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: 10091494
• 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/10091494
• 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; Lung Inflammation; 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; Receptor Protein-Tyrosine Kinases; Research; Respiratory Failure; Risk; 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; 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.

异基因血液和骨髓移植(allo-bmt)是许多儿科患者的唯一治疗方法。 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一个主要问题。 取得成功的障碍。多器官功能障碍综合征(MODS)研讨会由 NICHD在2015年3月发现呼吸衰竭、细胞毒性治疗的交付和并发症 与异基因骨髓移植相关的三个不同的因素导致多器官功能障碍综合征和儿科患者的死亡。这个 美国国立卫生研究院2018年6月的研讨会最近强调了骨髓移植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 儿童骨髓移植后的功能障碍。因此，开发新的战略可以减少 Allo-BMT后肺功能障碍的发生率和严重程度仍然是一个重要的未得到满足的需求。特发性 肺炎综合征(IPS)是骨髓移植后发生的一种经常致命的肺损伤形式。已经取得了进展 库克实验室发现，肿瘤坏死因子α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进入肺内。 这些见解导致了几项临床试验，以测试依那西普(一种二聚体肿瘤坏死因子α结合蛋白)在 BMT-使用IPS的收件人。虽然成功，但并不是所有患者对依那西普都有反应，这揭示了对 继续研究。血浆样本的蛋白质组学分析显示，人类和 实验性IPS和已确定的与EC损伤和疾病发病相关的候选蛋白质。其他内容 研究表明，IPS和血管生成素(Ang)-2蛋白之间存在未知的关联。血管紧张素-1 Ang-2是受体酪氨酸激酶Tie-2的多肽配体，代表激动剂/拮抗剂对 来规范欧共体的诚信。此外，Ang-2使内皮细胞对肿瘤坏死因子α敏感，并调节肿瘤坏死因子α诱导的黏附。 分子表达。因此，大量的临床前和临床数据为 遵循中心假说：在allo-BMT后早期炎症期间，Ang1：Ang2通路调节 细胞因子介导的EC激活和完整性，增加黏附分子的表达，并发展为 IPS。与这一应用相关，EC损伤和功能障碍是几个与BMT相关的共同主题 并发症包括IPS、移植物抗宿主病(GVHD)和肝静脉闭塞病(VOD) 导致骨髓移植后出现多器官功能障碍综合征。独立的生物标志物数据也表明，生物途径 在IPS期间导致EC损伤和泄漏可能在GVHD和VOD AS的发展过程中起作用 井。因此，这一应用的翻译研究潜力是巨大的：拟议的实验将 加深我们对移植后炎症如何导致血管内皮细胞损伤和器官的了解 功能障碍极有可能降低儿童骨髓移植受者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治疗对有需要的儿童的效用。