Chikako Ohta

Correlation between increased susceptibility to primary Toxoplasma gondii infection and depressed production of gamma interferon in pregnant mice.

To explore a possible mechanism of pregnancy‐associated suppression of T cell‐mediated immunity to Toxoplasma gondii, acquired resistance and gamma interferone (IFN‐γ) production in pregnant mice were compared with those in virgin mice after infection with the S‐273 strain of this protozoan parasite. The 50% lethal dose of this strain was less than 200 tachyzoites for pregnant mice and 2,800 organisms for virgin controls. Toxoplasma‐induced production of both IFN‐α and IFN‐γ in the bloodstream of pregnant mice was significantly depressed as compared with that in virgin controls. The administration of recombinant murine IFN‐γ (rMuIFN‐γ) resulted in a significant decrease of mortality and parasitic growth in the organs of pregnant mice infected with a lethal dose of S‐273 strain tachyzoites. Thus, the impairment of T cell‐mediated immune responses was evident in pregnant mice from the impaired IFN‐γ‐generating capacity and poor survival rate after primary infection with Toxoplasma. When mice with chronic Toxoplasma infection were injected with specific antigen, the resultant production of IFN‐γ was also significantly suppressed during pregnancy. However, there was no direct correlation between the serum levels of IFN‐γ and susceptibility to reinfection, since the mortality rate of chronically infected pregnant mice after the challenge with the high virulent RH strain was not significantly higher than that of virgin controls.

CD8+ T Lymphocytes Are the Major Cell Population Involved in the Early Gamma Interferon Response and Resistance to Acute Primary Toxoplasma gondii Infection in Mice

Gamma interferon (IFN‐γ) is known to be a major mediator influencing host defense against Toxoplasma (T.) gondii. To evaluate lymphocyte populations involved in this cytokine‐mediated early resistance to T. gondii, the effects of in vivo administration of monoclonal antibodies (MAbs) against T‐cell subsets and anti‐asialo GM1 antibody on the course of infection and IFN‐γ response were investigated in mice infected acutely with this parasitic protozoan. A single injection of anti‐CD8 MAb on day −1 or day 4 severely exacerbated the infection, in accordance with a marked suppression of endogenous IFN‐γ production. Moreover, the administration of anti‐IFN‐γ MAb on day 0 but not later than day 4 resulted in a total abrogation of resistance to T. gondii, suggesting that endogenous IFN‐γ produced during the first several days of infection is critical for the generation of antitoxoplasmal resistance in mice. In contrast, no significant increase in mortality was observed when injected with either anti‐CD4 MAb or anti‐asialo GM1 antibody on day − 1, while these antibodies reduced significantly the ability of mice to produce IFN‐γ. Indeed, simultaneous depletion of CD4+ and CD8+ cells had no greater suppressive effect on host defense and endogenous IFN‐γ production than depletion of CD8+ cells alone. Together, these results suggest that CD8+ T cells play a central role for resolution of acute toxoplasmosis by participating in endogenous IFN‐γ production. The possible role of early produced IFN‐γ in the development of protective immune response to T. gondii is also discussed.

Enhancement by recombinant human interleukin 2 of host resistance to toxoplasma gondii infection in pregnant mice

The lymphokine production by pregnant mice infected with a lethal dose of Toxoplasma gondii was evaluated in comparison with that by virgin mice infected with a sublethal dose of this protozoan parasite. Splenocytes taken from mice before and on the day after infection produced considerable amounts of IL‐2 in response to concanavalin A (Con A) stimulation, but the titers rapidly declined in both pregnant and virgin mice as infection progressed. A trace amount or undetectable level of IL‐2 was produced by splenocytes from acutely infected mice when stimulated with Toxoplasma lysate antigen (TLA). In contrast to the kinetics of IL‐2 production, the levels of IFN‐γ produced by splenocytes cultured with Con A or TLA increased steadily in the later stage of infection in both pregnant and virgin mice. Thus, the response to Con A or TLA of splenocytes to produce IL‐2 and IFN‐γ differed strikingly in acute toxoplasmosis in mice. The administration of rHuIL‐2 resulted in a significant decrease in the mortality of pregnant mice infected with a lethal dose of Toxoplasma. The combination of rHuIL‐2 and rMuIFN‐γ increased the survival rate slightly but not significantly compared with pregnant mice receiving either rHuIL‐2 or rMuIFN‐γ. Moreover, exogenously administered rHuIL‐2 enhanced the production of both IFN‐α and IFN‐γ in the bloodstreams of pregnant mice, in accordance with the decreased mortality. These results indicate that IL‐2 may play a significant role in modulating the host defense against Toxoplasma infection in pregnant mice.