Role of Nitric Oxide-Induced Immune Suppression in Toxoplasmosis During Pregnancy and in Infection by a Virulent Strain of Toxoplasma gondii

Abstract

The mechanisms by which immunocompetent mice resist Toxoplasma gondii infection have been partially elucidated. There is general agreement on the schematic cascade of immunological events during the acute stage of the infection: production of interleukin-12 (IL-12) by macrophages stimulates natural killer (NK) cellS to produce interferon (IFN)-γ (Denkers et al. 1993; Gazzinelli et al. 1993b; Seder et al. 1993; Hunter et al. 1994), which in turn activates macrophages to kill T. gondii by a combination of oxygen-dependent (Wilson et al. 1980), reactive nitrogen intermediate (RNI)-dependent (Adams et al. 1990; Gazzinelli et al. 1992; Langermans et al. 1992) and tryptophan starvation mechanisms (Pfefferkorn 1984). IL-12 and IFN-γ are of paramount importance in the protective response to T. gondii (Suzuki et al. 1988; Subauste and Remington 1991; Gazzinelli et al. 1993b, Khan et al. 1994). IL-10 acts as an immunoregulatory cytokine during Toxoplasma infection. This cytokine was initially characterized by its production by the Th2 subset of CD4⁺ T cells and by its ability to suppress IFN-γ production by Th1-type cells (Fiorentino et al. 1989, 1991). IL-10 inhibits nitric oxide (NO) production in vitro (Gazzinelli et al. 1992), controls IFN-γ production in severe combined immunodeficiency (SCID) mice infected with T. gondii (Sher et al. 1993; Hunter et al. 1994) and limits T cell proliferation (Candolfi et al. 1995; Khan et al 1995). These data indicate that, schematically, a Th1-type response is protective and that a Th2-type response is detrimental.