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疗法 患有恶性和非恶性疾病。不幸的是，与治疗相关的并发症仍然是主要的 成功成果的障碍。多器官功能障碍综合征（MODS）研讨会由 NICHD在2015年3月确定了呼吸衰竭，细胞毒性疗法的递送和并发症 与Allo-BMT相关，是小儿患者的三个不同的MOD和死亡的不同贡献者。这 2018年6月的NIH研讨会最近强调了BMT后发生呼吸衰竭的重要性 专门召集以确定有关肺部的临床挑战和科学知识差距 小儿患者BMT后的功能障碍。因此，开发了减少的新型策略 Allo-BMT后肺功能障碍的发病率和严重程度仍然是一个明显的未满足需求。特发性 肺炎综合征（IPS）是BMT后发生的一种致命的肺损伤形式。进步一直在 理解负责IP的机制；库克实验室发现TNFα有助于 直接发生血管内皮细胞（EC）损伤，并调节供体细胞在肺中的随后影响。 这些见解导致了几项临床试验，测试了Etanercept（二聚体TNFα结合蛋白）的影响 与IPS的BMT重新质量。在成功的同时，并非所有患者都对Etanercept做出反应，揭示了对 继续研究。血浆样本的蛋白质组学评估显示，人与 实验IPS并确定了与EC损伤和疾病发作相关的蛋白质候选者。额外的 研究揭示了IPS与蛋白质血管素（ANG）-2之间的未知相关性。 ang-1 Ang-2是用于受体酪氨酸激酶的胡椒配体，TIE-2，代表激动剂 /拮抗剂对 调节EC的完整性。此外，Ang-2将ECS感知到TNFα并调节TNFα诱导的粘合剂 分子表达。因此，大量的临床前和临床数据为此提供了基础 遵循中心假设：在Allo-BMT之后早期炎症期间，ANG1：ANG2途径调节 细胞因子介导的EC激活和完整性，粘附分子表达增加以及发展 IPS。与此应用有关，EC损坏和功能障碍是几个与BMT相关的通用线程 包括IPS，GRAFT-VS-HOST疾病（GVHD）和肝脏的静脉疾病（VOD）在内的并发症 这有助于BMT之后的mod。独立的生物标志物数据还表明生物学途径 在IPS期间造成EC损伤和泄漏的原因可能在GVHD和VOD开发过程中运行 出色地。因此，该应用的翻译研究潜力很重要：拟议的实验将 增强我们对移植后感染如何促进血管EC损伤和器官的理解 功能障碍具有降低小儿BMT接受者和 从而改善结果并扩大了这种强大的细胞疗法对有需要的儿童的实用性。