Sato Shinri, Ogawa Yoko, Asai Kazuki, Shimizu Eisuke, Shimizu Shota, Taniguchi Hiroko, Okazaki Takahiro, Shimmura Shigeto, Negishi Kazuno, Hirayama Masatoshi
Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan.
Fujita Medical Innovation Center Tokyo, Fujita Health University, Tokyo, Japan.
Sci Rep. 2025 Jan 2;15(1):532. doi: 10.1038/s41598-024-84380-6.
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.
全身性给予 Janus 激酶（JAK）抑制剂对治疗慢性移植物抗宿主病（cGVHD）有效，但会伴有副作用。局部给药可有效减少副作用。我们旨在研究局部给予地尔戈替尼在小鼠模型中的潜在疗效趋势。将 B10.D2 的骨髓移植到 BALB/c 小鼠体内，导致硬皮病样移植物抗宿主病。在骨髓移植后 4 周，用样本分析的地尔戈替尼滴眼液或软膏治疗移植物抗宿主病小鼠。局部给予地尔戈替尼软膏和滴眼液可显著增加睑板腺（MG）面积，并减轻角膜上皮损伤。病理和免疫组化分析显示，地尔戈替尼治疗的移植物抗宿主病小鼠皮肤和眼睑的炎症和病理性纤维化显著减少。在载体处理的移植物抗宿主病小鼠的背部皮肤和眼睑中，信号转导和转录激活因子（STAT）1、STAT3 和 STAT5A 的磷酸化显著增加；局部给予地尔戈替尼可显著降低这些磷酸化 STAT 分子的表达。地尔戈替尼滴眼液可显著减轻移植物抗宿主病小鼠角膜的角膜上皮损伤、睑板腺腺泡耗竭和炎性细胞浸润。JAK/STAT 信号通路在移植物抗宿主病小鼠中显著上调。总之，我们的数据表明，局部给予地尔戈替尼有可能减轻硬皮病样移植物抗宿主病小鼠皮肤和眼睛中 cGVHD 表型的严重程度。
