Tofacitinib is an oral small molecule targeting the intracellular Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways approved for the treatment of active rheumatoid arthritis (RA). We investigated the effects of tofacitinib on the response of RA lymphocytes to B and T cell collagen epitopes in their native and post-translationally modified forms. In particular, peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy subjects were cultured with type II collagen peptides (T261-273, B359-369, carT261-273, citB359-369) or with phorbol myristate acetate (PMA)/ionomycin/CD40L in the presence or absence of 100 nM tofacitinib for 20 h and analyzed by fluorescence activated cell sorter (FACS). Cultures without brefeldin A were used for cytokine supernatant enzyme-linked immunosorbent assay (ELISA) analysis. Tofacitinib down-regulated inflammatory cytokines by stimulated B [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] and T [interferon (IFN)-γ, IL-17 or TNF-α] cells in the short term, while a significant reduction of IL-17 and IL-6 levels in peripheral blood mononuclear cell (PBMC) supernatant was also observed. IL-10 was significantly reduced in collagen-stimulated B cells from patients with RA and increased in controls, thus mirroring an altered response to collagen self-epitopes in RA. Tofacitinib partially prevented the IL-10 down-modulation in RA B cells stimulated with collagen epitopes. In conclusion, the use of tofacitinib exerts a rapid regulatory effect on B cells from patients with RA following stimulation with collagen epitopes while not reducing inflammatory cytokine production by lymphocytes.

Lymphocyte modulation by tofacitinib in patients with rheumatoid arthritis

Ceribelli, Angela;Selmi, Carlo;De Santis, Maria
2021-01-01

Abstract

Tofacitinib is an oral small molecule targeting the intracellular Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways approved for the treatment of active rheumatoid arthritis (RA). We investigated the effects of tofacitinib on the response of RA lymphocytes to B and T cell collagen epitopes in their native and post-translationally modified forms. In particular, peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy subjects were cultured with type II collagen peptides (T261-273, B359-369, carT261-273, citB359-369) or with phorbol myristate acetate (PMA)/ionomycin/CD40L in the presence or absence of 100 nM tofacitinib for 20 h and analyzed by fluorescence activated cell sorter (FACS). Cultures without brefeldin A were used for cytokine supernatant enzyme-linked immunosorbent assay (ELISA) analysis. Tofacitinib down-regulated inflammatory cytokines by stimulated B [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] and T [interferon (IFN)-γ, IL-17 or TNF-α] cells in the short term, while a significant reduction of IL-17 and IL-6 levels in peripheral blood mononuclear cell (PBMC) supernatant was also observed. IL-10 was significantly reduced in collagen-stimulated B cells from patients with RA and increased in controls, thus mirroring an altered response to collagen self-epitopes in RA. Tofacitinib partially prevented the IL-10 down-modulation in RA B cells stimulated with collagen epitopes. In conclusion, the use of tofacitinib exerts a rapid regulatory effect on B cells from patients with RA following stimulation with collagen epitopes while not reducing inflammatory cytokine production by lymphocytes.
2021
Janus kinase
acquired immunity
collagen epitope
post-translational modifications
regulatory effect
targeted synthetic DMARDs
Adult
Aged
Arthritis, Rheumatoid
Collagen Type II
Cytokines
Epitopes, T-Lymphocyte
Female
Humans
Interleukin-10
Interleukin-17
Interleukin-6
Janus Kinases
Leukocytes, Mononuclear
Lymphocytes
Male
Middle Aged
Piperidines
Protein Kinase Inhibitors
Pyrimidines
Tumor Necrosis Factor-alpha
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11699/68461
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