PROJECT SUMMARY: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative cellular
therapy for many pediatric patients with malignant and non-malignant disorders. Approximately 2500 pediatric
HSCT are currently performed annually in the U.S. Unfortunately, transplant-related complications remain a
major barrier to successful outcomes particularly graft-versus-host disease (GVHD). The lung is a target of
GVHD leading to noninfectious acute lung injury and respiratory failure called idiopathic pneumonia syndrome
(IPS), often fatal. The significance of respiratory failure occurring after HSCT was recently underscored by a
June 2018 NIH workshop specifically convened to identify clinical challenges and scientific knowledge gaps
regarding pulmonary dysfunction after HSCT in pediatric patients. Mechanistic basic understanding is lacking,
and thus there remains a paucity of therapies and biological correlative studies offered. The Paczesny
laboratory has discovered that: (1) soluble STimulation-2 (sST2), the “alarmin” interleukin-33 (IL-33) decoy
receptor, as a biomarker for risk of GVHD as well as of IPS (N. Engl. J. Med, 2013; Biol Blood Marrow
Transplant. 2018); (2) Mechanistically, we have shown that sST2, secreted by cytopathic T effector cells,
sequesters IL-33, limiting its availability to T cells expressing the transmembrane molecule form of ST2, mostly
cytoprotective regulatory T cells (Science Translational Medicine, 2015); (3) blockade of sST2 with a
neutralizing monoclonal antibody (anti-ST2 mAb) or small molecule compounds reduced GVHD severity and
mortality (Science Translational Medicine, 2015; Journal of Clinical Investigation Insights, 2019), and (4) In
preliminary unpublished data, IL-33 local treatment or blockade of sST2 decrease frequencies of donor IFNγ
producing T cells while increasing recipient IL-9 producing innate lymphoid cells type 2 (ILC2s) that controls
acute lung injury after HSCT. This significant body of preclinical and clinical data provides the basis for the
following hypothesis: Early after HSCT, the ST2/IL-33 pathway regulate IL-9-mediated ILC2s activation and
integrity, decreasing sST2 and cytopathic T effector cells, and preventing the development of IPS. Our new
hypothesis will be tested with three specific aims: 1) Confirm the pathogenic cellular mechanisms of anti-ST2
neutralizing antibody mediated regulation of inflammation in the lung following HSCT in several experimental
IPS models; 2) Establish the role of IL9-ILC2s on inducing cytoprotective regulatory T cells; and 3) Elucidate
the molecular mechanisms of endogenous IL-33/membrane ST2 signaling that stimulates IL-9 production by
lung recipient ILC2s and the source of secreted soluble ST2 as a barrier to IL-33 protective effect on ILC2s.
The translational research potential of this application is significant as these studies will enhance our
understanding of how alarmins and their receptors after HSCT contribute to lung injury with the potential to
modulate these pathways and reduce the risk and severity of respiratory failure in pediatric HSCT recipients,
and thereby improve outcomes and extend the use of HSCT as well as other novel cellular therapies.
