The role of IL-6 in the inflammatory and humoral response to adenoviral vectors.

Background: The major concern for the use of adenoviral vectors for gene therapy is the viral-induced immune response that has been shown to be responsible for short-term transgene expression and inefficient viral readministration. In vivo studies and clinical trials with recombinant adenovirus have suggested a role for interleukin 6 (IL-6) in the inflammatory reaction that follows Ad-infection. IL-6 plays an important role in the acute-phase innate response, in the differentiation of B-cells and in the activation of the Th2 cell subsets.

Methods: To clarify the role of IL-6 in the immune response to Ad-vectors, we used IL-6 knock-out mice (IL-6 -/- ). E1/E3 deleted recombinant adenoviruses encoding reporter genes were administered to wild type or IL-6-/- mice; transgene expression kinetics and immune response were analyzed.

Results: Acute phase protein production was significantly diminished in IL-6 -/- mice after adenoviral injection. No significant difference between wild type and knock-out animals in the level or the nature of leucocyte recruitment in the liver was detectable. A minor decrease in the IgG response to Ad-recombinants was observed in knock-out mice. Gene transfer efficiency, both in terms of levels and duration of transgene expression, were comparable in IL-6+/+ and IL-6-/- mice. An increase in IL-1beta and tumor necrosis factor-alpha (TNF-alpha) levels was observed in the sera of IL-6 -/- mice as compared to wild type animals: this phenomenon represents a possible compensatory mechanism for the establishment of the immune phenotype observed in mutant mice.

Conclusions: IL-6 plays a role in the acute phase response to adenoviral vectors. Nevertheless, possibly due to a compensatory mechanism exerted by other cytokines, the antibody and cellular responses to adenoviruses are very similar in wild type and IL-6 -/- mice.