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

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $408,895

## Abstract

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 injur...

## Key facts

- **NIH application ID:** 9865391
- **Project number:** 1R01HD100485-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** KENNETH R COOKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,895
- **Award type:** 1
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9865391

## Citation

> US National Institutes of Health, RePORTER application 9865391, Inflammatory mechanisms responsible for the development of multiple organ dysfunction in pediatric patients following allogeneic blood and marrow transplantation (BMT). (1R01HD100485-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9865391. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*