Anti-inflammatory and anti-fibrotic effects of topical pan-JAK inhibitor in a chronic graft-versus- host disease model mouse

Abstract

Abstract Systemic administration of Janus kinase (JAK) inhibitors is effective in treating chronic graft-versus-host disease (cGVHD) but is associated with side effects. Topical drug administration is an effective approach in minimizing these effects. We aimed to demonstrate the efficacy of topical delgocitinib administration in a cGVHD mouse model. Allogenic bone-marrow transplantation (BMT) was performed from B10.D2. to BALB/c mice, leading to cGVHD. cGVHD mice were treated with delgocitinib eye drops or ointments; their samples were analyzed 4 weeks post-BMT. Topical delgocitinib ointment and eye-drop administration significantly increased the meibomian-gland (MG) area and attenuated corneal epithelial damage. Pathological and immunohistochemical analyses revealed a substantial reduction in inflammation and pathological fibrosis of the skin and eyelids in delgocitinib-treated cGVHD mice. Signal transducer and activator of transcription (STAT)1, STAT3, and STAT5A phosphorylation was significantly increased in the back skin and eyelids of vehicle-treated cGVHD mice; topical delgocitinib administration significantly reduced the expression of these phosphorylated STAT molecules. Delgocitinib eye drops significantly attenuated corneal epithelial damage, MG acinar depletion, and inflammatory cells infiltration in cGVHD mouse corneas. The JAK/STAT signaling pathway was significantly upregulated in cGVHD mice. In summary, a topical delgocitinib administration attenuated cGVHD phenotype severity in the skin and eyes of cGVHD mice.