Modulation of human T cell responses and macrophage functions by onchocystatin, a secreted protein of the filarial nematode Onchocerca volvulus.
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.
Schönemeyer
A
A
Department of Molecular Parasitology and Institute of Medical Immunology, Charite Medical School, Humboldt University, Berlin, Germany.
Lucius
R
R
Sonnenburg
B
B
Brattig
N
N
Sabat
R
R
Schilling
K
K
Bradley
J
J
Hartmann
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015801:Helminth Proteins / Q000494:pharmacology / Q000502:physiology*; D006790:Host-Parasite Interactions / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D009000:Monocytes / Q000187:drug effects*; D017181:Onchocerca volvulus / Q000502:physiology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D021122:Protein Subunits; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014373:Tuberculin / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D015703:Antigens, CD; D051940:B7-2 Antigen; C497964:CD86 protein, human; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D018076:DNA, Complementary; D006684:HLA-DR Antigens; D015801:Helminth Proteins; D008562:Membrane Glycoproteins; D010835:Phytohemagglutinins; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D014373:Tuberculin; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C076278:Onchocystatin protein, Onchocerca volvulus; D018664:Interleukin-12; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C028217:cathepsin S