TLR4与小鼠半相合造血干细胞移植后急性GVHD关系的实验研究

The relationship between TLR4 and acute graft-versus-host disease in murine haploidentical hematopoietic stem cell transplantation model

目的:探讨Toll样受体4(Toll-like receptor 4,TLR4)对半相合造血干细胞移植(HSCT)小鼠急性移植物抗宿主病(acute graft-versus-host disease,a-GVHD)的影响及其可能机制。方法:建立小鼠半相合HSCT模型,随机分为分为实验1组(n=12):每只小鼠按20μg/kg输注TLR4激动剂-脂多糖(LPS);实验2组(n=12):每只小鼠按20μg/kg输注TLR4单克隆抗体;对照组(n=12):其中6只小鼠按20μg/kg输注灭菌生理盐水,另6只半相合HSCT移植后不作任何处理。观察各组小鼠的a-GVHD临床表现及生存时间,检测小鼠血清中白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)变化情况,并于移植后14 d对小鼠肝脏进行病理分析。结果:与对照组相比较,实验2组的GVHD严重程度、生存率以及病理改变均明显轻于对照组(P<0.05),而实验1组的上述改变则明显较对照组为重。结论:针对TLR4的抑制剂对半相合HSCT小鼠的a-GVHD具有一定的预防作用。

Objective：To investigate the effect of Toll-Like receptor 4 （TLR4） on the severity of acute graft-versus-host disease （GVHD） after haploidentical stem cell transplantation （HSCT） in mouse and explore its potential mechanism. Methods：Establish a mouse model of MHC haploidentical bone marrow transplantation. The mice were randomly divided into the experimental group 1（n= 12）：each mouse was received 20 μg/kg infusion of TLR4 agonist LPS; the experimental group 2 （n=12） ：each mouse was received 20μg/kg infusion of TLR4 monoclonal antibody; the control group （n=12）：six mice were received 20 μg/kg infusion of sterile saline; other six mice without any treatment after transplantation. We observed the clinical manifestation of GVHD and the survival rate by using Kaplan-Meier analysis. On the 14th day after transplantation,the histopathology of GVHD was evaluated in the liver, and the change of serum IL-1β,TNF-α was detected. Results：Compared with the control group,the mice in the experimental group 2 had reduced severity of acute GVHD symptoms,improved survival rate （P 〈 0.05） and less histopathological evidence of GVHD. Correspondingly,the above changes of the mice in the experimental group 1 were severe. Conclusion：The TLR4 inhibitors can prevent acute GVHD in murine haplo-HSCT model.