title: Enhanced survival during experimental Listeria monocytogenes sepsis in neonatal mice prophylactically treated with Th1 and macrophage immunoregulatory cytokines and mediators.
abstract: BACKGROUND
  Impairments in T-cell and macrophage-mediated host defense lead to increased infection-related morbidity and mortality in neonates, partly because of immaturity in T helper (Th)1 function. Listeria monocytogenes (Lm) is an intracellular pathogen disproportionately causing severe disease among neonates and the immunocompromised. Intact macrophage and Th1-mediated immune responses are critical for Lm clearance. We and others have previously demonstrated downregulation of Th1 and macrophage immunoregulatory cytokines in cord blood versus adult peripheral blood. We sought to determine whether therapeutic or prophylactic single agent or combination recombinant murine interleukin (rmIL)-12, rmIL-18, recombinant murine macrophage-colony stimulating factor (rmM-CSF), recombinant murine granulocyte macrophage-colony stimulating factor (rmGM-CSF) and recombinant murine interferon (rmIFN)-γ would enhance survival during experimental neonatal Lm sepsis.
  
  
  METHODS
  A 90% lethal dose (LD90) of Lm was established in C57/BL/6 neonatal mice. rmIL-12, rmIL-18, rmM-CSF, rmGM-CSF and rmIFN-γ were administered singly or sequentially, before or after LD90 Lm inoculation; ampicillin was administered 24 hours after inoculation.
  
  
  RESULTS
  Therapeutic doses of rmIL-12, rmIL-18, rmM-CSF, rmGM-CSF and rmIFN-γ as single agents and sequential therapy with rmM-CSF + (rmIL-12 and/or rmIL-18) + rmIFN-γ in addition to ampicillin were not associated with increased survival. However, prophylactic single doses of rmIL-12, rmIL-18, rmM-CSF and rmIFN-γ and prophylactic sequential doses of rmM-CSF + (rmIL-12 and/or rmIL-18) + rmIFN-γ in addition to ampicillin were associated with significantly enhanced survival compared with ampicillin alone.
  
  
  CONCLUSIONS
  These data suggest prophylactic administration of macrophage and Th1 immunoregulatory cytokines can potentially overcome deficits in neonatal immunity to protect against Lm.
authors.affiliation: From the *Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA; †Department of Pediatrics, University of California San Francisco, San Francisco, CA; ‡Department of Pediatrics, New York Medical College, Valhalla, NY; §Department of Pediatrics, Children's Hospital and Health Center, San Diego, CA; and Department of ¶Medicine, ‖Pathology, **Microbiology and Immunology, and ††Cell Biology and Anatomy, New York Medical College, Valhalla, NY.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Geyer
authors.forename: Kavita
authors.initials: K
authors.lastname: Radhakrishnan
authors.forename: Carmella
authors.initials: C
authors.lastname: Van de Ven
authors.forename: Mandhir S
authors.initials: MS
authors.lastname: Suri
authors.forename: Janet
authors.initials: J
authors.lastname: Ayello
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Cairo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018890:Chemoprevention / Q000379:methods; D016207:Cytokines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007167:Immunotherapy / Q000379:methods*; D008089:Listeria monocytogenes / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control*; D016019:Survival Analysis; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines