Antagonizing deactivating cytokines to enhance host defense and chemotherapy in experimental visceral leishmaniasis.

TitleAntagonizing deactivating cytokines to enhance host defense and chemotherapy in experimental visceral leishmaniasis.
Publication TypeJournal Article
Year of Publication2005
AuthorsMurray HW, Flanders KC, Donaldson DD, Sypek JP, Gotwals PJ, Liu J, Ma X
JournalInfect Immun
Date Published2005 Jul
KeywordsAnimals, Cytokines, Female, Interleukin-13, Interleukin-4, Leishmaniasis, Visceral, Mice, Mice, Inbred BALB C, Receptors, Interleukin, Receptors, Interleukin-10, Transforming Growth Factor beta

In experimental visceral leishmaniasis, inhibition of interleukin 10 (IL-10) signaling enhances Th1-cell-associated responses, promoting gamma interferon (IFN-gamma) secretion, granuloma assembly, macrophage activation with substantial liver parasite killing, and synergy with pentavalent antimony (Sb) chemotherapy. To determine if inhibiting other suppressive cytokines has similar therapeutic potential, Leishmania donovani-infected BALB/c mice were injected with anti-IL-4 monoclonal antibody or receptor fusion antagonists of IL-13 or transforming growth factor beta (TGF-beta). Targeting IL-13 or TGF-beta enabled inhibition of L. donovani replication but little parasite killing; anti-IL-4 had no effect. None of the three antagonists promoted IFN-gamma production, granuloma maturation, or Sb efficacy. Excess IL-13 and TGF-beta exacerbated liver infection; however, effects were transient. Among IL-10, IL-4, IL-13, and TGF-beta, cytokines capable of disabling Th1-cell mechanisms (including those which support chemotherapy), IL-10 appears to be the appropriate target for therapeutic inhibition in visceral L. donovani infection.

Alternate JournalInfect Immun
PubMed ID15972476
PubMed Central IDPMC1168607
Grant ListR01 AI045899 / AI / NIAID NIH HHS / United States
AI 16369 / AI / NIAID NIH HHS / United States
AI45899 / AI / NIAID NIH HHS / United States

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