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

异基因血液和骨髓移植（allo-BMT）是许多儿科患者的唯一治愈性治疗方法 恶性和非恶性疾病。不幸的是，治疗相关的并发症仍然是一个主要的 成功的障碍。多器官功能障碍综合征（MODS）研讨会由 2015年3月，NICHD确定了呼吸衰竭、细胞毒性治疗和并发症 与allo-BMT相关，是儿科患者MODS和死亡的三个不同因素。的 最近，2018年6月的NIH研讨会强调了BMT后发生呼吸衰竭的重要性 专门召开会议，以确定有关肺部疾病的临床挑战和科学知识差距 儿科患者骨髓移植后的功能障碍。因此，开发新的战略，减少 allo-BMT后肺功能障碍的发生率和严重程度仍然是一个显著未满足的需求。特发 肺炎综合征（IPS）是BMT后发生的一种常见的致命性肺损伤形式。进展 为了了解IPS的机制，库克实验室发现TNFα有助于 直接导致血管内皮细胞（EC）损伤，并调节供体细胞随后流入肺。 这些见解导致了几项临床试验，测试依那西普（一种二聚体TNFα结合蛋白）在 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。血浆样品的蛋白质组学评价揭示了人与人之间惊人的相似性。 实验IPS和鉴定的蛋白候选物与EC损伤和疾病发作相关。额外 研究揭示了IPS和蛋白质血管生成素（Ang）-2之间迄今未知的关联。Ang-1 和Ang-2是受体酪氨酸激酶Tie-2的肽配体，并代表激动剂/拮抗剂对 规范EC完整性。此外，Ang-2可使内皮细胞对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研究提供了基础： 以下中心假设：在allo-BMT后早期炎症期间，Ang 1：Ang 2通路调节 姜黄素介导的EC活化和完整性，增加的粘附分子表达，以及 IPS。与此应用相关，EC损伤和功能障碍是几种与BMT相关的疾病中的共同点。 并发症包括IPS，移植物抗宿主病（GVHD）和肝静脉闭塞性疾病（VOD）， 导致骨髓移植后多器官功能障碍综合征。独立的生物标志物数据也表明， 在IPS期间导致EC损伤和渗漏的可能在GVHD和VOD的发展期间起作用， 好.因此，该应用的转化研究潜力是显著的： 增强我们对移植后炎症如何导致血管EC损伤和器官损伤的理解， 功能障碍具有很大的潜力，以降低儿童BMT接受者的MODS的风险和严重程度， 从而改善结果，并扩大这种强大形式的细胞疗法对有需要的儿童的效用。

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.