A monoclonal antibody against RAGE alters gene expression and is protective in experimental models of sepsis and pneumococcal pneumonia.
The RAGE (receptor for advanced glycation end products) is believed to play a role in sepsis by perpetuating inflammation. The interaction of RAGE with a variety of host-derived ligands that accumulate during stress and inflammation further induces the expression of RAGE. It was previously shown that a rat anti-RAGE monoclonal antibody protected mice from lethality in a cecal ligation and puncture model. We studied the effects of a humanized anti-RAGE monoclonal antibody in the murine pneumococcal pneumonia model of sepsis. Moreover, a gene expression analysis was performed in lung tissue of animals that underwent cecal ligation and puncture and treated with the rat anti-RAGE monoclonal antibody, compared with controls. Administration of humanized anti-RAGE mAb 6 h after intratracheal infection with Streptococcus pneumoniae improved mortality in BALB/c mice whether a 7.5 mg/kg (P < 0.01) or a 15 mg/kg dose (P < 0.01) was administered in combination with antibiotics. Gene expression analysis showed that many of the genes modulated by treatment with the anti-RAGE antibody were those that play an important role in regulating inflammation. Anti-RAGE monoclonal antibody offered a survival advantage to septic mice. This protective role in treated animals is supported by the observed gene expression profile changes of genes involved in sepsis and inflammation.
Infectious Disease Division, Memorial Hospital of RI, The Warren Alpert School of Medicine of Brown University, Providence, Rhode Island, USA.
Eirini
E
Christaki
Steven M
SM
Opal
James C
JC
Keith
Nubar
N
Kessimian
John E
JE
Palardy
Nicolas A
NA
Parejo
Xiang Yang
XY
Tan
Nicole
N
Piche-Nicholas
Lioudmila
L
Tchistiakova
George P
GP
Vlasuk
Kathleen M
KM
Shields
Jeffrey L
JL
Feldman
Edward R
ER
Lavallie
Maya
M
Arai
William
W
Mounts
Debra D
DD
Pittman
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000378:metabolism* / Q000382:microbiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology*; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000472:pathogenicity
D000911:Antibodies, Monoclonal; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic