CONSTRUCTION OF RECOMBINANT HUMAN TYPE-5 ADENOVIRUSES EXPRESSING RODENT IL-6 GENES - AN APPROACH TO INVESTIGATE IN-VIVO CYTOKINE FUNCTION

The majority of biologic functions assigned to cytokines have been cha racterized by in vitro assay systems which may not necessarily reflect cytokine roles in vivo. Recently, recombinant virus approaches have a llowed tissue-specific expression of foreign gene products in experime ntal animal models. We have constructed recombinant human type 5 adeno viruses, deficient in the E3 region of the genome, with incorporated r odent IL-6 cDNA that express significant levels of biologically active IL-6 on infection both in vitro and in vivo. After i.p. injection, th e liver, spleen, and peritoneum appear to be primary sites of expressi on, whereas the lung and bronchus are the main sites of expression aft er intratracheal instillation. Injection i.p. of BALB/c mice with the murine rIL-6 virus causes an increase in serum levels of bioactive IL- 6 for up to 6 days post-infection, whereas similar changes are not see n in animals infected with control viruses. Coincident with enhanced p lasma levels of IL-6, we detect raised serum levels of hepatic-derived acute phase proteins. Associated with the expression of IL-6 in the l iver and spleen, at 7 days we note a fourfold splenomegaly with expans ion of B and T cell compartments, as well as the presence of lymphoid aggregates in the liver. These morphologic changes had resolved by 16 days. Our findings demonstrate that recombinant human type 5 adenoviru ses expressing cDNA for various cytokines could be used as a transient pseudo-transgenic animal model to investigate the biologic function o f cytokines in vivo.