Abstract
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-alpha. 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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Antigens, Bacterial / immunology
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Antigens, CD / biosynthesis
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Antigens, CD / genetics
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Antigens, CD / immunology
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B7-2 Antigen
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Cathepsin B / antagonists & inhibitors
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Cathepsin L
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Cathepsins / antagonists & inhibitors
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Cysteine Endopeptidases
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Cysteine Proteinase Inhibitors / pharmacology
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Cysteine Proteinase Inhibitors / physiology*
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Cytokines / biosynthesis
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Cytokines / genetics
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DNA, Complementary / genetics
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Female
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Gene Expression Regulation / drug effects
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HLA-DR Antigens / biosynthesis
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HLA-DR Antigens / genetics
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HLA-DR Antigens / immunology
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Helminth Proteins / pharmacology
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Helminth Proteins / physiology*
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Host-Parasite Interactions / immunology
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Humans
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Interleukin-10 / biosynthesis
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Interleukin-10 / genetics
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Interleukin-10 / immunology
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Interleukin-12 / biosynthesis
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Interleukin-12 / genetics
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Leukocytes, Mononuclear / drug effects*
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Leukocytes, Mononuclear / immunology
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Lymphocyte Activation / drug effects*
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Macrophages / drug effects
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology
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Monocytes / drug effects*
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Onchocerca volvulus / physiology*
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Phytohemagglutinins / pharmacology
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Protein Subunits
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Rabbits
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Recombinant Fusion Proteins / pharmacology
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T-Lymphocytes / drug effects*
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T-Lymphocytes / immunology
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Tuberculin / immunology
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
Substances
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Antibodies, Monoclonal
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Antigens, Bacterial
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Antigens, CD
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B7-2 Antigen
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CD86 protein, human
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Cysteine Proteinase Inhibitors
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Cytokines
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DNA, Complementary
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HLA-DR Antigens
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Helminth Proteins
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Membrane Glycoproteins
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Phytohemagglutinins
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Protein Subunits
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Recombinant Fusion Proteins
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Tuberculin
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Tumor Necrosis Factor-alpha
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Interleukin-10
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Onchocystatin protein, Onchocerca volvulus
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Interleukin-12
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Cathepsins
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Cysteine Endopeptidases
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Cathepsin B
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CTSL protein, human
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Cathepsin L
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cathepsin S