The involvement of TH12 cytokines in protective immunity against schistosoma japonicum infection (original) (raw)
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Immunology, 2003
Interleukin-12 (IL-12) is essential to resistance to Trypanosoma cruzi infection because it stimulates the synthesis of interferon-g (IFN-g) that activates macrophages to a parasiticidal effect. Investigation of mice deprived of IL-12 genes (IL-12 knockout mice) has confirmed the important role of IL-12 and IFN-g in controlling parasitism in T. cruzi infection. However, it has not yet been addressed whether a shift towards a T helper type 2 (Th2) pattern of cytokine response occurred in these mice that might have contributed to the aggravation of the infection caused by IL-12 deprivation. We examined the course of T. cruzi (Y strain) infection and the regulation of cytokine responses and nitric oxide production in C57BL/6 IL-12 p40-knockout mice. The mutant mice were extremely susceptible to the infection as evidenced by increased parasitaemia, tissue parasitism and mortality in comparison with the control C57BL/6 mouse strain (wild-type) that is resistant to T. cruzi. A severe depletion of parasite-antigen-specific IFN-g response, without an increase in IL-4 or IL-10 production, accompanied by reduced levels of nitric oxide production was observed in IL-12 knockout mice. We found no evidence of a shift towards a Th2-type cytokine response. In IL-12 knockout mice, the residual IFN-g production is down-regulated by IL-10 but not by IL-4 and nitric oxide production is stimulated by tumour necrosis factor-a. Parasite-specific immunoglobulin G1 antibody levels were similar in IL-12 knockout and wild-type mice, whereas IL-12 knockout mice had much higher levels of immunoglobulin G2b.
Interleukin-12 stimulation of lymphoproliferative responses in Trypanosoma cruzi infection
Immunology, 2001
The cytokine interleukin-12 (IL-12) is essential for resistance to Trypanosoma cruzi infection because it stimulates the synthesis of interferon-c (IFN-c), a major activator of the parasiticidal effect of macrophages. A less studied property of IL-12 is its ability to amplify the proliferation of T or natural killer (NK) lymphocytes. We investigated the role of endogenously produced IL-12 in the maintenance of parasite antigen (T-Ag)-speci®c lymphoproliferative responses during the acute phase of T. cruzi infection. We also studied whether treatment with recombinant IL-12 (rIL-12) would stimulate TAg -speci®c or concanavalin A (Con A)-stimulated lymphoproliferation and abrogate the suppression that is characteristic of the acute phase of infection. Production of IL-12 by spleen-cell cultures during T. cruzi infection increased in the ®rst days of infection (days 3±5) and decreased as infection progressed beyond day 7. The growth-promoting activity of endogenous IL-12 on TAg -speci®c proliferation was observed on day 5 of infection. Treatment of cultures with rIL-12 promoted a signi®cant increase in Con A-stimulated proliferation by spleen cells from normal or infected mice. Enhanced TAg -speci®c proliferation by rIL-12 was seen in spleen cell cultures from infected mice providing that nitric oxide production was inhibited by treatment with the competitive inhibitor N G-monomethyl-L-arginine (NMMA). Enhancement of proliferation promoted by IL-12 occurred in the presence of neutralizing anti-interleukin-2 (IL-2) antibody, suggesting that this activity of IL-12 was partly independent of endogenous IL-2. Thymidine incorporation levels achieved with rIL-12 treatment of the cultures were < 50% of those stimulated by rIL-2 in the same cultures.
Cellular Immunology, 1992
Heat-or merthiolate-inactivated Tg~anoso~~ra equiperdwn was administered to recipient mice that were subsequently challenged with viable inocula ofthe same stabilate. Only mice inoculated with merthiolate-killed parasites were completely protected from a challenge inoculum of IO) trypanosomes, an effect that was abolished by prior immunosuppression of mice. Immune sera from protected animals contained high levels of interferon (IFN)-y and specific IgGZa antibodies. Spleen cells from these mice produced high amounts of interleukin (IL)-2 and IFN-y in vitro in response to specific antigen or concanavalin A. whereas splenocytes from mice receiving heatkilled parasites produced high amounts of IL-6. In contrast. the production of tumor necrosis factor (TNF)-a and colony-stimulating activity (CSA) was not significantly different in mice receiving either killed parasite preparation. The protection in immunized mice was associated with the detection of strong delayed-type hypersensitivity (DTH) to T cquiprrdmn antigens. an effect that could be adoptively transferred onto naive recipients by specifically immune CD4* Iymphocytes. These results suggest that the development of protective immunity in mice to T cqgciprrdron by our immunization protocol may involve the activity of helper/DTH T cells, particularly those of the Th I subset. .P IYYZ Academic press. ~nc.
Infection and Immunity, 1996
Host resistance to infection by Trypanosoma cruzi is dependent on both natural and acquired immune responses. During the first week of infection in mice, NK cell-derived gamma interferon (IFN-gamma) is involved in controlling intracellular parasite replication, mainly through the induction of NO biosynthesis by activated macrophages. Interleukin-12 (IL-12) has been shown to be a powerful cytokine in inducing IFN-gamma synthesis by NK cells, as well as in mediating resistance to different intracellular protozoa. We have therefore studied the ability of T. cruzi to elicit IL-12 synthesis by macrophages and the role of this cytokine in controlling parasite replication during acute infection in mice. Our results show that macrophages cultured in the presence of live trypomastigote forms (but not epimastigotes) release IL-12 that can induce IFN-gamma production by normal spleen cells. IL-12 was detected in as little as 12 h after the addition of the trypomastigotes, and the level of IL-1...
T cells and immunopathogenesis of experimental African trypanosomiasis
Immunological Reviews, 2008
African trypanosomes are pathogens for humans and livestock. They are single-cell, extra-cellular parasites that cause persistent infections of the blood and induce profound immunosuppression. Here, we review recent work on experimental African trypanosomiasis, especially infections with Trypanosoma congolense, in mice with regard to mechanisms of immunosuppression and immunopathology. The center of the immunopathology is the T-cell-independent production of antibodies to the variant surface glycoprotein (VSG) of trypanosomes, the anti-VSG antibody-mediated phagocytosis of trypanosomes by macrophages, and the subsequent profound dysregulation of the macrophage system. Depending on the genetics of the host and the parasite load, the malfunction of the macrophage system is enhanced by interferon-g produced by parasite-specific, major histocompatibility complex class II-restricted, matrix-adherent CD4 1 T cells or downregulated by interleuin-10 produced by parasite-specific, CD4 1 CD25 high Forkhead box protein 3 1 regulatory T cells. There is a physiological conflict of the two relevant cytokines interleukin-10 and interferon-g in regulating the immunopathology versus regulating the induction and effect of protective immune responses. On the basis of very recent work in our laboratory, we propose a hypothetical model suggesting a cross-regulation of natural killer T cells and CD4 1 CD25 high Forkhead box protein 3 1 regulatory T cells in experimental infections with T. congolense.
Does interleukin-2 restore lymphocyte responses suppressed by Trypanosoma cruzi?
Immunology, 1993
There has been disagreement about the ability of exogenous interleukin-2 (IL-2) to restore responsiveness to lymphocytes from either Tr'panosoma cruzi-infected animals or normal individuals co-cultured with this parasite. The discrepancy has been attributed to the use of different strains of mice or T. cruzi isolates, or to the use of lymphoid cells from different organs. As T. cruzi inhibits the expression of IL-2 receptors by activated lymphocytes in vitro, we were able to test whether restoration of responsiveness by exogenous IL-2 might depend on the level of suppression present in the system. Human or mouse lymphocytes stimulated with phytohaemagglutinin (PHA) exhibited gradual decreases in IL-2 receptor expression, [3H]thymidine incorporation and IL-2 secretion as the concentration of T. cruzi in the culture increased. Exogenous IL-2 afforded a degree of restoration of both IL-2 receptor expression and ["H]thymidine uptake which was substantial at the lower, but very small-if any-at the higher, parasite concentrations tested. Trypanosoma cruzi could not have competed with the lymphocytes for IL-2 because it did not bind significant amounts of this cytokine. These results suggested that the controversy about the corrective effects of IL-2 may be more apparent than real, reflecting variations in the extent of immunosuppression present in different model systems of T. cru-i-associated immunosuppression.
Trypanosoma cruzi:IL-10, TNF, IFN-γ, and IL-12 Regulate Innate and Acquired Immunity to Infection
Experimental Parasitology, 1996
Control of the acute phase of Trypanosoma cruzi infections is critically dependent on cytokinemediated macrophage activation to intracellular killing. We investigated the roles of IL-10, TNF, IFN-␥, and IL-12 in the control of parasitism by innate and specific immunity. Mice with disrupted IL-10 genes (IL-10 KO) infected with Y strain T. cruzi have lower parasite numbers in the blood and tissues and higher IFN-␥ and nitric oxide (NO) production by spleen cells than wild type (WT) mice. Treatment of IL-10 KO and WT mice with recombinant IL-10 resulted in increased parasitemia. Mice with disrupted recombinase-activating genes (RAG/KO) that lack B and T cells provided a model for determining the importance of innate immunity to resistance. RAG/KO and WT mice had similar parasitemia levels until Day 13 of infection, suggestive of effective control of parasitism by the innate immune system during the early phase of infection; from then on parasitemia was higher in RAG/KO. Double RAG/IL-10 KO mice and RAG/KO mice had superimposable parasitemia curves, indicating that in the absence of T and B cells, endogenous IL-10 does not limit the efficacy of the innate immune system. Treatment of infected RAG/KO, IL-10/KO, and WT mice with anti-IFN-␥, anti-TNF, or anti-IL-12 neutralizing mAbs increased parasitemia levels showing the importance of endogenous production of these cytokines in the control of parasitism by innate and specific immune responses. Spleen cells from anti-IL12-treated WT mice had diminished production of IFN-␥ and NO, suggesting that early IFN-␥ synthesis is most dependent on IL-12 stimulation.
Parasite Immunology, 1999
We studied IL-4, IL-10 and IFN-g secretion by splenocytes and the plasma levels of different isotypes of antibodies against various antigens of Trypanosoma congolense in highly susceptible BALB/c and relatively resistant C57BL/6 mice during the early course of infection with T. congolense. The patterns of appearance of cytokine spotforming cells in the spleens were essentially similar in the two mouse strains although higher numbers were detected in the spleens of BALB/c than C57BL/6 mice on some days post-infection. However, the amount of IL-4, IL-10 and IFN-g secreted into the culture fluids was dramatically different. From day 4 forward, splenocytes from BALB/c mice secreted very high levels of these cytokines. In contrast, splenocytes from infected C57BL/6 mice did not secrete detectable levels of IL-4 throughout the period tested. The secretion of IL-10 and IFN-g by C57BL/6 splenocytes only became appreciable on day 6 and was down-regulated by day 8, when the first wave of parasitaemia was being controlled. At days 6-8, splenocytes from infected C57BL/6 mice secreted twofold higher amounts of IL-12 p40 than those from BALB/c mice. Infected BALB/c mice mounted an earlier IgM antibody response to variant surface glycoprotein (VSG), formalin-fixed T. congolense and whole T. congolense lysates than did infected C57BL/6 mice. However, they failed to make any detectable IgG3 and IgG2a antibody responses to these antigens whereas infected C57BL/6 mice made strong IgG3 and IgG2a responses. We speculate that enhanced resistance against T. congolense infections in mice may be mediated by IL-12 dependent synthesis of IgG2 antibodies to VSG and possibly also common trypanosomal antigens.