Samuvel Devadoss J, Saxena Nishant, Dhindsa Jasdeep S, Singh Avtar K, Gill Gurmit S, Grobelny Damian W, Singh Inderjit
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Charles P. Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, United States of America.
PLoS One. 2015 Oct 29;10(10):e0141781. doi: 10.1371/journal.pone.0141781. eCollection 2015.
Sphingosine-1-phosphate receptor 1 (S1P1) mediated regulation of lymphocyte egress from lymphoid organs is recognized as the mechanism of FTY720 (Fingolimod, Gilenya) efficacy in relapsing-remitting forms of multiple sclerosis (RRMS). In this study we describe a novel S1P1 agonist AKP-11, next generation of S1P1 agonist, with immunomodulatory activities in cell culture model and for therapeutic efficacy against an animal model of MS, i.e. experimental autoimmune encephalomyelitis (EAE) but without the adverse effects observed with FTY720. Like FTY720, AKP-11 bound to S1P1 is internalized and activates intracellular AKT and ERKs cellular signaling pathways. In contrast to FTY720, AKP-11 mediated S1P1 downregulation is independent of sphingosine kinase activity indicating it to be a direct agonist of S1P1. The S1P1 loss and inhibition of lymphocyte egress by FTY720 leads to lymphopenia. In comparison with FTY720, oral administration of AKP-11 caused milder and reversible lymphopenia while providing a similar degree of therapeutic efficacy in the EAE animal model. Consistent with the observed reversible lymphopenia with AKP-11, the S1P1 recycled back to cell membrane in AKP-11 treated cells following its withdrawal, but not with withdrawal of FTY720. Accordingly, a smaller degree of ubiquitination and proteolysis of S1P1 was observed in AKP-11 treated cells as compared to FTY720. Consistent with previous observations, FTY720 treatment is associated with adverse effects of bradycardia and lung vascular leaks in rodents, whereas AKP-11 treatment had undetectable effects on bradycardia and reduced lung vascular leaks as compared to FTY720. Taken together, the data documents that AKP-11 treatment cause milder and reversible lymphopenia with milder adverse effects while maintaining therapeutic efficacy similar to that observed with FTY720, thus indicating therapeutic potential of AKP-11 for treatment of MS and related autoimmune disorders.
1-磷酸鞘氨醇受体1（S1P1）介导的淋巴细胞从淋巴器官流出的调节被认为是FTY720（芬戈莫德，吉立安）在复发缓解型多发性硬化症（RRMS）中发挥疗效的机制。在本研究中，我们描述了一种新型S1P1激动剂AKP-11，它是下一代S1P1激动剂，在细胞培养模型中具有免疫调节活性，并且对实验性自身免疫性脑脊髓炎（EAE）这一MS动物模型具有治疗效果，同时没有观察到FTY720的不良反应。与FTY720一样，与S1P1结合的AKP-11会被内化并激活细胞内的AKT和ERK细胞信号通路。与FTY720不同的是，AKP-11介导的S1P1下调独立于鞘氨醇激酶活性，表明它是S1P1的直接激动剂。FTY720导致的S1P1丢失和淋巴细胞流出抑制会引起淋巴细胞减少。与FTY720相比，口服AKP-11引起的淋巴细胞减少较轻且可逆，同时在EAE动物模型中提供了相似程度的治疗效果。与观察到的AKP-11导致的可逆性淋巴细胞减少一致，在撤药后，AKP-11处理的细胞中S1P1会重新回到细胞膜，但FTY720撤药后则不会。因此，与FTY720相比，在AKP-11处理的细胞中观察到的S1P1泛素化和蛋白水解程度较小。与之前的观察结果一致，FTY720治疗与啮齿动物的心动过缓和肺血管渗漏等不良反应相关，而与FTY720相比，AKP-11治疗对心动过缓没有可检测到的影响，并且减少了肺血管渗漏。综上所述，数据表明AKP-11治疗引起的淋巴细胞减少较轻且可逆，不良反应也较轻，同时保持了与FTY720相似的治疗效果，因此表明AKP-11在治疗MS和相关自身免疫性疾病方面具有治疗潜力。
