AUTHOR=Reikvam Håkon , Grønningsæter Ida-Sofie , Mosevoll Knut Anders , Lindås Roald , Hatfield Kimberley , Bruserud Øystein 

TITLE=Patients with Treatment-Requiring Chronic Graft versus Host Disease after Allogeneic Stem Cell Transplantation Have Altered Metabolic Profiles due to the Disease and Immunosuppressive Therapy: Potential Implication for Biomarkers

JOURNAL=Frontiers in Immunology

VOLUME=Volume 8 - 2017

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01979

DOI=10.3389/fimmu.2017.01979

ISSN=1664-3224

ABSTRACT=Chronic graft versus host disease (cGVHD) is a common long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The objective of our study was to compare the metabolic profiles for allotransplant recipients and thereby identify metabolic characteristics of patient with treatment-requiring cGVHD. The study included 51 consecutive patients (29 men and 22 women; median age 44 years, range 16-69 years) transplanted with peripheral blood stem cells derived from HLA-matched family donors. All serum samples investigated by global metabolomic profiling were collected approximately one year post-transplant (median 358 days). Thirty-one of the 51 patients (61 %) had cGVHD one year post-transplant. The affected organs were (number of patients) liver/bile duct (23), eyes (15), gastrointestinal tract (14), skin (13), mouth (10), lungs (3) and urogenital tract (1). We compared the metabolic profile for patients with and without cGVHD, and a Random Forrest Classification Analysis then resulted in 75% accuracy in differentiating the two groups. The top-30 ranked metabolites from this comparison included increased levels of bile acids, several metabolites from the cytokine-responsive kynurenine pathway for tryptophan degradation, proinflammatory lipid metabolites, phenylalanine and tyrosine metabolites derived from the gut microbial flora, and metabolites reflecting increased oxidative stress. However, nine of these top-30 ranked metabolites were probably altered due to cyclosporine or steroid treatment, and we therefore did a hierarchical clustering analysis including all 51 patients but only based on the other 21 cGVHD-specific metabolites. This analysis identified three patient subsets: one cluster included mainly patients without cGVHD and had generally low metabolite levels; another cluster included mainly patients with cGVHD (most patients with at least three affected organs) and high metabolite levels, and the last intermediate group including cGVHD patients with limited organ involvement. We conclude that allotransplant recipients with cGVHD have an altered metabolic profile caused both by the disease and its immunosuppressive treatment.