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Pim Kinases as Therapeutic Targets in Early Rheumatoid Arthritis

Lookup NU author(s): Dr Nicola Maney, Dr Ben Barron-Millar, Dr Christopher CareyORCiD, Ian Herron, Dr Amy AndersonORCiD, Emeritus Professor Andrew MellorORCiD, Professor John IsaacsORCiD, Dr Arthur PrattORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

Objective: As well as being an established oncoprotein and therapeutic target in cancer, proviral integration site for Moloney murine leukemia virus 1 (Pim-1) is implicated in human autoimmunity. This study was undertaken to investigate Pim-1 and its family members as potential therapeutic targets in early rheumatoid arthritis (RA).Methods: A flow cytometry assay for PIM1 transcript measurement in peripheral blood mononuclear cells from patients with early arthritis was validated and applied as a biomarker of Pim-1 activity at the cellular level. Synovial protein expression was similarly determined by multiplex immunofluorescence in tissue samples from untreated RA patients and non-RA disease controls. Functional consequences of Pim kinase family manipulation in freshly isolated CD4+ T cells from these individuals were ascertained, along with the impact of Pim inhibition on mice with collagen-induced arthritis (CIA).Results: The percentage of circulating CD4+ T cells positive for PIM1 transcript by flow cytometry proved a faithful surrogate for gene expression and was significantly higher in patients with early RA than in those with other diseases. Pim-1 protein levels were similarly up-regulated in synovial CD4+ T cells from patients with early RA. Ex vivo, exposure of T cell receptor-stimulated early RA CD4+ T cells to Pim kinase inhibitors restrained their activation and proliferative capacity. Diminished production of proinflammatory cytokines (interferon-γ and interleukin-17) and an expanded CD25^high FoxP3+ Treg cell fraction were also observed in exposed versus unexposed cells. Finally, administration of Pim inhibitors robustly limited arthritis progression and cartilage destruction in CIA.Conclusion: Our findings indicate that Pim kinases are plausible therapeutic targets in a readily identifiable subgroup of patients with early RA. Repurposing of Pim inhibitors for this disease should be considered.

Publication metadata

Author(s): Maney NJ, Lemos H, Barron-Millar B, Carey C, Herron I, Anderson AE, Mellor AL, Isaacs JD, Pratt AG

Publication type: Article

Publication status: Published

Journal: Arthritis and Rheumatology

Year: 2021

Volume: 73

Issue: 10

Pages: 1820-1830

Print publication date: 01/10/2021

Online publication date: 28/03/2021

Acceptance date: 18/03/2021

Date deposited: 10/11/2023

ISSN (print): 2326-5191

ISSN (electronic): 2326-5205

Publisher: Wiley

URL: https://doi.org/10.1002/art.41744

DOI: 10.1002/art.41744

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