Using interleukin-10 (IL-10)-deficient (IL-10(-/-)) mice, previous studies
revealed a pathological immune response after infection with Trypanosoma cr
uzi that is associated with CD4(+) T cells and overproduction of proinflamm
atory cytokines, In this study we further investigate the pathology and pot
ential mediators for the mortality in infected animals, T. cruzi-infected I
L-10-/- mice showed reduced parasitemia accompanied by increased systemic r
elease of gamma interferon (IFN-gamma), IL-12, and reactive nitrogen interm
ediates and over-production of tumor necrosis factor alpha (TNF-alpha). Des
pite this early resistance, IL-10(-/-) mice died within the third week of i
nfection, whereas all control mice survived acute infection. The clinical m
anifestation with weight loss, hypothermia, hypoglycemia, hyperkalemia, and
increased liver-derived enzymes in the blood together with hepatic necrosi
s and intravascular coagulation in moribund mice indicated a toxic shock-li
ke syndrome, possibly mediated by the systemic TNF-alpha overproduction. In
deed, high production of systemic TNF-alpha significantly correlated with m
ortality, and moribund mice died with critically high TNF-alpha concentrati
ons in the blood. Consequent treatment with and TNF-alpha antiserum attenua
ted pathological changes in T. cruzi-infected IL-10(-/-) mice acid signific
antly prolonged survival; the mice died during the fourth week postinfectio
n, again with a striking correlation between regaining high systemic TNF-al
pha concentrations and the time of death. Since elevated serum IL-12 and IF
N-gamma concentrations were not affected by the administration of antiserum
, these studies suggest that TNF-alpha is the direct mediator of this toxic
shock syndrome. In conclusion, induction of endogenous IL-10 during experi
mentally induced Chagas' disease seems to be crucial for counterregulating
an overshooting proinflammatory cytokine response resulting in TNF-alpha-me
diated toxic shock.