An antibody that blocks the "programmed cell death" pathway may help the immune system fight off sepsis-related fungal infections, according to animal studies reported in SHOCK®: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches, Official Journal of the Shock Society. The journal is published in the Lippincott portfolio by Wolters Kluwer.
The findings support recent clinical studies using the anti-PD-1 antibody to treat life-threatening, opportunistic infections with Aspergillus fungus in patients with immune system suppression due to sepsis. Led by Asada Leelahavanichkul, MD, PhD, and Patcharee Ritprajak, DDS, PhD, Chulalongkorn University, Bangkok, the researchers write, "Adjunctive anti-PD-1 therapy may become a promising strategy for advanced immunotherapy against lethal fungal infection."
'Immune checkpoint inhibitor' improves survival in Aspergillus infection
The experiments study evaluated the use of anti-PD-1 antibody – a recently developed type of immunotherapy called checkpoint inhibitor therapy – to reactivate the immune system's ability to combat sepsis-related fungal infections. "Sepsis, a syndrome of organ dysfunction due to the imbalance of host immune response against systemic infection, remains the leading cause of death in the intensive care unit," the authors explain.
In patients with sepsis, an overwhelming inflammatory response leads to immune exhaustion or paralysis, leaving the patient vulnerable to opportunistic infections. One common infection, especially in tropical regions, is Aspergillus fungi. This infection, called aspergillosis, carries a high risk of death even with antifungal medications.
Developed to treat certain types of advanced cancers, anti-PD-1 immunotherapy has recently been successfully used to treat bacterial sepsis and sepsis-related Aspergillus infections. The researchers designed an experiment to clarify how anti-PD-1antibody works to combat these lethal infections.
Sepsis was induced in mice, producing immune system suppression with high expression of PD-1 by immune cells. The animals were then infected with Aspergillus, mimicking the situation when patients with sepsis develop secondary aspergillosis. Despite antifungal drugs, the survival rate in mice with Aspergillus infection was just ten percent.
But in animals receiving anti-PD-1 antibody along with antifungal therapy, the survival rate improved to 40 percent. Anti-PD-1 therapy also led to sharply reduced levels of Aspergillus in the blood, brain, lung, and kidney.
Anti-PD-1 treatment also led to increases of certain immune-active substances called cytokines (interferon-gamma and interleukin-17) that play a critical role in protective immunity against Aspergillus. Meanwhile, the anti-inflammatory cytokine interleukin-10 decreased, suggesting reversal of sepsis-induced immune suppression. Further experiments suggested that anti-PD-1 restored immune function by stimulating a group of "CD86-positive" cells in the spleen.
The experimental findings in mice support recent reports of successful anti-PD-1 immunotherapy in patients with sepsis-related fungal infections. Anti-PD-1 antibody seems to "reinvigorate" exhausted immune system cells, enabling them to attack the potentially fatal infection.
The findings warrant continued clinical studies of anti-PD-1 immunotherapy for patients with sepsis. Drs. Leelahavanichkul and Ritprajak and colleagues believe. They conclude, "[Our] study highlights the important role of immune response in collaboration with an antifungal agent, and strengthens the beneficial effect of PD-1 blockade on post-sepsis aspergillosis."
Vu, C.T.B. et al. (2019) Blockade of PD-1 Attenuated Post-Sepsis Aspergillosis via The Activation Of IFN-γ and The Dampening of IL-10. SHOCK®: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches. doi.org/10.1097/SHK.0000000000001392.