Rheumatology Unit, Department of Medicine (DIMED), University of Padova, Padova, Italy.
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
Front Immunol. 2018 Sep 11;9:2081. doi: 10.3389/fimmu.2018.02081. eCollection 2018.
To explore the effects of SERPINB3 administration in murine lupus models with a focus on lupus-like nephritis. 40 NZB/W F1 mice were subdivided into 4 groups and intraperitoneally injected with recombinant SERPINB3 (7.5 μg/0.1 mL or 15 μg/0.1 mL) or PBS (0.1 mL) before (group 1 and 2) or after (group 3 and 4) the development of proteinuria (≥100 mg/dl). Two additional mice groups were provided by including 20 MRL/ mice which were prophylactically injected with SERPINB3 (10 mice, group 5) or PBS (10 mice, group 6). Time of occurrence and levels of anti-dsDNA and anti-C1q antibodies, proteinuria and serum creatinine, overall- and proteinuria-free survival were assessed in mice followed up to natural death. Histological analysis was performed in kidneys of both lupus models. The Th17:Treg cell ratio was assessed by flow-cytometry in splenocytes of treated and untreated MRL/ mice. Statistical analysis was performed using non parametric tests and Kaplan-Meier curves, when indicated. Autoantibody levels and proteinuria were significantly decreased and time of occurrence significantly delayed in SERPINB3-treated mice vs. controls. In agreement with these findings, proteinuria-free and overall survival were significantly improved in SERPINB3-treated groups vs. controls. Histological analysis demonstrated a lower prevalence of severe tubular lesions in kidneys of group 5 vs. group 6. SERPINB3-treated mice showed an overall trend toward a reduced prevalence of severe lesions in both strains. Th17:Treg ratio was significantly decreased in splenocytes of MRL/ mice treated with SERPINB3, compared to untreated control mice. SERPINB3 significantly improves disease course and delays the onset of severe glomerulonephritis in lupus-prone mice, possibly inducing a more tolerogenic immune phenotype.
探讨了 SERPINB3 在以狼疮样肾炎为重点的狼疮小鼠模型中的作用。40 只 NZB/W F1 小鼠被分为 4 组，在出现蛋白尿（≥100mg/dl）之前（第 1 组和第 2 组）或之后（第 3 组和第 4 组）腹腔内注射重组 SERPINB3（7.5μg/0.1mL 或 15μg/0.1mL）或 PBS（0.1mL）。另外提供了两组 20 只 MRL/小鼠，其中 10 只预防性注射 SERPINB3（第 5 组），10 只注射 PBS（第 6 组）。对随访至自然死亡的小鼠进行抗 dsDNA 和抗 C1q 抗体、蛋白尿和血清肌酐、总生存和无蛋白尿生存的时间评估。对两种狼疮模型的肾脏进行组织学分析。通过流式细胞术评估治疗和未治疗的 MRL/小鼠脾细胞中的 Th17:Treg 细胞比值。在需要时使用非参数检验和 Kaplan-Meier 曲线进行统计分析。与对照组相比，SERPINB3 治疗组的自身抗体水平和蛋白尿显著降低，发病时间显著延迟。与对照组相比，SERPINB3 治疗组的无蛋白尿和总生存显著改善。组织学分析表明，第 5 组肾脏的严重肾小管病变发生率低于第 6 组。SERPINB3 治疗组两种品系的严重病变发生率均呈降低趋势。与未治疗的对照小鼠相比，SERPINB3 治疗的 MRL/小鼠脾细胞中的 Th17:Treg 比值显著降低。SERPINB3 可显著改善疾病进程，延迟狼疮易感小鼠严重肾小球肾炎的发病，可能诱导更耐受的免疫表型。
