Abstract: Filarial parasites are known to induce a large range of immunoregulatory mechanisms, including the induction of alternatively activated macrophages and regulatory T cells. These mechanisms are used to evade and down-modulate the host's immune system, to support parasite survival. Several reports have focused on some of these mechanisms, in humans and murine models, but the complex immunoregulatory networks associated with filarial infections remain unclear. Recent publications have conferred a role for regulatory T cells in the ability of helminth parasites to modulate human immune responses, such cells promoting the induction of the non-complement-fixing immunoglobulin G4 (IgG4). High plasma concentrations of IgG4 have been reported in hypo-responsive and asymptomatic cases of helminth infection. In both human lymphatic filariasis and onchocerciasis, the asymptomatic infections are characterised by high plasma concentrations of IgG4 (compared with those of IgE) and of the complement-fixing antibodies IgG1, IgG2 and IgG3. In asymptomatic filarial infection, elevations in IgG4 are also often associated with high worm loads and with high plasma levels of the immunomodulatory interleukin-10. Here, various aspects of the induction of IgG4 in humans and it roles in the immunomodulation of the human responses to filarial parasites are reviewed.
Abstract: Regulatory T cells exert their function through the modulation of both T and B cell responses. Our previous studies demonstrated that IL-10-producing Treg (Tr1) can induce B cells to secrete IgG4 in a cell-contact-dependent manner. The benefit of such non-inflammatory B-cell responses is apparent in the hyporesponsive state of patients with helminth infections such as Onchocerciasis. Here, we investigated the mechanisms involved to induce IgG4, within B:Tr-cell co-cultures, using IL-10-producing tetanus-toxoid-specific regulatory T cell lines and clones (Tr-TCC) from human PBMC. During the generation process, we found that increasing Foxp3 levels in regulatory T cell lines correlated with their ability to induce IgG4 in B cells. Using Tr-TCC, we found that blocking glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) molecules selectively prevented IgG4 production as did neutralizing Ab to glucocorticoid-induced tumour necrosis factor receptor-related protein ligand (GITR-L), IL-10 and TGF-beta. Furthermore, the prevention of IgG4 induction by anti-GITR Ab was reversed by excess rIL-10 but not rTGF-beta. In contrast, anti-ICOS and anti-CTLA-4 Abs had no effect. When compared with Tr-TCC, freshly isolated CD4+CD25+ T cells, but not effector T cell populations, induced low levels of IgG4, which were also blocked by anti-GITR and anti-GITR-L Ab. Thus, the mechanism of IgG4 induction by regulatory cells involves GITR-GITR-L interactions, IL-10 and TGF-beta.
Abstract: Twenty extracts from nine Benin medicinal plants, traditionally used to treat malaria, were screened for in vitro antiplasmodial activity towards Plasmodium falciparum K1 chloroquine resistant and 3D7 chloroquine sensitive strains. All plants showed antiplasmodial activity below 10 microg/ml. Nine extracts exhibited IC50 values below 5 microg/ml towards one or both of the two strains. The most active extract towards the sensitive 3D7 strain was the methanolic extract of Croton lobatus aerial part, with an IC50 value of 0.38 microg/ml. The best inhibition of the growth of Plasmodium falciparum resistant K1 strain was observed with the methylene chloride extract of Hybanthus enneaspermus and with the methanolic extract of Croton lobatus roots (IC50=2.57 and 2.80 microg/ml, respectively).
