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CD28 homodimer interface mimetic peptide acts as a preventive and therapeutic agent in models of severe bacterial sepsis and gram-negative bacterial peritonitis.
Ramachandran, Girish; Kaempfer, Raymond; Chung, Chun-Shiang; Shirvan, Anat; Chahin, Abdullah B; Palardy, John E; Parejo, Nicolas A; Chen, Yaping; Whitford, Melissa; Arad, Gila; Hillman, Dalia; Shemesh, Ronen; Blackwelder, William; Ayala, Alfred; Cross, Alan S; Opal, Steven M.
Afiliación
  • Ramachandran G; Center for Vaccine Development, University of Maryland Medical School, Baltimore.
  • Kaempfer R; Institute of Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem.
  • Chung CS; Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
  • Shirvan A; Atox Bio, Rehovot, Israel.
  • Chahin AB; Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
  • Palardy JE; Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
  • Parejo NA; Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
  • Chen Y; Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
  • Whitford M; Center for Vaccine Development, University of Maryland Medical School, Baltimore.
  • Arad G; Institute of Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem.
  • Hillman D; Institute of Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem.
  • Shemesh R; Atox Bio, Rehovot, Israel.
  • Blackwelder W; Center for Vaccine Development, University of Maryland Medical School, Baltimore.
  • Ayala A; Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
  • Cross AS; Center for Vaccine Development, University of Maryland Medical School, Baltimore.
  • Opal SM; Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Providence.
J Infect Dis ; 211(6): 995-1003, 2015 Mar 15.
Article en En | MEDLINE | ID: mdl-25305323
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Peritonitis / Antígenos CD28 / Sepsis / Infecciones por Escherichia coli / Antibacterianos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: J Infect Dis Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Peritonitis / Antígenos CD28 / Sepsis / Infecciones por Escherichia coli / Antibacterianos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: J Infect Dis Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos