CD40 and CD80/86 act synergistically to regulate inflammation and mortality in polymicrobial sepsis.
BACKGROUND
Costimulatory molecules, including the CD40-CD154 and CD80/86-CD28 dyads, play a prominent role in regulating inflammation in the adaptive immune response. Studies from our group and others suggest a potentially important role for these costimulatory cascades in innate immunity as well.


OBJECTIVE
To determine the role of CD80/86 alone and in combination with CD40 in lethal polymicrobial sepsis in mice and humans.


METHODS
The murine cecal ligation and puncture (CLP) model was used to determine the role of CD80/86 alone and in combination with CD40 using wild-type mice, CD80/86(-/-) mice, and novel CD40/80/86(-/-) mice. Expression of cell-bound and soluble costimulatory molecules was assessed in humans via ELISA and flow cytometry.


RESULTS
Lethal CLP was associated with up-regulation of CD40 and CD80/86 and their respective ligands CD28 and CD154 on innate effector cells. Blockade or deletion of CD80/86 attenuated mortality and inflammatory cytokine production during CLP. CD40/80/86(-/-) mice exhibited further reductions in mortality, lung injury, and inflammatory cytokine production compared with CD80/86(-/-) mice. Finally, humans with sepsis had increased monocyte expression of CD40 and CD80 compared with healthy control subjects; with higher levels in subjects requiring vasopressor support. Levels of soluble CD28 and CD154 were significantly higher in patients who died compared with those who lived.


CONCLUSIONS
These data demonstrate a central role for CD40 and CD80/86 in the innate immune response and suggest that combined inhibition of CD40 and CD80/86 may improve mortality in sepsis. Expression of costimulatory molecules may serve as biomarkers for outcome in septic patients.
Nolan
Anna
A
Oregon Health and Science University, Division of Pulmonary and Critical Care, Mail Code UHN67, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Weiden
Michael
M
Kelly
Ann
A
Hoshino
Yoshihiko
Y
Hoshino
Satomi
S
Mehta
Nehal
N
Gold
Jeffrey A
JA
D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism*; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism*; D015415:Biomarkers; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology*; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000401:mortality; D015854:Up-Regulation
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D015415:Biomarkers; D019013:CD40 Antigens