CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Toxic mediators during systemic treatment with interleukin-12 (IL-12) and IL-18 in cancer gene therapy
Autor/es:
BARRIOS B; CEJAS H; RODRIGUEZ GALÁN MC
Lugar:
BUENOS AIRES
Reunión:
Congreso; Primer Congreso Franco-Argentino de Inmunología; 2010
Resumen:
Interleukin 12 is a pro-inflamatory cytokine with several anti-tumoral properties. Recombinant IL-12 is currently used as treatment in different type of cancer. However, its systemic expression presents high toxicity manifested by fever, vomiting, diarrhea and hepatotoxicity. Previously, we found that co-expression of IL-12 and IL-18 significantly attenuate IL-12 toxic effects. Here, we investigated possible mediators involved in the toxicity observed after IL-12 expression. Then, we used hydrodynamic shear of cDNA to achieve systemic production of IL-12+/-IL-18 in C57BL/6 mice (6-12 weeks old). We demonstrated that after cDNAs treatments, high sera levels of IL-12, IFNgama and TNFalpha are detected. Systemic expression of IL12 alone or IL-12+IL-18 modified the absolute cell number of the splenocyte subsets analyzed (T CD4+, T CD8+, B cells, NK/NKT cells, macrophages and dendritic cells). Moreover, IL-12+/-IL-18 expression induced changes in systemic parameters like a drop in the body weight and elevation of sera levels of the hepatic enzymes ALT and AST. We also observed manifestation of liver toxicity evaluated by hepatic histology. Most of these parameters were significantly attenuated in IL-12+IL-18 mice compared to IL-12 mice. When nitric oxide (NO) was evaluated as possible toxic mediator in this model, we observed that either the expression of iNOS or NO by splenocyte from IL-12+/-IL-18 mice was significantly elevated. However, no improvement in survival was perceived in iNOS KO mice compared to WT mice after IL-12+/-IL-18 treatments. When we investigated the toxic effects of TNFalpha, we found that abolishment of TNFalpha signals observed in TNFalpha or TNFR I KO mice demonstrated a considerable increase in survival together with lower systemic levels of ALT and AST after IL-12 cDNA treatment. These data might contribute to the design of new immunotherapy anti-tumoral strategies to allow the use of IL-12 in cancer patients by minimizing its toxic side effects.