Sclerotic-Type Cutaneous Chronic Graft-Versus-Host Disease Exhibits Activation of T Helper 1 and OX40 Cytokines

Sclerotic-type cutaneous chronic graft-versus-host disease (ScGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation, with profound morbidity. A dearth of effective, targeted treatment options necessitates further investigation into the molecular mechanisms underlying this T-cell-mediated disease. In this study, we compared the transcriptome in skin biopsies from pediatric and young adult (<25 years) patients with ScGvHD (n=7) to that in demographically matched healthy controls (n=8) and patients with atopic dermatitis (n=10), using RNA-seq with RT-qPCR and immunohistochemistry validation. Differential expression was defined as |fold-change/FCH|>1.5 and false discovery rate/FDR<0.05. ScGvHD exhibited strong and significant Th1-skewing through key related cytokines and chemokines (CXCL9/10/11, IFN-γ, STAT1). Several markers related to the TSLP-OX40 axis were significantly upregulated relative to both controls and lesional AD, including OX40L, TSLP, and IL-33, as well as fibroinflammatory signatures characterized in a prior study in systemic sclerosis. Gene Set Variation Analysis reflected marker-level findings, showing greatest enrichment of the Th1 and fibroinflammatory pathways, with no global activation identified in Th2 or Th17/Th22. Cell-type deconvolution revealed significant representation of macrophages and vascular endothelial cells. ScGvHD in young patients may therefore be characterized by strong Th1-related upregulation with a unique TSLP-OX40 signature, suggesting new therapeutic avenues for this devastating disease.