Attenuation of Interleukin-12 (IL-12) systemic toxicity by IL-18 in gene therapy in a B16 melanoma murine model: Role of endogenous IL-10 production

RODRÍGUEZ GALÁN MC; CORREA SG.; REYNOLDS D; YOUNG HA

Viña del Mar, Chile.

Congreso; 9th Latin American Congress of Imunology (ALAI).; 2009

Asociación Latinoamericana de Inmunología (ALAI)

<!-- /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-1610611985 1107304683 0 0 159 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman","serif"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:ES; mso-fareast-language:ES;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Recombinant IL-12 protein is currently used as treatment in cancer patients; however, its systemic expression still presents high toxicity. Here, we used hydrodynamic shear of cDNA as a tool to achieve systemic expression of IL-12. We found sustained but toxic levels of serum IL-12 in 6-7 week old B6 mice after a single injection of the cDNA. Unexpectedly, we observed that co-injection of IL-12+IL-18 cDNAs presented similar anti-tumor activity with a significant attenuation in IL-12 toxicity evaluated by morbidity and survival of the mice. Toxicity seems to be induced by IFNg and TNFa. Interestingly, after IL-12+IL-18 expression, serum IL-10 levels were faster and higher than after IL-12 cDNA treatment possibly controlling IFNg and TNFa serum levels. Analysis of sorted spleen cells subsets from IL-12+IL-18 mice demonstrate that the main producers of these cytokines are CD8+ and CD11b/c+ cells for TNFa, CD4+ and CD8+ cells for IFNg and CD4+ and CD11b/c+ cells for IL-10. Together, early IL-10 expression induced after IL-12+IL-18 cDNA treatment is critical to rapidly attenuate IL-12 toxicity without affecting its anti-tumor capacity. These data could contribute to the design of less toxic/more efficient protocols for the treatment of cancer.