NYMC Faculty Publications

Enhanced Survival During Experimental Listeria Monocytogenes Sepsis in Neonatal Mice Prophylactically Treated With Th1 and Macrophage Immunoregulatory Cytokines and Mediators

Author Type(s)

Faculty

DOI

10.1097/INF.0000000000000442

Journal Title

The Pediatric Infectious Disease Journal

First Page

330

Last Page

337

Document Type

Article

Publication Date

12-1-2014

Department

Pediatrics

Keywords

Animals, Animals, Newborn, Chemoprevention, Cytokines, Disease Models, Animal, Immunotherapy, Listeria monocytogenes, Macrophages, Mice, Inbred C57BL, Sepsis, Survival Analysis, Th1 Cells, Treatment Outcome

Disciplines

Medicine and Health Sciences

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.

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