RGD Reference Report - Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. - Rat Genome Database

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

Authors: Chang, Katherine C  Burnham, Carey-Ann  Compton, Stephanie M  Rasche, David P  Mazuski, Richard J  McDonough, Jacquelyn S  Unsinger, Jacqueline  Korman, Alan J  Green, Jonathan M  Hotchkiss, Richard S 
Citation: Chang KC, etal., Crit Care. 2013 May 11;17(3):R85. doi: 10.1186/cc12711.
RGD ID: 40818234
Pubmed: (View Article at PubMed) PMID:23663657
DOI: Full-text: DOI:10.1186/cc12711


INTRODUCTION: Fungal 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.
METHODS: Fungal 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.
RESULTS: Anti-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.
CONCLUSIONS: Immuno-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.

Annotation

Disease Annotations    
Fungemia  (IEP,IMP,ISO)

Objects Annotated

Genes (Rattus norvegicus)
Cd274  (CD274 molecule)
Pdcd1  (programmed cell death 1)

Genes (Mus musculus)
Cd274  (CD274 antigen)
Pdcd1  (programmed cell death 1)

Genes (Homo sapiens)
CD274  (CD274 molecule)
PDCD1  (programmed cell death 1)


Additional Information