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• W2910154973 abstract "Background Rheumatoid arthritis is an immune-mediated disease, in which immune cell activation leads to destructive inflammation of the joints. In this context the treatment with JAK inhibitor tofacitinib has been proven to be effective. In mice treatment with tofacitinib resulted in reduced specific antibody responses, failure to generate germinal centres, and partial block of B cell development in the bone marrow. Conversely in vivo treatment of psoriasis arthritis patients as well as of rheumatioid arthritis patients with tofacitinib results in an increase of relative and absolute numbers of B cells in the first 4–8 weeks from beginning of treatment. It is known that mouse early B cell development is strongly dependent on IL-7 signalling, while this is not essential in humans. Nevertheless other cytokines are important in determining the fate and development of B lymphocytes. Hence, the outcome of JAK inhibition in early B cell development remains to be studied Objectives To assess the impact of JAK inhibition on early B cell development in vitro Methods We used a in vitro model in which CD34+ cells isolated from cord blood are cultivated subsequently in SCF, Flt3-L and IL-6, then SCF, Flt3-L and IL-7 and finally in cytokine-free medium(.1 The culture reproduces all stages of development from common lymphocytes progenitors to immature B cells. Results With the addition of tofacitinib to the in vitro culture we observed an increase in the absolute numbers of lymphoid precursors developing in vitro especially at week 5 and 6 of culture. Specifically, JAK inhibition led to an increase of pre-B and immature B cells by week 5 and 6. These data are in contrast with the early B cell development block observed in the tofacitinib treated mouse, but are in line with the rapid increase of B cells in peripheral blood after 4–8 weeks of tofacitinib treatment in patients. Analysis of induction of fate determining genes (EBF, E2A, PAX-5) showed an earlier and stronger induction of fate determining genes. Conclusions Our data indicate that JAK inhibition may promote early B cell development by enhancing the commitment of lymphoid precursors to the B cell compartment, contributing to a temporary increase in relative and absolute numbers of B cell in peripheral blood of treated patients. These data contribute to our understanding of human B cell development, prompt us to further analyse the quality of B cell output from the bone marrow in JAK inhibited patients, and may provide cues to understand the outcome of JAK inhibition treatment in rheumatic diseases. Reference [1] Kraus H, et al. A feeder-free differentiation system identifies autonomously proliferating B cell precursors in human bone marrow. J Immunol. 2014Feb 1;192(3):1044–54. Disclosure of Interest None declared" @default.
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• W2910154973 date "2018-06-01" @default.
• W2910154973 modified "2023-09-24" @default.
• W2910154973 title "THU0040 Enhancement of early human b cell development by jak inhibition" @default.
• W2910154973 doi "https://doi.org/10.1136/annrheumdis-2018-eular.5190" @default.
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