Investigating the impact of JAK inhibitor tofacitinib on the CD4+ T cell-dendritic cell interactions in murine models of rheumatoid arthritis

Bedaj, Marija (2020) Investigating the impact of JAK inhibitor tofacitinib on the CD4+ T cell-dendritic cell interactions in murine models of rheumatoid arthritis. PhD thesis, University of Glasgow.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune condition manifested by synovial inflammation and joint destruction and is associated with high morbidity and mortality. While the existing biologic therapies revolutionised the management of RA, considerable unmet needs in disease management require the development of new therapeutic agents. Janus kinases (JAKs) are intracellular tyrosine kinases employed by Type I and Type II cytokine receptors and transducing the signals from a range of cytokines and growth factors. They are indispensable in mediating the signaling of inflammatory cytokines implicated in the pathogenesis of autoimmune conditions, thus present attractive targets for therapeutic intervention. Tofacitinib was the first JAK inhibitor approved for the treatment of RA, which was effective in patients refractory to existing treatments. Among its immunomodulatory mechanisms, tofacitinib was reported to impair the proliferation, differentiation, and pro-inflammatory cytokine production in CD4+ T cells, both in vitro and in vivo. However, the impact of tofacitinib as well as the stage of the drug interference (priming or re-activation) on cognate CD4+ T cell-dendritic cell (DC) interaction, which underlies both breakdown of self-tolerance and autoimmune response propagation in RA, remains to be elucidated.
Using the antigen-specific cell system both in vitro and in vivo, I have shown that tofacitinib treatment impaired the priming of the CD4+ T cells by DCs, resulting in their diminished ability to differentiate into T helper 1 (Th1) subset and exhibit associated T-bet expression and IFNy production. This effect on CD4+ T cells was observed both in vitro and in vivo and persisted upon secondary antigenic challenge. On the contrary, the antigen-experienced CD4+ T cells primed in the absence of tofacitinib retained their functional capacity upon re-activation in the presence of the drug. Tofacitinib efficacy assessment in the mouse model of early RA similarly revealed that the antigen-experienced CD4+ T lymphocytes, from both adoptively transferred and endogenous populations, remained unaffected by tofacitinib treatment. While JAK inhibitor had no impact on paw thickness, it induced notable (although non-significant) improvement in features of joint pathology, which, together with the absence of effect on CD4+ T lymphocytes, suggested tofacitinib targeting other inflammatory cells contributing to the autoimmune response. Overall, these results have shown that tofacitinib interferes with the naive CD4+ T cell differentiation into the Th1 subset, thereby indicating a mechanism by which tofacitinib might in part achieve clinical efficacy in RA patients. The antigen-specific system and early RA mouse model are warranted as useful platforms for further investigation of tofacitinib immunomodulatory mechanisms with the view of the optimization of its clinical use.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Rheumatoid arthritis, Janus kinase (JAK) inhibitors, CD4+ T cell-DC interactions, CD4+ T cell priming and differentiation, antigen-experienced CD4+ T cell re-activation, murine 'breach of tolerance' model of rheumatoid arthritis.
• Subjects: Q Science > QR Microbiology > QR180 Immunology; R Medicine > RB Pathology; R Medicine > RM Therapeutics. Pharmacology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Immunology & Infection
• Funder's Name: Versus Arthritis (ARTRESUK)
• Supervisor's Name: Garside, Professor Paul
• Date of Award: 2020
• Depositing User: Miss Marija Bedaj
• Unique ID: glathesis:2020-81633
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 07 Sep 2020 12:16
• Last Modified: 31 Aug 2022 10:33
• Thesis DOI: 10.5525/gla.thesis.81633
• URI: https://theses.gla.ac.uk/id/eprint/81633