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SHR Neuro Cancer Cardio Lipid Metab Microb

Rizzi, M; Lorenzetti, R; Fischer, K; Staniek, J; Janowska, I; Troilo, A; Strohmeier, V; Erlacher, M; Kunze, M; Bannert, B; Kyburz, D; Voll, RE; Venhoff, N; Thiel, J.
Impact of tofacitinib treatment on human B-cells in vitro and in vivo.
J AUTOIMMUN. 2017; 77: 55-66. Doi: 10.1016/j.jaut.2016.10.005
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Co-authors Med Uni Graz: Thiel Jens
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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.
Find related publications in this database (using NLM MeSH Indexing): Antibody Formation - drug effects; Arthritis, Rheumatoid - drug therapy, immunology, metabolism; B-Lymphocytes - drug effects, immunology, metabolism; Cells, Cultured - administration & dosage; Cytidine Deaminase - metabolism; Humans - administration & dosage; Immunoglobulin Class Switching - drug effects; Immunomodulation - administration & dosage; Interleukin Receptor Common gamma Subunit - metabolism; Lymphocyte Activation - drug effects, immunology; Lymphocyte Count - administration & dosage; Piperidines - pharmacology, therapeutic use; Plasma Cells - drug effects, immunology, metabolism; Protein Kinase Inhibitors - pharmacology, therapeutic use; Pyrimidines - pharmacology, therapeutic use; Pyrroles - pharmacology, therapeutic use; Signal Transduction - drug effects
Find related publications in this database (Keywords): B -lymphocytes; Tofacitinib; Immune modulation; tsDMARDs; JAR inhibitors; Rheumatoid arthritis