Impact of tofacitinib treatment on human B-cells in vitro and in vivo.
J Autoimmun
; 77: 55-66, 2017 02.
Article
em En
| MEDLINE
| ID: mdl-27793425
ABSTRACT
B-cells are pivotal to the pathogenesis of rheumatoid arthritis and tofacitinib, a JAK inhibitor, is effective and safe in its treatment. Tofacitinib interferes with signal transduction via cytokine receptors using the common γ-chain. Despite extensive data on T-lymphocytes, the impact of tofacitinib on B-lymphocytes is poorly understood. In this study we assessed the effect of tofacitinib on B-lymphocyte differentiation and function. Tofacitinib treatment strongly impaired in vitro plasmablast development, immunoglobulin secretion and induction of B-cell fate determining transcription factors, Blimp-1, Xbp-1, and IRF-4, in naïve B-cells. Interestingly, class switch and activation-induced cytidine deaminase (AICDA) induction was only slightly reduced in activated naïve B-cells. The effect of tofacitinib on plasmablast formation, immunoglobulin secretion and proliferation was less profound, when peripheral blood B-cells, including not only naïve but also memory B-cells, were stimulated. In line with these in vitro results, the relative distribution of B-cell populations remained stable in tofacitinib treated patients. Nevertheless, a temporary increase in absolute B-cell numbers was observed 6-8 weeks after start of treatment. In addition, B-cells isolated from tofacitinib treated patients responded rapidly to in vitro activation. We demonstrate that tofacitinib has a direct impact on human naïve B-lymphocytes, independently from its effect on T-lymphocytes, by impairing their development into plasmablasts and immunoglobulin secretion. The major effect of tofacitinib on naïve B-lymphocyte development points to the potential inability of tofacitinib-treated patients to respond to novel antigens, and suggests planning vaccination strategies prior to tofacitinib treatment.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Pirimidinas
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Pirróis
/
Linfócitos B
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Inibidores de Proteínas Quinases
Limite:
Humans
Idioma:
En
Revista:
J Autoimmun
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2017
Tipo de documento:
Article