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

Abstract

Sclerotic-type cutaneous chronic graft-versus-host disease 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 (aged <25 years) patients with sclerotic-type cutaneous chronic graft-versus-host disease (n = 7) with that in demographically matched healthy controls (n = 8) and patients with atopic dermatitis (n = 10) using RNA sequencing with RT-PCR and immunohistochemistry validation. Differential expression was defined as fold change > 1.5 and false discovery rate < 0.05. Sclerotic-type cutaneous chronic graft-versus-host disease exhibited strong and significant T helper (Th)1 skewing through key related cytokines and chemokines (CXCL9/10/11, IFNG/IFN-γ, STAT1/signal transducer and activator of transcription 1). Several markers related to the TSLP-OX40 axis were significantly upregulated relative to those in both controls and lesional atopic dermatitis, including TNFSF4/OX40L, TSLP, and IL33, as well as fibroinflammatory signatures characterized in a prior study in systemic sclerosis. Gene set variation analysis reflected marker-level findings, showing the greatest enrichment of the Th1 and fibroinflammatory pathways, with no global activation identified in Th2 or Th17/Th22. Cell-type deconvolution revealed a significant representation of macrophages and vascular endothelial cells. Sclerotic-type cutaneous chronic graft-versus-host disease 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.

• Authors: Madeline Kim, Yael Renert-Yuval, Polina Stepensky, Ehud Even-Or, Irina Zaidman, Tahel Fachler, Michal Neumark, Mariana Zamir, Monali NandyMazumdar, Digpal Gour, Paola Facheris, Britta Carroll, Ying Liu, Mitchelle L Yu Ekey, Elizabeth Andrews, Marguerite Meariman, Michael Angelov, Swaroop Bose, Yeriel D Estrada, Vered Molho-Pessach, Emma Guttman-Yassky
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 144 Issue 3 Pg. 563-572.e9 (Mar 2024) ISSN: 1523-1747 [Electronic] United States
• PMID: 37742913 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• TNFSF4 protein, human
• OX40 Ligand

Topics

• Young Adult
• Humans
• Child
• Cytokines (metabolism)
• Dermatitis, Atopic (genetics, pathology)
• Bronchiolitis Obliterans Syndrome
• Endothelial Cells (metabolism)
• Th2 Cells (metabolism)
• Skin Diseases
• Graft vs Host Disease (genetics)
• OX40 Ligand