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Functional relevance of the multi-drug transporter abcg2 on teriflunomide therapy in an animal model of multiple sclerosis.
Journal of Neuroinflammation ( IF 9.3 ) Pub Date : 2020-01-08 , DOI: 10.1186/s12974-019-1677-z
Lisa Thiele Née Schrewe 1, 2 , Kirsten Guse 1, 2 , Silvia Tietz 1 , Jana Remlinger 1 , Seray Demir 2 , Xiomara Pedreiturria 2 , Robert Hoepner 1 , Anke Salmen 1 , Maximilian Pistor 1, 2 , Timothy Turner 3 , Britta Engelhardt 4 , Dirk M Hermann 5 , Fred Lühder 6 , Stefan Wiese 7 , Andrew Chan 1
Affiliation  

BACKGROUND The multi-drug resistance transporter ABCG2, a member of the ATP-binding cassette (ABC) transporter family, mediates the efflux of different immunotherapeutics used in multiple sclerosis (MS), e.g., teriflunomide (teri), cladribine, and mitoxantrone, across cell membranes and organelles. Hence, the modulation of ABCG2 activity could have potential therapeutic implications in MS. In this study, we aimed at investigating the functional impact of abcg2 modulation on teri-induced effects in vitro and in vivo. METHODS T cells from C57BL/6 J wild-type (wt) and abcg2-knockout (KO) mice were treated with teri at different concentrations with/without specific abcg2-inhibitors (Ko143; Fumitremorgin C) and analyzed for intracellular teri concentration (HPLC; LS-MS/MS), T cell apoptosis (annexin V/PI), and proliferation (CSFE). Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6J by active immunization with MOG35-55/CFA. Teri (10 mg/kg body weight) was given orally once daily after individual disease onset. abcg2-mRNA expression (spinal cord, splenic T cells) was analyzed using qRT-PCR. RESULTS In vitro, intracellular teri concentration in T cells was 2.5-fold higher in abcg2-KO mice than in wt mice. Teri-induced inhibition of T cell proliferation was two fold increased in abcg2-KO cells compared to wt cells. T cell apoptosis demonstrated analogous results with 3.1-fold increased apoptosis after pharmacological abcg2-inhibition in wt cells. abcg2-mRNA was differentially regulated during different phases of EAE within the central nervous system and peripheral organs. In vivo, at a dosage not efficacious in wt animals, teri treatment ameliorated clinical EAE in abcg2-KO mice which was accompanied by higher spinal cord tissue concentrations of teri. CONCLUSION Functional relevance of abcg2 modulation on teri effects in vitro and in vivo warrants further investigation as a potential determinant of interindividual treatment response in MS, with potential implications for other immunotherapies.

中文翻译:

在多发性硬化症动物模型中,多种药物转运蛋白abcg2在特立氟胺治疗上的功能相关性。

背景技术ATP结合盒(ABC)转运蛋白家族的成员之一,多药耐药转运蛋白ABCG2介导了多发性硬化症(MS)中使用的不同免疫治疗药物(例如特立氟胺(teri),克拉屈滨和米托蒽醌)的流出。细胞膜和细胞器。因此,ABCG2活性的调节可能在MS中具有潜在的治疗意义。在这项研究中,我们旨在研究abcg2调节功能在体外和体内对teri诱导的作用的功能影响。方法用不同浓度的teri处理C57BL / 6 J野生型(wt)和abcg2-敲除(KO)小鼠的T细胞,使用/不使用特定的abcg2-抑制剂(Ko143; Fumitremorgin C),并分析细胞内teri浓度(HPLC) ; LS-MS / MS),T细胞凋亡(annexin V / PI)和增殖(CSFE)。通过用MOG35-55 / CFA主动免疫,在C57BL / 6J中诱导了实验性自身免疫性脑脊髓炎(EAE)。个别疾病发作后,每天口服一次Teri(10 mg / kg体重)。使用qRT-PCR分析abcg2-mRNA表达(脊髓,脾T细胞)。结果在体外,abcg2-KO小鼠的T细胞中细胞内teri浓度比wt小鼠高2.5倍。与wt细胞相比,abcg2-KO细胞中Teri诱导的T细胞增殖抑制作用增加了两倍。在wt细胞​​中进行药理学abcg2抑制后,T细胞凋亡显示出类似的结果,凋亡增加了3.1倍。在中枢神经系统和周围器官的EAE的不同阶段,abcg2-mRNA受到差异调节。在体内,在野生动物中无效的剂量下,teri治疗改善了abcg2-KO小鼠的临床EAE,并伴有较高的teri脊髓组织浓度。结论abcg2调节在体外和体内对teri效应的功能相关性值得进一步研究,作为MS中个体间治疗反应的潜在决定因素,并可能对其他免疫疗法产生影响。
更新日期:2020-01-08
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