. Unfortunately, treatment-related complications remain a major barrier to successful outcomes. A multiple organ dysfunction syndrome (MODS) workshop convened by the NICHD in March 2015 identified respiratory failure, the delivery of cytotoxic therapies and complications associated with allo-BMT as three distinct contributors to MODS and death in pediatric patients. The significance of respiratory failure occurring after BMT was recently underscored by a June 2018 NIH workshop specifically convened to identify clinical challenges and scientific knowledge gaps regarding pulmonary dysfunction after BMT in pediatric patients. Hence, the development of novel strategies that reduce the incidence and severity of pulmonary dysfunction after allo-BMT remains a significant unmet need. Idiopathic pneumonia syndrome (IPS) is a frequently fatal form of lung injury occurring after BMT. Progress has been made to understand the mechanisms responsible for IPS; the Cooke lab discovered that TNFα contributes directly to vascular endothelial cell (EC) injury and regulates the subsequent influx of donor cells into the lung. These insights lead to several clinical trials testing the effects of etanercept (a dimeric TNFα binding protein) in BMT-recipients with IPS. While successful, not all patients respond to etanercept revealing a critical need for continued research. Proteomic evaluation of plasma sample revealed striking similarities between human and experimental IPS and identified protein candidates that associate with EC injury and disease onset. Additional studies revealed a here-to-fore unknown association between IPS and the protein angiopoietin (Ang)-2. Ang-1 and Ang-2 are peptide ligands for the receptor tyrosine kinase, Tie-2 and represent an agonist / antagonist pair that regulate EC integrity. Moreover, Ang-2 sensitizes ECs to TNFα and regulates TNFα-induced adhesion molecule expression. Hence a significant body of pre-clinical and clinical data provides the basis for the following central hypothesis: During inflammation early after allo-BMT, the Ang1:Ang2 pathways regulate cytokine-mediated EC activation and integrity, increased adhesion molecule expression, and development of IPS. Pertinent to this application, EC damage and dysfunction is a common-thread among several BMT-related complications including IPS, graft-vs-host disease (GVHD) and veno-occlusive disease (VOD) of the liver all of which contribute to MODS after BMT. Independent biomarker data also suggest that biologic pathways contributing to EC injury and leak during IPS are likely operative during the development of GVHD and VOD as well. The translational research potential of this application is therefore significant: Proposed experiments will enhance our understanding of how inflammation after transplant contributes to vascular EC injury and organ dysfunction with great potential to reduce the risk and severity of MODS in pediatric BMT recipients and thereby improve outcomes and broaden the utility of this powerful form of cellular therapy to children in need.

同种异体血液和骨髓移植（allo-BMT）是许多儿科患者的唯一治疗方法 恶性和非恶性疾病。不幸的是，与治疗相关的并发症仍然是一个主要的问题 成功结果的障碍。多器官功能障碍综合征（MODS）研讨会由 NICHD 于 2015 年 3 月发现呼吸衰竭、细胞毒性治疗和并发症 与异基因 BMT 相关的是儿科患者 MODS 和死亡的三个不同因素。这 2018 年 6 月 NIH 研讨会最近强调了 BMT 后发生呼吸衰竭的重要性 专门召开会议以确定有关肺病的临床挑战和科学知识差距 儿科患者 BMT 后功能障碍。因此，开发新的策略来减少 同种异体骨髓移植后肺功能障碍的发生率和严重程度仍然是一个重大的未满足的需求。特发性 肺炎综合征 (IPS) 是 BMT 后发生的一种常见的致命性肺损伤。已取得进展 了解负责 IPS 的机制；库克实验室发现 TNFα 有助于 直接作用于血管内皮细胞（EC）损伤并调节供体细胞随后流入肺部。 这些见解引发了多项临床试验，测试依那西普（一种二聚体 TNFα 结合蛋白）在 具有 IPS 的 BMT 接受者。虽然成功，但并非所有患者都对依那西普有反应，这表明对依那西普的迫切需求 继续研究。血浆样本的蛋白质组学评估揭示了人类和人类之间惊人的相似之处 实验性 IPS 并确定了与 EC 损伤和疾病发作相关的候选蛋白质。额外的 研究揭示了 IPS 与血管生成素 (Ang)-2 蛋白之间迄今为止未知的关联。血管紧张素1 Ang-2 和 Ang-2 是受体酪氨酸激酶 Tie-2 的肽配体，代表激动剂/拮抗剂对 规范 EC 完整性。此外，Ang-2 使 EC 对 TNFα 敏感并调节 TNFα 诱导的粘附 分子表达。因此，大量的临床前和临床数据为 以下中心假设：在同种异体 BMT 后早期的炎症过程中，Ang1:Ang2 通路调节 细胞因子介导的 EC 激活和完整性、粘附分子表达增加以及 IPS。与此应用相关，EC 损伤和功能障碍是几种 BMT 相关的共同点 并发症包括 IPS、移植物抗宿主病 (GVHD) 和肝静脉闭塞病 (VOD) BMT 后会导致 MODS。独立的生物标志物数据还表明，生物途径 IPS 期间导致 EC 损伤和渗漏的因素可能在 GVHD 和 VOD 的发展过程中起作用，因为 出色地。因此，该应用的转化研究潜力是巨大的：拟议的实验将 增强我们对移植后炎症如何导致血管内皮细胞损伤和器官的理解 功能障碍具有降低儿科 BMT 接受者 MODS 风险和严重程度的巨大潜力 从而改善结果并扩大这种强大的细胞疗法对有需要的儿童的效用。