ADENOVIRUS-MEDIATED GENE-TRANSFER IN RAT-LIVER OF INTERLEUKIN-4 BUT NOT INTERLEUKIN-10 PRODUCES SEVERE ACUTE HEPATITIS

Several immune responses are either limited to or concentrated in a gi ven organ, Cytokines produced during ongoing immune responses have org an-localized effects that can be only partially mimicked upon their sy stemic delivery. Recombinant adenoviruses are efficient vectors to ind uce transient organ-localized cytokine expression. This allows in vivo analysis of the effects of cytokines produced spatially and temporall y in a manner comparable to that observed during immune responses. The authors generated recombinant adenovirus for rat IL-4 (AdIL-4) and IL -10 (AdIL10) to analyse the in vivo effects of these two important imm unoregulatory molecules after gene transfer in the liver. It was first established that AdIL-4 and AdIL-10 were able to direct the productio n of biologically active cytokines by different rat cell types in vitr o. Intraportal injection of doses of up to 10(10) pfu of AdIL-10 or co ntrol non-coding recombinant adenovirus were well-tolerated, and hepat ic histology showed only mild alterations. Conversely, animals receivi ng more than 2.5 x 10(9) pfu of AdIL-4 showed dose-dependent mortality , with clinical signs of hepatic dysfunction. Liver histology in anima ls receiving 2.5 x 10(9) pfu of AdIL-4 showed severe acute hepatitis w ith maximal lesions between day 7 and 14 and almost complete normaliza tion by day 28 after gene transfer. The leukocyte infiltrate was compo sed primarily of mononuclear cells, but eosinophils and mast cells wer e significantly increased as compared to control animals. Hepatic func tion was also altered in animals that received AdIL-4, with kinetics s imilar to that of histological lesions. Our study describes a model fo r investigating cytokine function in vivo through liver-localized tran sgene expression mediated by adenoviral vectors and demonstrates that liver production of IL-4 but not IL-10 results in acute severe hepatit is. (C) 1997 Academic Press Limited.