Lo Pizzo Marianna, La Barbera Lidia, Rizzo Chiara, Mohammadnezhad Leila, Camarda Federica, Ciccia Francesco, Guggino Giuliana
Biomedicine, Neuroscience and Advanced Diagnostic, University of Palermo, Italy.
Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, P. Giaccone University of Palermo, Italy.
Clin Exp Rheumatol. 2024 Mar;42(3):593-600. doi: 10.55563/clinexprheumatol/hhcnmt. Epub 2023 Sep 21.
Recent evidence suggests that innate lymphoid cells (ILCs) might be involved in rheumatoid arthritis (RA) pathogenesis and individuals at risk of RA exhibited an increased frequency of ILC1. JAK3 participates in ILC1 and ILC3 differentiation. Tofacitinib and the Janus Kinase (JAK) 3 inhibitor, PF-06651600, impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ and the proliferation of ILC1 and ILC3. Our study aims to evaluate the ex vivo effects of tofacitinib in RA patients and to investigate if ILC1s and ILC3s are specific targets of tofacitinib in RA.
Twenty RA patients starting tofacitinib and 10 RA patients starting anti-TNFα were enrolled. Peripheral blood mononuclear cells (PBMCs) from RA patients, collected before and three months after therapy, were cultured to evaluate ILC1 and ILC3 frequencies and the respective production of IFN-γ and IL-17 by flow cytometry analysis. PBMCs of RA patients were in vitro cultured with tofacitinib to evaluate the dose effects on ILC frequencies.
RA patients showed a significant expansion of ILC1 but not ILC3. Unlike anti-TNFα treated patients, in whom no reduction in ILCs was reported, after three months of tofacitinib therapy the overall ILC frequency was reduced, as well as the ILC1 ability to release IFN-γ. In vitro treatment of PBMCs with tofacitinib demonstrated a dose-dependent reduction in the frequency of ILCs compared to untreated cells.
Our preliminary results demonstrate that tofacitinib modulates the innate immune response by reducing the frequency of ILC1 cells and their production of IFN-γ.
近期证据表明，固有淋巴细胞（ILC）可能参与类风湿关节炎（RA）的发病机制，且有RA风险的个体中ILC1频率增加。JAK3参与ILC1和ILC3的分化。托法替布和Janus激酶（JAK）3抑制剂PF-06651600会损害人上皮内ILC1（iILC1）产生IFN-γ的能力以及ILC1和ILC3的增殖。我们的研究旨在评估托法替布对RA患者的体外作用，并研究ILC1和ILC3是否为托法替布在RA中的特异性靶点。
招募了20名开始使用托法替布的RA患者和10名开始使用抗TNFα的RA患者。收集RA患者治疗前及治疗三个月后的外周血单个核细胞（PBMC）进行培养，通过流式细胞术分析评估ILC1和ILC3的频率以及IFN-γ和IL-17的各自产生情况。将RA患者的PBMC与托法替布进行体外培养，以评估其对ILC频率的剂量效应。
RA患者显示出ILC1显著扩增，但ILC3未扩增。与未报告ILC减少的抗TNFα治疗患者不同，托法替布治疗三个月后，总体ILC频率降低，ILC1释放IFN-γ的能力也降低。与未处理的细胞相比，用托法替布体外处理PBMC显示ILC频率呈剂量依赖性降低。
我们的初步结果表明，托法替布通过降低ILC1细胞的频率及其IFN-γ的产生来调节固有免疫反应。
