Alleviation of exhaustion-induced immunosuppression and sepsis by immune checkpoint blockers sequentially administered with antibiotics—analysis of a new mathematical model

Abstract

Abstract Background Sepsis-associated immune dysregulation, involving hyper-inflammation and immunosuppression, is common in intensive care patients, often leading to multiple organ dysfunction and death. The aim of this study was to identify the main driving force underlying immunosuppression in sepsis, and to suggest new therapeutic avenues for controlling this immune impairment and alleviating excessive pathogen load. Methods We developed two minimalistic (skeletal) mathematical models of pathogen-associated inflammation, which focus on the dynamics of myeloid, lymphocyte, and pathogen numbers in blood. Both models rely on the assumption that the presence of the pathogen causes a bias in hematopoietic stem cell differentiation toward the myeloid developmental line. Also in one of the models, we assumed that continuous exposure to pathogens induces lymphocyte exhaustion. In addition, we also created therapy models, both by antibiotics and by immunotherapy with PD-1/PD-L1 checkpoint inhibitors. Assuming realistic parameter ranges, we simulated the pathogen-associated inflammation models in silico with or without various antibiotic and immunotherapy schedules. Results Computer simulations of the two models show that the assumption of lymphocyte exhaustion is a prerequisite for attaining sepsis-associated immunosuppression, and that the ability of the innate and adaptive immune systems to control infections depends on the pathogen’s replication rate. Simulation results further show that combining antibiotics with immune checkpoint blockers can suffice for defeating even an aggressive pathogen within a relatively short period. This is so as long as the drugs are administered soon after diagnosis. In contrast, when applied as monotherapies, antibiotics or immune checkpoint blockers fall short of eliminating aggressive pathogens in reasonable time. Conclusions Our results suggest that lymphocyte exhaustion crucially drives immunosuppression in sepsis, and that one can efficiently resolve both immunosuppression and pathogenesis by timely coupling of antibiotics with an immune checkpoint blocker, but not by either one of these two treatment modalities alone. Following experimental validation, our model can be adapted to explore the potential of other therapeutic options in this field.

Keywords

• Simulations
• Dynamic model
• T lymphocyte exhaustion
• Immunosuppression
• Checkpoint blockers
• Hyper-inflammation