LAUSR

OBJECTIVES Cladribine tablet therapy is an efficacious treatment for multiple sclerosis (MS), however, its mechanism of action on T and B cell subsets remains unclear. The purpose of this study was to investigate the treatment effects of cladribine on the peripheral pool of T and B cells subsets and reactivity towards central nervous system (CNS) antigens. METHODS In this cross-sectional exploratory study, frequencies and absolute counts of peripheral T and B cell subsets and B cell cytokine production from untreated patients with relapsing-remitting MS (RRMS) and patients treated with cladribine for one year were measured using flow cytometry. Autoreactivity was assessed using a FluoroSpot assay. RESULTS We found that one year after initiation of cladribine treatment, a lower number of CD4+ T cells was persisting whereas CD19+ B cell counts were normalized compared to untreated patients with RRMS. Follicular helper T (Tfh) cells and their effecter subsets producing cytokines exerting distinct B cell helper activity were lower and, additionally, the peripheral B cell pool was skewed towards a naïve and anti-inflammatory phenotype. Finally, reactivity to the recently identified CNS-enriched autoantigen RAS guanyl-releasing protein 2 (RASGRP2), but not to myelin basic protein and myelin oligodendrocyte glycoprotein, was lower in cladribine-treated patients. INTERPRETATION Together these investigations on T and B cell subsets suggest that cladribine treatment impairs the B-T cell crosstalk and reduces their ability to mediate pathogenic effector functions. This may result in specific reduction of autoreactivity to RASGRP2 which is expressed in B cells and brain tissue. This article is protected by copyright. All rights reserved.