Co-expression of IL-18 strongly attenuates IL-12-induced systemic toxicity through a rapid induction of IL-10 withoutaffecting its anti-tumor capacity.

RODRIGUEZ-GALAN MC, REYNOLDS D, CORREA SG, IRIBARREN P, WATANABE M, YOUNG HA.

AMER ASSOC IMMUNOLOGISTS

Lugar: 183(1):740-46. ; Año: 2009 vol. 181 p. 740 - 740

L-12 is an excellent candidate for the treatment of cancer due to its ability to drive strong antitumor responses. Recombinant IL-12 protein is currently used in cancer patients; however, systemic expression of rIL-12 presents disadvantages including cost and dose limitation due to its toxicity. In this study, we used hydrodynamic shear of cDNA as a tool to achieve systemic expression of IL-12. We found that sustained but toxic levels of serum IL-12 could be generated in 6- to 7-wk-old B6 mice after a single injection of the cDNA. Unexpectedly, we observed that when IL-12 cDNA is coinjected with IL-18 cDNA, IL-12 antitumor activity was maintained, but there was a significant attenuation of IL-12 toxicity, as evidenced by a greater survival index and a diminution of liver enzymes (ALT and AST). Interestingly, after IL-12 plus IL-18 cDNA administration, more rapid and higher IL-10 levels were observed than after IL-12 cDNA treatment alone. To understand the mechanism of protection, we c