In vivo modulation of the murine immune response to Francisella tularensis LVS by administration of anticytokine antibodies

D. A. Leiby, A. H. Fortier, R. M. Crawford, R. D. Schreiber, C. A. Nacy

Research output: Contribution to journalArticle

137 Scopus citations

Abstract

The role(s) of gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-4 (IL-4) in establishment and maintenance of protective immunity to Francisella tularensis LVS in mice (C3H/HeN) was examined by selective removal of these cytokines in vivo with neutralizing antibodies. The 50% lethal dose (LD50) for mice infected intradermally with F. tularensis alone was 136,000 CFU; treatment of mice with anti-IFN-γ or anti-TNF-α at the time of infection significantly reduced (P << 0.05) the LD50 to 2 and 5 CFU, respectively. Abrogation of protective immunity, however, was effective only when anti-IFN-γ or anti-TNF-α was administered prior to day 3 postinfection. In contrast, the LD50 for mice treated with anti-IL-4 was repeatedly higher (555,000 CFU) than for controls; this difference, however, was not significant (P > 0.05). Thus, IL-4 may be detrimental, while IFN-γ and TNF-α were clearly crucial to the establishment of protective immunity to F. tularensis during a primary infection. The importance of IFN-γ and TNF-α during a secondary immune response to F. tularensis was also investigated. Spleen cells from immune mice passively transfer protective immunity to recipient mice in the absence of confounding antibody-mediated immunity. This passive transfer of immunity, however, was abrogated by treatment of recipient mice with anti-IFN-γ or anti-TNF-α at the time of challenge infection. That anticytokines effectively abrogate protective immunity very early in the course of infection with F. tularensis suggests that T-cell-dependent activation of macrophages for microbicidal activity is unlikely. These T-cell-independent events early in the course of infection may suppress bacterial replication until a T-cell-dependent response ultimately clears the bacteria.

Original languageEnglish
Pages (from-to)84-89
Number of pages6
JournalInfection and immunity
Volume60
Issue number1
StatePublished - Jan 1 1992
Externally publishedYes

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