Newcastle University Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Newcastle University Translational and Clinical Research Institute, Newcastle University, and Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Arthritis Rheumatol. 2021 Oct;73(10):1820-1830. doi: 10.1002/art.41744. Epub 2021 Aug 24.
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).
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).
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 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.
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.
原癌基因和癌症治疗靶点 Moloney 鼠白血病病毒整合位点 1（Pim-1）也是人类自身免疫的相关因素。本研究旨在探讨 Pim-1 及其家族成员作为早期类风湿关节炎（RA）潜在治疗靶点的可能性。
验证了用于检测早期关节炎患者外周血单个核细胞中 PIM1 转录物的流式细胞术检测，并将其作为细胞水平 Pim-1 活性的生物标志物进行应用。通过对未经治疗的 RA 患者和非 RA 疾病对照的组织样本进行多重免疫荧光检测，同样确定了滑膜蛋白表达。在从这些个体中分离的新鲜 CD4+T 细胞中，确定了 Pim 激酶家族操作的功能后果，以及 Pim 抑制对胶原诱导性关节炎（CIA）小鼠的影响。
流式细胞术检测到的循环 CD4+T 细胞中 PIM1 转录本的百分比是基因表达的忠实替代物，在早期 RA 患者中明显高于其他疾病患者。早期 RA 患者滑膜 CD4+T 细胞中的 Pim-1 蛋白水平也同样上调。在体外，用 Pim 激酶抑制剂处理 T 细胞受体刺激的早期 RA CD4+T 细胞可抑制其激活和增殖能力。与未暴露的细胞相比，暴露的细胞中促炎性细胞因子（干扰素-γ和白细胞介素-17）的产生减少，CD25FoxP3+Treg 细胞比例增加。最后，给予 Pim 抑制剂可显著限制 CIA 中的关节炎进展和软骨破坏。
我们的研究结果表明，Pim 激酶是早期 RA 患者中一个易于识别的亚组的潜在治疗靶点。应考虑将 Pim 抑制剂重新用于该疾病。
