Blockage of macrophage-mediated PD1/PD-L1 pathways inhibits tuberculosis relapse in mice / 中国比较医学杂志

ABSTRACT

Objective To study the immune intervention effect and mechanism of blockage of macrophage-mediated PD1 /PD-L1 pathways with functional PD-L1(programmed cell death ligand-1,PD-L1)monoclonal antibody upon tuberculosis(TB)relapse in mice. Methods Female C57BL/6 mice were infected by tail vein injection of 106CFU M. tuberculosis H37Rv to obtain active TB infection. Two weeks postinfection, the mice in different groups were administered isoniazid(10 mg/kg)(group ISO)and isoniazid combined with PD-L1 monoclonal antibody(50 μg/each)(group ISO+PD-L1)respectively,continued for four weeks to obtain latent infection. The subsequent relapse was monitored. Among the treatment groups,the TB relapse was induced by TNF-α antibody(50 ug/each)for four weeks from the beginning of latent stage. At each scheduled time point, bacterial loads and pathological changes in the lung, spleen and liver were quantitatively analyzed,thereby,the in vivo intervention effect of PD-L1 monoclonal antibody on tuberculosis recurrence in mice was revealed. The in vitro experiment was further explored whether knock-down the expression of PD-L1 on the infected macrophages could accerlate the macrophage apoptosis. Results The bacterial burden reached 3-4 Lg(CFU/mL),and granuloma lesions were extensive in the lung, spleen and liver in the all infected groups, which appeared as active TB stage at 2nd week postinfection. After treated,the bacterial burden of the lung,spleen and liver was decreased, and the pathological lesions alleviated in the group ISO and group ISO+PD-L1, compared with the model control group, showing significant differences, but there was no significant difference between the two treatment groups. However, compared with the group ISO,the group ISO+PD-L1 had a significantly lower bacterial load and milder pathological lesions during the relapse period. Futhermore, knock-down the expression of PD-L1 on macrophages with anti-PD-L1 or PD-L1-siRNA promoted apoptosis in macrophages. Conclusions Blockade of the PD1/PD-L1 pathway by PD-L1 functional antibody can inhibit TB relapse in mice,and knock-down the expression of PD-L1 on macrophages or PD1/PD-L1 pathway with functional antibody can promote apoptosis in macrophages,which together indicate that PD-L1 blockage can effectively promote isoniazid treatment of TB and remarkably inhibit the recurrence of TB in mice.