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: 10333218
• 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/10333218
• 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; 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; 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（alloo - bmt）是许多儿科患者唯一的治疗方法