Functional relevance of the multi-drug transporter abcg2 on teriflunomide therapy in an animal model of multiple sclerosis.

Thiele née Schrewe, Lisa; Guse, Kirsten; Tietz, Silvia; Remlinger, Jana; Demir, Seray; Pedreiturria, Xiomara; Hoepner, Robert; Salmen, Anke; Pistor, Maximilian; Turner, Timothy; Engelhardt, Britta; Hermann, Dirk M; Lühder, Fred; Wiese, Stefan; Chan, Andrew (2020). Functional relevance of the multi-drug transporter abcg2 on teriflunomide therapy in an animal model of multiple sclerosis. Journal of neuroinflammation, 17(1), p. 9. BioMed Central 10.1186/s12974-019-1677-z

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Unit Sahli Building > Forschungsgruppe Neurologie
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurology
04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Thiele, Lisa; Guse, Kirsten; Tietz, Silvia Martina; Remlinger, Jana Silke; Hoepner, Robert; Salmen, Anke; Pistor, Maximilian; Engelhardt, Britta and Chan, Andrew Hao-Kuang

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1742-2094

Publisher:

BioMed Central

Language:

English

Submitter:

Chantal Kottler

Date Deposited:

06 Jul 2020 17:05

Last Modified:

12 Jul 2020 02:42

Publisher DOI:

10.1186/s12974-019-1677-z

PubMed ID:

31915017

Uncontrolled Keywords:

Experimental autoimmune encephalomyelitis Multiple sclerosis Teriflunomide abcg2

BORIS DOI:

10.7892/boris.145002

URI:

https://boris.unibe.ch/id/eprint/145002

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