Interleukin 10 and interferon gamma regulation of experimental Trypanosoma cruzi infection.

Abstract

SummaryStudies were undertaken to determine whether interleukin 10, (Ibl0) a cytokine shown to inhibit interferon 3' (IFN-~/) production, was involved in Tryfanosoma cruzi infections in mice. Exogenous IFN-3, protects mice from fatal infection with T. ctuzi. Furthermore, resistant B6D2 mice developed fatal T. cruzi infections when treated with neutralizing anti-IFN-3, monoclonal antibody (mAb). Thus, endogenous as well as exogenous IFN-3' is important in mediating resistance to this parasite. Because both T. cruzi-susceptible (B6) and -resistant (B6D2) mouse strains produced IFN-3, during acute infection, we looked for the concomitant production of mediators that could interfere with IFN-3,-mediated resistance to T. cruzi. We found that IL-10-specific mRNA was produced in the spleens of mice with acute T. cruzi infections. In addition, spleen cell culture supernatants from infected B6 mice, and to a lesser extent B6D2 mice, elaborated an inhibitor(s) of IFN-3' production. This inhibitor(s) was neutralized by anti-Ibl0 mAb. These experiments demonstrated the production of biologically active IL-10 during T. cruzi infection. In further studies in vitro, it was shown that IL-10 blocked the ability of IFN-'y to inhibit the intraceUular replication of T. cruzi in mouse peritoneal macrophages. Thus, in addition to its known ability to inhibit the production of IFN-% Ibl0 (cytokine synthesis inhibitory factor), may also inhibit the effects of IFN-% These experiments demonstrate that IL-10 is produced during infection with a protozoan parasite and suggest a regulatory role for this cytokine in the mediation of susceptibility to acute disease.

Trypanosoma cruzi:Protective Immunity in Mice Immunized with Paraflagellar Rod Proteins Is Associated with a T-Helper Type 1 Response

“…This observation also is consistent with the relatively low levels of IFN-␥ observed in the nonprotected groups, since IL-10 has been shown to be an antagonist of IFN-␥ (Silva et al 1992). This correlation between cytokine profiles and level of infection is in keeping with previous reports that the Th2-associated cytokines IL-4 and IL-10 are associated with a higher susceptibility to infection (Silva et al 1991;Gazzinelli et al 1992;Rottenberg et al 1995), while the Th1-associated cytokine IFN-␥ plays a positive role in resistance to T. cruzi, possibly by activation of macrophages (Petray et al 1993;McCabe et al 1991;Silva et al 1992) and release of NO (Munoz-Fernandez et al 1992;Gazzinelli et al 1992). While these results indicate that the nonprotected groups show a mixed Th1/Th2 response, and the protected groups primarily exhibit a Th1-type response, it is surprising that the high level of IFN-␥ observed with PAR + Freund's (sc) is associated with an isotype profile that shows low levels of IgG2a and high levels of IgG1.…”

Immunization with recombinant paraflagellar rod protein induces protective immunity against Trypanosoma cruzi infection

“…This is not surprising given the critical role for IFN-␥ in protective immunity against T. cruzi. IFN-␥ knockout mice and mice that have been depleted of IFN-␥ show markedly increased susceptibility to infection [6,8]. Conversely, addition of exogenous IFN-␥ during infection has been shown to ameliorate disease [7].…”

“…In vitro, CD4 + , but not CD8 + , splenic T cells from PFR-immune mice are able to produce IFN-␥ and induce nitric oxide production by T. cruzi-infected macrophage cells [2,6]. IFN-␥ has been shown to be critical for the protective immune response against T. cruzi in both experimental infection and vaccine models [7][8][9][10]. Likewise, nitric oxide has been shown to be a potent anti-microbial agent and highly effective against T. cruzi [11].…”

Murine susceptibility to Chagas' disease maps to chromosomes 5 and 17

“…8,10,11 This suggests that in inbred mice, recessive alleles may be responsible for susceptibility. We compared parasite tissue burdens during early experimental T. cruzi infection in susceptible C57BL/6 and DBA/2 inbred mice and in resistant B6D2F1 (C57BL/ 6 Â DBA/2) hybrid mice by quantitative PCR.…”