THU0183 Treatment with Tofacitinib Inhibits Human Naïve B Lymphocyte Development and Function In Vitro

BackgroundB cells are pivotal to the pathogenesis of many autoimmune diseases including rheumatoid arthritis (RA). Tofacitinib, a JAK inhibitor, is effective and safe in the treatment of RA. Tofacitinib interferes with signal transduction via cytokine receptors using the common γ-chain.ObjectivesDespite of extensive data on T lymphocytes, the impact of tofacitinib on B lymphocytes is poorly understood. In this study we assess the effect of tofacitinib on the differentiation of naive B-lymphocytes and their function.MethodsSorted human B cells from cord blood or buffy coat were stimulated in the presence of increasing doses of tofacitinib. B cell phenotypes were determined by flow cytometry. Immunoglobulin concentrations were measured by ELISA. The expression of B cell fate determining genes PRDM1, IRF4, XBP1, and AICDA was analyzed by quantitative RT-PCR.ResultsTofacitinib treatment strongly impaired plasmablast development, immunoglobulin secretion and induction of PRDM1, IRF-4, and XBP-1 from naive B cells. Interestingly, class switch and AICDA induction from activated naive B cells was only slightly reduced. B cells purified from buffy coats, including naive and memory B cells, stimulated in the presence of tofacitinib, showed only a moderate reduction in plasmablast formation, immunoglobulin secretion and proliferation.ConclusionsWe demonstrated that tofacitinib has a direct impact on human naive B-lymphocytes, independently from its effect on T lymphocytes, by impairing their development into plasmablasts and immunoglobulin secretion. Tofacitinib predominantly affects naive B lymphocytes, while its effect on total peripheral B cells containing naive and memory B cells is less pronounced. Our data are of clinical importance as they suggest that vaccinations should be performed prior to tofacitinib treatment. Furthermore, impairement of B cell function by tofacitimib may directly contribute to its therapeutic effects. This fact has implications for the potential use of tofacitinib in B cell-mediated diseases.Disclosure of InterestNone declared