title: CD28 homodimer interface mimetic peptide acts as a preventive and therapeutic agent in models of severe bacterial sepsis and gram-negative bacterial peritonitis.
abstract: BACKGROUND
  Severe gram-negative bacterial infections and sepsis are major causes of morbidity and mortality. Dysregulated, excessive proinflammatory cytokine expression contributes to the pathogenesis of sepsis. A CD28 mimetic peptide (AB103; previously known as p2TA) that attenuates CD28 signaling and T-helper type 1 cytokine responses was tested for its ability to increase survival in models of polymicrobial infection and gram-negative sepsis.
  
  
  METHODS
  Mice received AB103, followed by an injection of Escherichia coli 0111:B4 lipopolysaccharide (LPS); underwent induction E. coli 018:K1 peritonitis induction, followed by treatment with AB103; or underwent cecal ligation and puncture (CLP), followed by treatment with AB103. The effects of AB103 on factors associated with and the lethality of challenge infections were analyzed.
  
  
  RESULTS
  AB103 strongly attenuated induction of tumor necrosis factor α and interleukin 6 (IL-6) by LPS in human peripheral blood mononuclear cells. Receipt of AB103 following intraperitoneal injection of LPS resulted in survival among 73% of CD1 mice (11 of 15), compared with 20% of controls (3 of 15). Suboptimal doses of antibiotic alone protected 20% of mice (1 of 5) from E. coli peritonitis, whereas 100% (15 of 15) survived when AB103 was added 4 hours following infection. Survival among mice treated with AB103 12 hours after CLP was 100% (8 of 8), compared with 17% among untreated mice (1 of 6). In addition, receipt of AB103 12 hours after CLP attenuated inflammatory cytokine responses and neutrophil influx into tissues and promoted bacterial clearance. Receipt of AB103 24 hours after CLP still protected 63% of mice (5 of 8).
  
  
  CONCLUSIONS
  Single-dose AB103 reduces mortality in experimental models of polymicrobial and gram-negative bacterial infection and sepsis, warranting further studies of this agent in clinical trials.
authors.affiliation: Center for Vaccine Development, University of Maryland Medical School, Baltimore.
authors.forename: Girish
authors.initials: G
authors.lastname: Ramachandran
authors.affiliation: Institute of Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem.
authors.forename: Raymond
authors.initials: R
authors.lastname: Kaempfer
authors.affiliation: Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
authors.forename: Chun-Shiang
authors.initials: CS
authors.lastname: Chung
authors.affiliation: Atox Bio, Rehovot, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Shirvan
authors.affiliation: Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
authors.forename: Abdullah B
authors.initials: AB
authors.lastname: Chahin
authors.affiliation: Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
authors.forename: John E
authors.initials: JE
authors.lastname: Palardy
authors.affiliation: Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Parejo
authors.affiliation: Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center for Vaccine Development, University of Maryland Medical School, Baltimore.
authors.forename: Melissa
authors.initials: M
authors.lastname: Whitford
authors.affiliation: Institute of Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem.
authors.forename: Gila
authors.initials: G
authors.lastname: Arad
authors.affiliation: Institute of Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem.
authors.forename: Dalia
authors.initials: D
authors.lastname: Hillman
authors.affiliation: Atox Bio, Rehovot, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Shemesh
authors.affiliation: Center for Vaccine Development, University of Maryland Medical School, Baltimore.
authors.forename: William
authors.initials: W
authors.lastname: Blackwelder
authors.affiliation: Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala
authors.affiliation: Center for Vaccine Development, University of Maryland Medical School, Baltimore.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Cross
authors.affiliation: Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Opal
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018106:CD28 Antigens / Q000737:chemistry* / Q000627:therapeutic use; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry; D020556:Neutrophil Infiltration / Q000187:drug effects; D010538:Peritonitis / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D054730:Protein Interaction Domains and Motifs; D018805:Sepsis / Q000188:drug therapy / Q000517:prevention & control*
chemical_list: D000900:Anti-Bacterial Agents; D018106:CD28 Antigens; D018925:Chemokines; D008070:Lipopolysaccharides; C000597133:AB103
keywords: CD28 homodimer interface; cecal ligation and puncture; gram-negative sepsis; lipopolysaccharide; mimetic peptide; peritonitis