Administration of anti-CD3 monoclonal antibody during experimental Chagas' disease induces CD8+ cell-dependent lethal shock.
The injection of the 145-2C11 anti-CD3 MoAb in mice induces a polyclonal T cell activation resulting in the release of several cytokines, including interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). As these cytokines are known to be involved in the host defence against Trypanosoma cruzi, we measured serum levels of IFN-gamma and TNF-alpha after injection of the 145-2C11 MoAb in the course of experimental murine Chagas' disease. Compared with control mice, T. cruzi-infected BALB/c mice were found to be primed to secrete very high levels of IFN-gamma and TNF-alpha from the second and the first week of infection, respectively, up to the chronic phase. In vivo cell depletion experiments indicated that CD8+ T cells were responsible for these dramatic hyperproductions of IFN-gamma and TNF-alpha. While all control mice survived anti-CD3 MoAb injection, a high lethality rate was observed in T. cruzi-infected mice within 24 h after anti-CD3 MoAb challenge. Pretreatment with neutralizing anti-IFN-gamma MoAb or depletion of CD8+ T cell population dramatically decreased the mortality induced by anti-CD3 MoAb in T. cruzi-infected mice. Finally, we showed that anti-CD3 MoAb injection in T. cruzi-infected mice was followed by a massive release of nitric oxide (NO) metabolites, which was partially reduced by IFN-gamma or TNF-alpha neutralization. The administration of the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) before anti-CD3 MoAb challenge did not prevent and even enhanced lethality in T. cruzi-infected mice, suggesting that NO overproduction and lethal shock are not causally related. We conclude that injection of anti-CD3 MoAb in the course of experimental Chagas' disease induces a CD8+ cell-dependent shock mediated by IFN-gamma and TNF-alpha.
Jacobs
F
F
Laboratoire Pluridisciplinaire de Recherche Expérimentale Biomédicale, Hôpital Erasme, Brussels, Belgium.
Dubois
C
C
Carlier
Y
Y
Goldman
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D014355:Chagas Disease / Q000276:immunology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D012769:Shock / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016827:CD8 Antigens; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma