Project Details

Serum Amyloid A1 (SAA1) as a Novel Biomarker and Therapeutic Target in Graft-versus-Host Disease (GVHD)

Kristie Ramos, MD

Summary

BACKGROUND: Graft-versus-host disease (GVHD) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT) that affects 30-70% of HSCT recipients and is the leading cause of pediatric HSCT-related morbidity and mortality. Recent studies have identified serum amyloid A1 (SAA1), a vitamin A binding protein, soluble phospholipase A2 (sPLA2), and SAA1:lipid nanoparticles as integral players in CD36-mediated inflammation that could mitigate GVHD. GAP: Our proposal seeks to address the limited advances that have been made in the prediction, prevention, and non-immune suppressive treatment of children with GVHD. HYPOTHESIS: We hypothesize that SAA1:lipid nanoparticles are key mediators of the inflammatory cascade that results in the development of GVHD, and that interruption of CD36-mediated signaling will reduce the frequency and severity of GVHD. METHODS: Our first study aim will evaluate SAA1:lipid nanoparticles, sPLA2, and soluble CD36 in a large cohort of pediatric HSCT recipients, which include those that did and did not receive pre-transplant vitamin A, as well as those that did and did not develop GVHD. Our second study aim will investigate the implications of CD36-mediated signaling in GVHD pathogenesis using a CD36 knockout mouse model. RESULTS: To date, we have found that patients who received pre-transplant high-dose vitamin A had lower SAA1 levels (p=0.003) and reduced incidence of acute gastrointestinal (GI) (p=0.02) and chronic GVHD (p=0.01). In a separate study, we observed higher SAA1 levels at time of GI GVHD diagnosis as compared to those without (p=0.0001). Most recently, we measured longitudinal plasma SAA1 levels in pediatric HSCT recipients (n=130) and found that higher SAA1 levels were associated with increased non-relapse mortality as early as day +7 (HR 2.48, p=0.001) and day +14 (HR 2.04, p=<0.001), with higher SAA1 levels at day +21 associated with both acute GVHD (HR 1.46, p=0.055) and the later development of chronic GVHD (HR 1.57, p=0.04). IMPACT: Our study is highly significant as SAA1 could be validated as an early biomarker for GVHD and CD36-mediated inflammation could be mitigated with non-immune suppressive agents to reduce frequency and severity of GVHD.