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Determinants of response to interleukin-10 receptor blockade immunotherapy in experimental visceral leishmaniasis.

TitleDeterminants of response to interleukin-10 receptor blockade immunotherapy in experimental visceral leishmaniasis.
Publication TypeJournal Article
Year of Publication2003
AuthorsMurray HW, Moreira AL, Lu CM, DeVecchio JL, Matsuhashi M, Ma X, Heinzel FP
JournalJ Infect Dis
Volume188
Issue3
Pagination458-64
Date Published2003 Aug 01
ISSN0022-1899
KeywordsAnimals, Antibodies, Monoclonal, Disease Models, Animal, Female, Granuloma, Interferon-gamma, Interleukin-12, Leishmania donovani, Leishmaniasis, Visceral, Liver Neoplasms, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Receptors, Interleukin, Receptors, Interleukin-10
Abstract

In established Leishmania donovani visceral infection in normal mice, anti-interleukin (IL)-10 receptor (IL-10R) monoclonal antibody (MAb) treatment induced intracellular parasite killing within liver macrophages. IL-10R blockade maintained IL-12 protein 40, markedly increased interferon (IFN)-gamma serum levels, and enhanced tissue inducible nitric oxide synthase (iNOS) expression and granuloma assembly. Optimal MAb-induced killing, including synergism with antimony chemotherapy, required endogenous IL-12 and/or IFN-gamma and at least one IFN-gamma-regulated macrophage mechanism-iNOS or phagocyte oxidase. However, in IFN-gamma knockout mice, anti-IL-10R also induced both granuloma formation and leishmanistatic activity. As judged by IL-10R blockade, endogenous IL-10 primarily regulates killing in L. donovani infection by suppressing production of and responses to the Th1 cell-type cytokines, IL-12, and IFN-gamma. However, because anti-IL-10R also released IFN-gamma-independent effects, IL-10 appears to act more broadly and suppresses multiple antileishmanial mechanisms.

DOI10.1086/376510
Alternate JournalJ Infect Dis
PubMed ID12870129
Grant ListAI-16963 / AI / NIAID NIH HHS / United States
AI-35979 / AI / NIAID NIH HHS / United States
AI-45602 / AI / NIAID NIH HHS / United States
AI-45899 / AI / NIAID NIH HHS / United States

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