Delayed Immunomodulation Improves Immune Dysfunction in a Murine Model of PICS

Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) can occur following sepsis when there is an overwhelming systemic inflammatory response that leads to multiple organ dysfunction, significant morbidity, and chronic critical illness. Despite the increasing recognition of this clinical problem, there are no interventions that can reverse this response. This study aims to characterize the immune responses in a murine PICS model using cecal ligation and puncture (CLP) and assess the efficacy of various immunomodulatory agents, including G-CSF, GM-CSF, and anti-PD-L1 antibody, in reversing the immune dysfunction when given after day four, once the typical acute response to sepsis starts to subside. Our results showed that anti-PD-L1 therapy showed greater efficacy than G-CSF and GM-CSF in reversing immunosuppression post-CLP, as evidenced by improved immune cell numbers, immune function, MHC-II and CD11b expression on innate immune cells, and INFγ production from T cells. However, while improving certain immune parameters, anti-PD-L1 treatment did not allow for effective bacterial clearance when the mice were inoculated with Pseudomonas aeruginosa eight days after CLP. Interestingly, despite this decreased bacterial clearance, anti-PD-L1 therapy did not affect survival for CLP mice (100% survival) compared with untreated CLP mice (60% survival). These findings suggest that anti-PD-L1 therapy may improve some of the immune dysfunction seen after CLP and allow for improved survival towards secondary bacterial infections.