Moxibustion and anti-PD-1 antibody synergistically reverse immunosuppression and improve survival in septic mice

Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, leading to organ dysfunction. Despite advances in critical care, mortality remains high, particularly due to a late-stage immunosuppressive phase where patients become vulnerable to secondary infections. The PD-1/PD-L1 immune checkpoint pathway plays a crucial role in this immunosuppression, dampening T cell responses. Current standard-of-care often fails to address this profound immune paralysis, highlighting an urgent need for novel immunomodulatory strategies to restore immune function and improve patient outcomes.

Researchers established a CLP-induced sepsis mouse model to investigate the effects of moxibustion (Mox) and/or anti-PD-1 antibody. Mice were divided into control (CLP only), Mox monotherapy, anti-PD-1 monotherapy, and combination therapy groups. Specific doses and frequencies for moxibustion and anti-PD-1 antibody were not detailed in the abstract. Primary endpoints included survival rates, murine sepsis score, assessment of pathological damage in liver, lungs, and spleen, serum biochemical markers, systemic and local inflammation, intraperitoneal bacterial load, macrophage recruitment, T cell proportions (CD3⁺, CD4⁺, CD8⁺), CD3⁺ T cell apoptosis, Th1/Th2 balance, and expression of PD-1, PD-L1, and STAT3 via methods like flow cytometry and Western blot.

Both moxibustion and anti-PD-1 monotherapy significantly improved mouse survival rates, reduced murine sepsis scores, alleviated pathological damage in vital organs, and mitigated serum biochemical abnormalities. They also regulated systemic and local organ inflammation. The combination therapy demonstrated synergistic enhancement effects, yielding the most significant improvements across all measured metrics. The combined approach effectively reduced intraperitoneal bacterial load and enhanced macrophage recruitment. It also reversed sepsis-induced decreases in spleen T cell (CD3⁺, CD4⁺, CD8⁺) proportions and CD3⁺ T cell apoptosis, while correcting Th1/Th2 imbalance.

Combination therapy significantly downregulated PD-1 expression on spleen T cells and PD-L1 expression on neutrophils, further suppressing PD-1, PD-L1, and STAT3 expression in the spleen and reducing STAT3 nuclear translocation. These findings suggest the combination effectively alleviates both early inflammatory storms and late-stage immunosuppression in sepsis.