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*
Department of Molecular Parasitology and
Institute of Medical Immunology, Charite Medical School, Humboldt University, Berlin, Germany;
Division of Clinical Chemistry, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany;
Institute of Biochemistry, University of Jena, Jena, Germany; and
¶ Department of Biological Sciences, University of Salford, Manchester, United Kingdom
Immune responses of individuals infected with filarial nematodes
are characterized by a marked cellular hyporesponsiveness and a shift
of the cytokine balance toward a Th2/Th3 response. This modulation of
cellular immune responses is considered as an important mechanism to
avoid inflammatory immune responses that could eliminate the parasites.
We investigated the immunomodulatory potential of a secreted cysteine
protease inhibitor (onchocystatin) of the human pathogenic filaria
Onchocerca volvulus. Recombinant onchocystatin (rOv17),
a biologically active cysteine protease inhibitor that inhibited among
others the human cysteine proteases cathepsins L and S, suppressed the
polyclonally stimulated and the Ag-driven proliferation of human PBMC.
Stimulated as well as unstimulated PBMC in the presence of rOv17
produced significantly more IL-10, which was paralleled in some
situations by a decrease of IL-12p40 and preceded by an increase of
TNF-
. At the same time, rOv17 reduced the expression of HLA-DR
proteins and of the costimulatory molecule CD86 on human monocytes.
Neutralization of IL-10 by specific Abs restored the expression of
HLA-DR and CD86, whereas the proliferative block remained unaffected.
Depletion of monocytes from the PBMC reversed the rOv17-induced
cellular hyporeactivity, indicating monocytes to be the target cells of
immunomodulation. Therefore, onchocystatin has the potential to
contribute to a state of cellular hyporesponsiveness and is a possible
pathogenicity factor essential for the persistence of O.
volvulus within its human host.
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