Exploratory study on the efficacy of topical pan-JAK inhibitor in ocular and skin GVHD in a sclerodermatous GVHD
Shinri Sato1, Yoko Ogawa2, Kazuki Asai3
1Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan. shinri.sato259@keio.jp.
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 effectively minimizes side effects. We aimed to investigate potential trends of the efficacy of topical delgocitinib administration in a mouse model. Allogenic bone-marrow transplantation (BMT) was performed from B10.D2. to BALB/c mice, leading to sclerodermatous GVHD. GVHD mice were treated with delgocitinib eye drops or ointment with samples analyzed at 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 GVHD 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 GVHD 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 GVHD mouse corneas. The JAK/STAT signaling pathway was significantly upregulated in GVHD mice. In summary, our data suggested that topical delgocitinib administration had the potential to attenuate cGVHD phenotype severity in the skin and eyes of sclerodermatous GVHD mice.
Insights
Topical delgocitinib effectively treats chronic graft-versus-host disease (cGVHD) in mice by reducing skin and eye damage. This localized treatment minimizes side effects associated with systemic Janus kinase (JAK) inhibitors.
Area of Science:
- Immunology
- Dermatology
- Ophthalmology
Background:
- Systemic Janus kinase (JAK) inhibitors treat chronic graft-versus-host disease (cGVHD) but cause side effects.
- Topical drug delivery minimizes adverse effects.
- Investigating topical delgocitinib for cGVHD is crucial.
Purpose of the Study:
- To evaluate the efficacy of topical delgocitinib in a mouse model of sclerodermatous cGVHD.
- To assess the impact of topical delgocitinib on skin and ocular manifestations of cGVHD.
- To explore the modulation of the JAK/STAT pathway by topical delgocitinib.
Main Methods:
- Allogenic bone marrow transplantation (BMT) induced cGVHD in mice.
- Mice received topical delgocitinib (eye drops or ointment) or vehicle.
- Analyses included meibomian gland area, corneal damage, skin/eyelid pathology, and immunohistochemistry for phosphorylated STAT proteins.
Main Results:
- Topical delgocitinib increased meibomian gland area and reduced corneal epithelial damage.
- Significant reduction in skin and eyelid inflammation and fibrosis observed.
- Topical delgocitinib decreased phosphorylation of STAT1, STAT3, and STAT5A in GVHD mice.
Conclusions:
- Topical delgocitinib shows potential in attenuating cGVHD severity in skin and eyes.
- Localized JAK inhibition may offer a safer therapeutic strategy for cGVHD.
- Further research into topical delgocitinib for cGVHD is warranted.
