Anti-Adenovirus Immune Responses in Rats Are Enhanced by Interleukin 4 but Not Interleukin 10 Produced by Recombinant Adenovirus

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Abstract
Recombinant adenoviruses can be used for in vivo gene transfer with great efficiency. However, the duration of transgene expression and the possibility of readministering the virus are severely limited by the host anti-adenovirus immune response, which is controlled mainly by cytokine networks. Adenoviruses encoding IL-4 (AdIL-4) or IL-10 (AdIL-10) were administered to rats through the portal vein and the anti-adenovirus immune response was studied. As compared with administering adenoviruses without transgene (Addl324) or with the lacZ gene (AdlacZ), AdIL-4, but not AdIL-10, resulted in a significant increase in leukocytes 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 ELISA-detected anti-adenovirus antibodies, whereas AdIL-10 caused an increase in ELISA-detected antibodies alone. Anti-adenovirus antibodies were predominantly of Th1-dependent immunoglobulin subclasses in rats receiving Addl324, AdlacZ, or AdIL-10, whereas animals receiving AdIL-4 showed a predominance of Th2-dependent immunoglobulin subclasses. Type 1 (IFN-γ) and type 2 (IL-5) cytokines were increased only in livers from rats receiving AdIL-4. Rats receiving AdIL-4 showed increased anti-adenovirus cytotoxic T lymphocyte activity and CD8+ cell depletion prevented leukocyte infiltration in the liver. These results show that IL-4 increases local and systemic immune responses against recombinant adenoviruses. Adenovirus vectors have been proposed for efficient in vivo gene transfer. However, they often elicit a host anti-adenovirus immune response that severely limits transgene expression. To analyze the effects of cytokines in the context of adenovirus-mediated gene transfer, we have transduced rat livers with recombinant adenoviruses encoding rat interleukin 4 or interleukin 10 (AdIL-4 and AdIL-10, respectively) and analyzed the local and systemic anti-adenovirus immune responses. In this study, we report that AdIL-4, but not AdIL-10, enhances both cellular and humoral anti-adenovirus responses.