Oclacitinib, a Janus Kinase Inhibitor, Reduces the Frequency of IL-4- and IL-10-, but Not IFN-γ-, Producing Murine CD4+ and CD8+ T Cells and Counteracts the Induction of Type 1 Regulatory T Cells.

Agnieszka Jasiecka-Mikołajczyk,Jerzy J Jaroszewski,Tomasz Maślanka

doi:10.3390/molecules26185655

Agnieszka Jasiecka-Mikołajczyk, Jerzy J Jaroszewski + Show 1 more

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https://doi.org/10.3390/molecules26185655

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Abstract

The purpose of the present study was to broaden the knowledge and understanding of the effects of oclacitinib (OCL), a Janus kinase inhibitor, on T cells in the context of both the immune mechanisms underlying anti-inflammatory and anti-allergic properties of the drug and its safety. The results indicate that beneficial effects of OCL in the treatment of skin allergic diseases may be partially mediated by the inhibition of IL-4 production in CD4+ and CD8+ T cells. To a certain extent, the antiproliferative effect of OCL on CD8+ T cells may also contribute to its therapeutic effect. The study found that OCL does not affect the proliferation of CD4+ T cells or the number of IFN-γ- and IL-17-producing CD4+ and CD8+ T cells. Moreover, OCL was found to counteract the induction of type 1 regulatory T (Tr1) cells and to act as a strong inhibitor of IL-10 production in both CD4+ and CD8+ T cells. Thus, these results indicate that beneficial effects of OCL in the treatment of skin allergic diseases are not mediated through: (a) the abolishment of IFN-γ and IL-17-production in CD4+ and CD8+ T cells; (b) generation of Tr1 cells; (c) inhibition of CD4+ T cell proliferation; (d) induction of IL-10 production in CD4+ T cells. The results of this study strongly suggest that, with respect to the evaluated parameters, OCL exerts a suppressive effect on Th2- but not Th1-mediated immunity.

Highlights

Oclacitinib (OCL) is a novel immunomodulatory agent that has been registered for the treatment of pruritus in allergic dermatitis and atopic dermatitis (AD) in dogs
In order to achieve research objectives formulated in this paper, the present study by necessity was conducted on mouse lymphocytes because anti-canine monoclonal antibodies for flow cytometric detection of Tr1 cells and intracellular cytokine production as well as to obtain effective stimulation of cells are still not available for dogs
Taking all of the above into consideration, it can be concluded that the beneficial effects of OCL in the treatment of skin allergic diseases may be partially mediated by the inhibition of IL-4 production in Th2 and Tc2 cells

Summary

Introduction

Oclacitinib (OCL) is a novel immunomodulatory agent that has been registered for the treatment of pruritus in allergic dermatitis and atopic dermatitis (AD) in dogs. OCL acts as an inhibitor of the function of important pro-inflammatory, pro-allergic and pruritogenic cytokines via inhibition of the Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway [1]. In light of the above, the mechanism of OCL action would rely solely on the inhibition of cytokine-mediated signaling via blockade of the JAK-STAT signaling pathway. It is known, that the JAK-STAT signaling pathway is involved in the regulation of cytokine production [3], and that JAK inhibitors may produce an inhibitory or stimulating effect on the production of cytokines [4,5]

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