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 charac terized by a marked cellular hyporesponsiveness and a shift of the cytokine balance toward a Th2/Th3 response. This modulation of cellular immune resp onses is considered as an important mechanism to avoid inflammatory immune responses that could eliminate the parasites. We investigated the immunomod ulatory potential of a secreted cysteine protease inhibitor (onchocystatin) of the human pathogenic filaria Onchocerca volvulus. Recombinant onchocyst atin (rOv17), a biologically active cysteine protease inhibitor that inhibi ted among others the human cysteine proteases cathepsins L and S, suppresse d 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 dec rease of IL-12p40 and preceded by an increase of TNF-a. At the same time, r Ov17 reduced the expression of HLA-DR proteins and of the costimulatory mol ecule CD86 on human monocytes. Neutralization of IL-10 by specific Abs rest ored the expression of HLA-DR and CD86, whereas the proliferative block rem ained unaffected. Depletion of monocytes from the PBMC reversed the rOv17-i nduced cellular hyporeactivity, indicating monocytes to be the target cells of immunomodulation. Therefore, onchocystatin has the potential to contrib ute to a state of cellular hyporesponsiveness and is a possible pathogenici ty factor essential for the persistence of O. volvulus within its human hos t.