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 TNF? 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 TNF? 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 TNF? and regulates TNF?-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.
Transplant-related complications including idiopathic pneumonia syndrome (IPS), graft-vs- host disease (GVHD) and veno-occlusive disease (VOD) of the liver are the major contributors to the development of MODS after allogeneic blood and marrow transplantation (BMT) and continue to limit successful outcomes following this otherwise lifesaving procedure. The development of novel strategies to reduce the incidence and severity of these complications or treat the life-threatening aspects of each once established remains one of the most significant challenges facing our pediatric BMT patients. Experiments proposed in this application will enhance our understanding of how inflammation engendered early after transplant contributes to vascular injury and organ dysfunction with great potential to reduce the risk and severity of MODS and improve outcomes for BMT recipients.
