Jin Jing, Xue Nina, Liu Yuan, Fu Rong, Wang Mingjin, Ji Ming, Lai Fangfang, Hu Jinping, Wang Xiaojian, Xiao Qiong, Zhang Xiaoying, Yin Dali, Bai Liping, Chen Xiaoguang, Rao Shuan
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100050, China.
Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Acta Pharm Sin B. 2020 Feb;10(2):276-288. doi: 10.1016/j.apsb.2019.11.006. Epub 2019 Nov 14.
Psoriasis is characterized by abnormal proliferation of keratinocytes, as well as infiltration of immune cells into the dermis and epidermis, causing itchy, scaly and erythematous plaques of skin. The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently. Here, we showed that IMMH002, a novel orally active S1P modulator, desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus. Using different psoriasis animal models, we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PASI score and pathological injure evaluation. Mechanistically, IMMH002 regulated CD3 T lymphocytes re-distribution by inducing lymphocytes' homing, thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus. Our results suggest that the novel S1P agonist, IMMH002, exert extraordinary capacity to rapidly modulate T lymphocytes distribution, representing a promising drug candidate for psoriasis treatment.
银屑病的特征是角质形成细胞异常增殖，以及免疫细胞浸润至真皮和表皮，导致皮肤出现瘙痒、鳞屑和红斑斑块。目前对这种慢性炎症性皮肤病的认识仍不清楚，所有可用的治疗方法都有其局限性。在此，我们表明，新型口服活性鞘氨醇-1-磷酸（S1P）调节剂IMMH002使外周致病性淋巴细胞对来自二级淋巴器官和胸腺的流出信号脱敏。使用不同的银屑病动物模型，我们证明IMMH002可显著减轻皮肤损伤，这通过银屑病面积和严重程度指数（PASI）评分及病理损伤评估得以揭示。从机制上讲，IMMH002通过诱导淋巴细胞归巢来调节CD3 T淋巴细胞的重新分布，从而减少外周血和皮肤中T淋巴细胞的分布，但增加胸腺中的分布。我们的结果表明，新型S1P激动剂IMMH002具有快速调节T淋巴细胞分布的非凡能力，是一种很有前景的银屑病治疗候选药物。
