ANTI-ADENOVIRUS IMMUNE-RESPONSES IN RATS ARE ENHANCED BY INTERLEUKIN-4 BUT NOT INTERLEUKIN-10 PRODUCED BY RECOMBINANT ADENOVIRUS

Recombinant adenoviruses can be used for in vivo gene transfer with gr eat efficiency. However, the duration of transgene expression and the possibility of readministering the virus are severely limited by the h ost anti-adenovirus immune response, which is controlled mainly by cyt okine networks. Adenoviruses encoding IL-4 (AdIL-4) or IL-10 (AdIL-10) were administered to rats through the portal vein and the anti-adenov irus immune response was studied. As compared with administering adeno viruses without transgene (Addl324) or with the lacZ gene (AdlacZ), Ad IL-4, but not AdIL-10, resulted in a significant increase in leukocyte s in the liver, with a predominance of macrophages that peaked on days 7 and 14 after gene transfer and gradually returned to normal by day 28, AdIL-4 induced a significant increase in both neutralizing and ELI SA-detected anti-adenovirus antibodies, whereas AdIL-10 caused an incr ease in ELISA-detected antibodies alone. Anti-adenovirus antibodies we re predominantly of Th1-dependent immunoglobulin subclasses in rats re ceiving Addl324, AdlacZ, or AdIL-10, whereas animals receiving AdIL-4 showed a predominance of Th2-dependent immunoglobulin subclasses. Type 1 (IFN-gamma) and type 2 (IL-5) cytokines were increased only in live rs from rats receiving AdIL-4, Rats receiving AdIL-4 showed increased anti-adenovirus cytotoxic T lymphocyte activity and CD8(+) cell deplet ion prevented leukocyte infiltration in the liver, These results show that IL-4 increases local and systemic immune responses against recomb inant adenoviruses.