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Tofacitinib inhibits CD4 T cell polarisation to Th1 during priming thereby leading to clinical impact in a model of experimental arthritis


1, 2, 3, 4, 5

 

  1. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, UK.
  2. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, UK.
  3. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, UK.
  4. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, UK. paul.garside@glasgow.ac.uk
  5. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graeme Davies Building, University of Glasgow, and Research and Development Department, Antibody Analytics Ltd, Newhouse, Lanarkshire, UK. Research and Development Department, Antibody Analytics Ltd, Newhouse, Lanarkshire, U.K.

CER14758
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PMID: 34494958 [PubMed]

Received: 26/04/2021
Accepted : 09/07/2021
In Press: 07/09/2021

Abstract

OBJECTIVES:
Janus kinases (JAK) are key cell membrane orientated tyrosine kinases that regulate inflammatory responses by transducing signals received by cytokine receptors that directly influence the polarisation and function of Th cells. Tofacitinib is a pan-JAK inhibitor approved for the treatment of RA. In this study, we explored the effects of tofacitinib in the outcomes of CD4+ T cell-dendritic cell (DC) interactions and their impact in autoimmune arthritis.
METHODS:
The impact of tofacitinib in CD4+ T cell outcomes during priming or re-activation were analysed using antigen-specific in vitro and/or in vivo systems. A breach of self-tolerance model of arthritis was used to investigate the effects of tofacitinib in the outcomes of newly primed and antigen experienced CD4+ T cells.
RESULTS:
Tofacitinib inhibited Th1 polarisation during priming both in vitro and in vivo. In vitro, impaired T-bet expression and IFN-y production persisted upon secondary antigen challenge. Tofacitinib treatment during re-activation in vitro did not impact differentiation of antigen experienced CD4+ T cell towards Th1 phenotype. Moreover, JAK inhibition limited adaptive immune responses mediated by recently activated T cells and subsequent breach of self-tolerance in experimental arthritis.
CONCLUSIONS:
Our findings provide a novel mode of action for tofacitinib, demonstrating a potential therapeutic utility via homeostatic immune restoration in very early autoimmune arthritis.

Rheumatology Article

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