应用抗CD137L单克隆抗体阻断CD137/CD137L信号通路抑制小鼠SGVHD的发生

Inhibition of murine syngeneic graft versus host disease by blockade of CD137/CD137L signaling pathway with anti-CD137L mAb

目的:探讨抗CD137L单克隆抗体阻断CD137/CD137L信号通路在小鼠同基因型移植物抗宿主病(SGVHD)诱导中的作用,以阐明SGVHD的发生机制。方法:用致死剂量的X射线照射受体小鼠后,移植同基因骨髓细胞,从移植的当天开始连续21天腹腔注射环孢素A(CsA)诱导SGVHD。于诱导的第10天起给治疗组小鼠腹腔注射抗CD137L单克隆抗体进行干预治疗。观察各组小鼠的临床症状(体重下降,腹泻)、组织病理学和细胞因子改变。结果:抗CD137L单克隆抗体治疗组小鼠SGVHD的发生率明显低于诱导组小鼠SGVHD的发生率(25%vs 67%),两者差异具有统计学意义(P<0.01)。SGVHD小鼠肝脏和结肠组织病理学呈严重炎症细胞浸润,组织中细胞因子IL-12、IFN-γ、TNF-αmRNA水平升高。而抗体治疗组小鼠织病理学呈轻度炎症细胞浸润,组织中细胞因子IL-12、IFNγ-、TNF-αmRNA水平较低或检测不到。结论:单独用抗CD137L单克隆抗体阻断CD137/CD137L信号通路可明显抑制小鼠SGVHD的发生,提示CD137/CD137L信号通路在小鼠SGVHD免疫反应中是较为重要的通路之一。

Objective： To primarily explore the effects of blockade of CD137/CD137L signaling pathway with anti-CD137L monoclonal antibody on the induction of murine syngeneie graft versus host disease and to investigate the development mechanism of syngeneie GVHD. Methods：Recipient mice were lethally irradiated with X-ray, transplanted syngeneie bone marrow cells via tail vein and injected CsA peritoneally. Mice in treatment group were administered anfi-CD137L monoclonal antibody from the 10th day following transplantation and all mice were observed for clinical symptoms （such as weight loss and diarrhea） ,pathological changes and eytokine profiles. Results：The 67% of mice in CsA-indueed group had SGVHD which was higher than the incidence of 25% in anti-CD137 L mAb treatment group （ P 〈 0. 01 ）. Both severe inflammatory cells infiltrates and higher levels of IL-12, IFN-γ,TNF-α mRNA in liver and colon of SGVI-ID mice were detected in induction group mice, while the mice in treatment group had less inflammatory cells infiltrates and lower levels of IL-12, IFN-γ,TNF-α mRNA in liver and colon than the mice of SGVHD had. Conclusion： Blockade of CD137/CD137L signaling pathway with anti-CD137L monoclonal antibody alone can significantly inhibit the development of murine SGVHD and this demonstrates that CD137/CD137L signaling pathway plays a povital role in the induction of SGVHD.