Pim Kinases as Therapeutic Targets in Early Rheumatoid Arthritis.
Arthritis Rheumatol
; 73(10): 1820-1830, 2021 10.
Article
em En
| MEDLINE
| ID: mdl-33779060
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 CD25high 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Artrite Experimental
/
Artrite Reumatoide
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Linfócitos T CD4-Positivos
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Proteínas Proto-Oncogênicas c-pim-1
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Aged
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Aged80
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Animals
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Arthritis Rheumatol
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Reino Unido