Blockade ofthe negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis

Abstract

IntroductionFungal sepsis is an increasingly common problem in intensive care unit patients.Mortality from fungal sepsis remains high despite antimicrobial therapy that is highly active against most fungal pathogens, a finding consistent with defective host immunity that is present in many patients with disseminated fungemia.One recently recognized immunologic defect that occurs in patients with sepsis is T cell "exhaustion" due to increased expression of programmed cell death -1 (PD-1).This study tested the ability of anti-PD-1 and anti-programmed cell death ligand -1 (anti-PD-L1) antagonistic antibodies to improve survival and reverse sepsis-induced immunosuppression in two mouse models of fungal sepsis.MethodsFungal sepsis was induced in mice using two different models of infection, that is, primary fungal sepsis and secondary fungal sepsis occurring after sub-lethal cecal ligation and puncture (CLP).Anti-PD-1 and anti-PD-L1 were administered 24 to 48 h after fungal infection and effects on survival, interferon gamma production, and MHC II expression were examined.ResultsAnti-PD-1 and anti-PD-L1 antibodies were highly effective at improving survival in primary and secondary fungal sepsis.Both antibodies reversed sepsis-induced suppression of interferon gamma and increased expression of MHC II on antigen presenting cells.Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a second negative co-stimulatory molecule that is up-regulated in sepsis and acts like PD-1 to suppress T cell function, also improved survival in fungal sepsis.ConclusionsImmuno-adjuvant therapy with anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies reverse sepsis-induced immunosuppression and improve survival in fungal sepsis.The present results are consistent with previous studies showing that blockade of PD-1 and CTLA-4 improves survival in bacterial sepsis.Thus, immuno-adjuvant therapy represents a novel approach to sepsis and may have broad applicability in the disorder.Given the relative safety of anti-PD-1 antibody in cancer clinical trials to date, therapy with anti-PD-1 in patients with life-threatening sepsis who have demonstrable immunosuppression should be strongly considered.

T-Regulatory Cells and Programmed Death 1+ T Cells Contribute to Effector T-Cell Dysfunction in Patients with Chronic Obstructive Pulmonary Disease

“…significant changes in splenic T-cell IFN-g production were found in mice treated with either anti-PD-1 or anti-CTLA-4 antibodies (32).…”

Sepsis-induced immune dysfunction: can immune therapies reduce mortality?

“…Recent studies demonstrated neutrophil PD-L1 upregulation on neutrophils from septic mice and humans, resulting in the potentiation of lymphocyte apoptosis through contact inhibition, which correlated with outcome (117). Moreover, in clinically relevant animal models of bacterial sepsis, inhibition of PD-1 and PD-L1 signaling improved survival and reduced the incidence of fungal infections (118). Considering the beneficial impact on adaptive immunity and tumor eradication strategies, it makes sense that PD-1 and PD-1L could concomitantly serve as biomarkers of sepsis-initiated immune suppression as well as prospective therapeutic targets to reverse adaptive immune dysfunction and improve long-term survival.…”

Efficacy of β-Lactam-plus-Macrolide Combination Therapy in a Mouse Model of Lethal Pneumococcal Pneumonia

“…Brahmamdam et al (43), using a novel therapeutic strategy, reported that an anti-PD-1 antibody administered 24 h after cecal ligation and puncture prevented the sepsis-induced depletion of lymphocytes and dendritic cells and improved survival. More recently, Chang and collaborators (40) reported that the blockade of PD-1 and CTLA-4 by the respective antibodies improved survival in a Candida-challenged sepsis mouse model. Ceftriaxone-plus-azithromycin combination therapy may involve an optimal modulation of CTLA-4 and PD-1 expression to restore immune functions and contribute to enhanced survival in a mouse model of lethal pneumococcal pneumonia.…”

“…Nearly four decades of investigating anti-inflammation strategies against sepsis, based on the concept that excessive inflammation might be the main cause for the adverse outcomes of sepsis, have yielded disappointing results. However, there is now evidence that the immunosuppressive state involves a misbalance between proinflammatory reactions and anti-inflammatory responses following the initial hyperinflammation state in sepsis, which may contribute to the high mortality of sepsis (16,17,40). Among several target molecules that have been proposed to overcome the immunosuppressive state in sepsis patients, most attention has been focused on immune checkpoint receptors such as PD-1 and CTLA-4 as promising molecules, based on several clinical and experimental findings.…”