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IFN-γ receptor-deficient mice are hypersensitive to the anti-CD3-induced cytokine release syndrome and thymocyte apoptosis: Protective role of endogenous nitric oxide

par Matthys, Patrick;Froyen, Guy;Sobis, Halina;Van Damme, Jo;Billiau, Alfons;Verdot, Ludovic;Vray, Bernard ;Huang, Sui;Aguet, Michel
Référence The Journal of immunology, 155, 8, page (3823-3829)
Publication Publié, 1995

Article révisé par les pairs

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Résumé :

Mice with a disruption of the IFN-γ receptor α-chain gene (IFN-γRα0/0 mice) were found to be significantly more sensitive than their wild-type counterparts to induction of the anti-CD3-induced disease syndrome. Specifically, when given a selected dose of anti-CD3 Ab, IFN-γRα0/0 mice developed severe hypothermia and hypoglycemia, leading to 100% mortality within 72 h. In contrast, wild-type mice failed to develop overt pathologic manifestations and survived. Histologic examination revealed apoptosis in thymuses and spleens, which were significantly more pronounced in the mutant than in the wild-type mice, as confirmed by flow cytometric and DNA electrophoretic analysis. Apoptosis affected mainly CD4+CD8+ and CD4+CD8- thymocytes. Other histologic alterations were steatosis in livers, and erythrocyte extravasation and infiltration of apoptotic cells in lungs, all of which were exclusively observed in IFN-γRα0/0 mice. Blood levels of TNF, IL-2, IL-6, and IL-10 were slightly more elevated in IFN-γRα0/0 mice, but insufficiently so to explain increased disease severity. Thus, even more elevated cytokine levels in wild-type mice receiving high doses of anti-CD3 Ab were not associated with morbidity or apoptosis. Blood levels of IFN-γ were barely detectable in anti-CD3-challenged wild-type mice, but were relatively high in the mutant mice. Increased susceptibility of IFN-γRα0/0 mice was associated with impaired nitric oxide (NO) production, as indicated by significantly lower plasma nitrite levels and by more transient expression of spleen inducible NO synthase mRNA. Moreover, treatment of wild-type mice with the NO synthase inhibitor N-nitro-L-arginine methylester resulted in increased anti-CD3-induced morbidity and mortality. The data indicate that IFN-γRα0/0 mice produce less NO and are therefore more sensitive than wild-type mice to the deleterious effect of anti-CD3 Ab. Copyright © 1995 by The American Association of Immunologists.