Cheng Wei, Song Saizhe, Shen Yu, Liu Cuiping, Chang Xin, Wu Jian
Department of Rheumatology and Immunology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou 215006; Department of Dermatology, Changshu No. 2 People's Hospital, Suzhou 215501, China.
Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2025 Jul;41(7):620-628.
Objective To investigate the therapeutic effects of interleukin 23p19(IL-23p19) monoclonal antibody in the MRL/lpr lupus-like mouse model. Methods A total of 36 female MRL/lpr mice aged 8 weeks were randomly divided into 6 groups: PBS group (blank control), IgG group (isotype IgG), dexamethasone (DEX) group (positive control), and three IL-23p19 monoclonal antibody treatment groups with different dose gradients: low dose (LD, 1 mg/kg), medium dose (MD, 3 mg/kg), and high dose (HD, 10 mg/kg). Drug intervention began at 12 weeks of age via tail vein injection. Urine protein levels were measured using urine protein test strips; serum anti-dsDNA antibody levels were detected by ELISA; serum creatinine and blood urea nitrogen levels were measured using an automatic biochemical analyzer; renal histopathological changes were analyzed by H&E and PAS staining; immunofluorescence was used to assess IgG and C3 immune complex deposition in kidney tissues; flow cytometry was employed to examine the expression of T helper 1(Th1), Th2, Th17, T follicular helper (Tfh), and regulatory T cells(Treg) cell subsets in the spleen; and RT-qPCR was used to detect the expression of related transcription factors in the spleen. Results IL-23p19 monoclonal antibody reduced urine protein levels, alleviated splenomegaly, improved renal function, and decreased anti-dsDNA antibody levels in MRL/lpr mice. It also mitigated glomerulonephritis and reduced renal immune complex deposition. Furthermore, IL-23p19 monoclonal antibody significantly suppressed the proportion of Th1 and Th17 cells while upregulating Treg cell proportion in the spleen. Additionally, it downregulated T-bet and retinoic acid receptor-related orphan receptor γt (RORγt) mRNA levels and upregulated forkhead box P3(FOXP3) mRNA levels in the spleen. Conclusions IL-23p19 monoclonal antibody demonstrates significant therapeutic effects in MRL/lpr mice, likely through modulation of the Th17/Treg cell balance.
目的 探讨白细胞介素23p19（IL-23p19）单克隆抗体对MRL/lpr狼疮样小鼠模型的治疗作用。方法 将36只8周龄雌性MRL/lpr小鼠随机分为6组：PBS组（空白对照）、IgG组（同型IgG）、地塞米松（DEX）组（阳性对照），以及3个不同剂量梯度的IL-23p19单克隆抗体治疗组：低剂量（LD，1 mg/kg）、中剂量（MD，3 mg/kg）和高剂量（HD，10 mg/kg）。12周龄时通过尾静脉注射开始药物干预。使用尿蛋白试纸条测量尿蛋白水平；采用酶联免疫吸附测定法（ELISA）检测血清抗双链DNA（dsDNA）抗体水平；使用自动生化分析仪测量血清肌酐和血尿素氮水平；通过苏木精-伊红（H&E）和过碘酸雪夫（PAS）染色分析肾脏组织病理学变化；采用免疫荧光法评估肾脏组织中IgG和C3免疫复合物沉积；运用流式细胞术检测脾脏中辅助性T细胞1（Th1）、Th2、Th17、滤泡辅助性T细胞（Tfh）和调节性T细胞（Treg）亚群的表达；采用逆转录定量聚合酶链反应（RT-qPCR）检测脾脏中相关转录因子的表达。结果 IL-23p19单克隆抗体降低了MRL/lpr小鼠的尿蛋白水平，减轻了脾肿大，改善了肾功能，并降低了抗dsDNA抗体水平。它还减轻了肾小球肾炎并减少了肾脏免疫复合物沉积。此外，IL-23p19单克隆抗体显著抑制了脾脏中Th1和Th17细胞的比例，同时上调了Treg细胞比例。此外，它下调了脾脏中T-bet和视黄酸受体相关孤儿受体γt（RORγt）mRNA水平，并上调了叉头框P3（FOXP3）mRNA水平。结论 IL-23p19单克隆抗体在MRL/lpr小鼠中显示出显著的治疗作用，可能是通过调节Th17/Treg细胞平衡实现的。
