Role of cytokines in resistance to African trypanosomes

Abstract

The expression and role of cytokines in resistance to experimental Trypanosoma congolense infections in the highly susceptible BALB/c and relatively resistant C57BL/6 mice was studied. Higher levels of IL-4, IL-10 and IFN-ã were detected in the plasma of infected BALB/c than in C57BL/6 mice. In contrast, plasma levels of TNF-á were higher in C57BL/6 than in BALB/c mice. IL-10 and IFN-ã mRNA transcripts accumulated earlier and in higher concentrations in the spleens of susceptible than in resistant mice. TNF-á mRNA levels in the spleens were similar, but the hepatic TNF-á mRNA levels were higher in resistant than in susceptible mice on day 9. The kinetics of IL-4, IL-10 and IFN-ã spot-forming cells in the spleens were essentially similar but significantly higher numbers were detected in BALB/c than in C57BL/6 mice. Unstimulated and concanavalin A (Con A)-stimulated splenocytes from BALB/c mice secreted high amounts of IL-4, IL-10 and IFN-ã in cultures starting from day 4. Secretion of IL-4 by splenocytes from infected C57BL/6 mice was undetectable throughout the period tested. Secretion of IL-10 and IFN-ã became appreciable on day 6 but were down regulated by day 8. Treatment of infected BALB/c mice with Berenil resulted in cure and caused a dramatic decline in the secretion of IL-10 and IFN-ã by BALB/c splenocytes. Con A-induced proliferation of splenocytes from infected BALB/c mice was progressively suppressed. Anti-IL-10 or anti-IFN-ã antibodies effectively reversed this suppression. Whereas in vivo administrations of anti-IL-10 antibodies to BALB/c mice early during infection only moderately prolonged their survival period, anti-IFN-ã antibodies shifted the phenotype of susceptible BALB/c mice to a resistant-like phenotype. Most of the IL-4, IL-10 and IFN-ã found in the infected BALB/c mice were produced by adherent Thy1.2$\sp+$CD4$\sp-8\sp-$ splenocytes in synergy with adherent Thy1.2$\sp-$ cells. These adherent cells suppressed T and B cell responses. Infected BALB/c mice mounted an earlier IgM response to various antigens of T. congolense than did C57BL/6 mice. In contrast, C57BL/6 mice made a strong and sustained IgG2a and IgG3 response to these antigens. It is hypothesized that resistance to T. congolense infection in mice is mediated by a TH1 cell response.