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Project Details
Description
Summary
Chronic GVHD (cGVHD) is the major cause of late morbidity, mortality and compromised organ function
after allogeneic hematopoietic stem cell transplant (HCT). It can affect essentially all organs and tissues,
including the lungs, where the disease is termed Bronchiolitis Obliterans Syndrome (BOS). BOS is a
progressive, irreversible, and often fatal lung disease that occurs following HCT. BOS occurs in approximately
5-10% of HCT survivors and is considered the pulmonary manifestation of cGVHD. Approximately 10-15% of
cGVHD patients will develop BOS, and less than 15% of BOS patients survive 5 years. The primary site of
inflammation in BOS is the small airway, eventually leading to fibrosis. cGVHD results from a failure to achieve
immune tolerance after transplant. The mechanisms responsible for the failure of tolerance are complex
and involve multiple cell types, but T cells are central to this process. Resting T cells preferentially use
mitochondrial oxidative phosphorylation as basal energy. In acute GVHD, donor T cells exposed to host
alloantigen in an inflammatory environment rapidly differentiate and proliferate, with bioenergetic and
biosynthetic needs fulfilled by reprogramming metabolism and using multiple energy sources. In cGVHD,
metabolism demands are less well understood, but with the high energy demands of proliferating immune cells
in cGVHD, strategies to specifically block critical metabolic pathways may prove to be a novel treatment strategy.
In this Program, we focus on the critical questions that plague the field of cGVHD. We address shortcomings in
our understanding of the pathogenesis of human cGVHD and our ability to prioritize the next generation of
therapeutic strategies by defining the immune networks that characterize patients who develop cGVHD and
interrogate the mechanisms of both success and failure of cGVHD treatment regimens. We explore the unique
metabolic demands in cGVHD pathogenesis and lung injury repair and focus therapeutics on the most severe
manifestation of cGVHD, BOS. We employ novel organoid cultures and immunogenomics to pinpoint the cellular
and antigenic targets of BOS. We have assembled a collaborative, multidisciplinary team, uniquely poised to
make significant impact in the field.
Status | Active |
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Effective start/end date | 9/15/22 → 8/31/24 |
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Metabolomics of cGVHD
National Heart, Lung, and Blood Institute
8/31/23 → 8/30/24
Project: Research project
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Metabolomics of cGVHD
National Heart, Lung, and Blood Institute
9/1/22 → 8/30/23
Project: Research project