Document text
Principal Investigator: KENNETH R COOKE
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2023
Award: $400,716
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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.
Terms: <(TNF)-α><0-11 years old><ANG1><ANG1 Gene><ANGPT1><ANGPT1 gene><Adhesion Molecule><Adhesiveness><Adolescent and Young Adult><Agonist><Airway failure><Allogenic><Ang-2><Ang2><Angiopoietin 1 Gene><Angiopoietin 1 Receptor><Angiopoietin Receptor Tie-2><Angiopoietin-1><Angiopoietin-2><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Binding Proteins><Biological><Biological Markers><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Vessels><Blood capillaries><Bone Marrow Grafting><Bone Marrow Transplant><Bone Marrow Transplantation><CD106><CD106 Antigens><CD202B Antigen><CD62E Antigens><CD62P Antigens><Cachectin><Cell Adhesion Molecule E-Selectin><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cell Function><Cell Process><Cell Therapy><Cell physiology><Cell surface><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular injury><Cessation of life><Chemotactic Cytokines><Child><Child Youth><Childhood><Children (0-21)><Clinical><Clinical Data><Clinical Trials><Cytotoxic Chemotherapy><Cytotoxic Therapy><Data><Death><Development><Disease><Disorder><Dysfunction><E-Selectin><ELAM-1><Educational workshop><Enbrel><Endothelial Adhesion Molecule 1><Endothelial Cells><Endothelial Leukocyte Adhesion Molecule-1><Endothelial TEK Tyrosine Kinase><Epithelial-Specific Protein Receptor Tyrosine Kinase TIE-2><Equilibrium><Etanercept><Evaluation><Functional disorder><Funding><GMP-140><GvHD><HPGF><Hepatic Disorder><Hepatocyte-Stimulating Factor><Homologous Chemotactic Cytokines><Homologous Wasting Disease><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><INCAM-110><Idiopathic pneumonia syndrome><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Incidence><Inducible Cell Adhesion Molecule 110><Inflammation><Inflammatory><Injury><Intercrines><Interleukin-6><KIAA0003><Knowledge><LECAM-2><LECAM-3><Lead><Leukocyte Endothelial Cell Adhesion Molecule 2><Life><Ligand Binding Protein><Ligand Binding Protein Gene><Ligands><Link><Liver diseases><Lung><Lung Inflammation><Lung Respiratory System><Lung damage><MGI-2><MOF syndrome><Macrophage-Derived TNF><Malignant><Malignant - descriptor><Marrow Transplantation><Mediating><Mice><Mice Mammals><Modern Man><Monocyte-Derived TNF><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><Myeloid Differentiation-Inducing Protein><NHLBI><NICHD><NIH><National Heart, Lung, and Blood Institute><National Institute of Child Health and Human Development><National Institute of Children's Health and Human Development><National Institutes of Health><Non-Malignant><Onset of illness><Organ><Outcome><P-Selectin><Pathway interactions><Patients><Pb element><Peptides><Physiopathology><Plasma><Plasma Serum><Plasmacytoma Growth Factor><Platelet alpha-Granule Membrane Protein><Pneumonitis><Procedures><Production><Protein Binding><Proteins><Proteomics><Pulmonary Inflammation><Receptor Protein><Research><Respiratory Failure><Reticuloendothelial System, Serum, Plasma><Risk Reduction><Role><Runt Disease><SIS cytokines><Sampling><Selectins><Severities><Subcellular Process><TEK Tyrosine Kinase><TIE-2 Receptor><TIE-2 Receptor Tyrosine Kinase><TIE-2-RTK><TIE2 Tyrosine Kinase><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Tek Receptor><Testing><Tie2 Receptor><Translational Research><Translational Science><Transplant Recipients><Transplantation><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tunica Interna Endothelial Cell Kinase><Tyrosine-Protein Kinase Receptor TEK><Tyrosine-Protein Kinase Receptor TIE-2><United States National Institutes of Health><VCAM><VCAM-1><Vascular Cell Adhesion Molecule><Vascular Cell Adhesion Molecule-1><Vascular Endothelial Cell><Vaso-Occlusive Disease><Veno-Occlusive Disease><Work><Workshop><antagonism><antagonist><balance><balance function><bio-markers><biologic><biologic marker><biomarker><bound protein><capillary><cell adhesion protein><cell damage><cell injury><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular damage><cellular therapeutic><cellular therapy><chemoattractant cytokine><chemokine><child patients><curative intervention><curative therapeutic><curative therapy><curative treatments><cytokine><damage to cells><developmental><dimer><disease onset><disorder onset><endothelial leukocyte adhesion molecule><experiment><experimental research><experimental study><experiments><graft versus host disease><graft vs host disease><graft vs. host disease><heavy metal Pb><heavy metal lead><hepatic disease><hepatopathy><improved><improved outcome><injuries><injury to cells><injury to the vasculature><insight><interferon beta 2><kids><liver disorder><lumican><lung injury><multiorgan failure><multiple organ system failure><new approaches><nonmalignant><novel approaches><novel strategies><novel strategy><p140 TEK><pathophysiology><pathway><pediatric><pediatric patients><pre-clinical><preclinical><predicting response><prediction of response><predictive response><predictor of response><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><receptor><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><response prediction><risk-reducing><social role><translation research><translational investigation><transplant><transplant patient><vascular><vascular injury><youngster>