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 the rapy is the viral-induced immune response chat has been shown to be respons ible for short-term transgene expression and inefficient viral readministra tion. 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 inna te 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, w e used IL-6 knock-out mice (IL-6(-/-)). E1/E3 deleted recombinant adenoviru ses 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 wi ld type and knock-out animals in the level or the nature of leucocyte recru itment in the liver was detectable. A minor decrease in the IgG response to Adrecombinants was observed in knock-out mice. Gene transfer efficiency, b oth in terms of levels and duration of transgene expression, were comparabl e in IL-6(+/+) and IL-6(-/-) mice. An increase in IL-1 beta and tumor necro sis factor-alpha (TNF-alpha) levels was observed in the sera of IL-6(-/-) m ice as compared to wild type animals: this phenomenon represents a possible compensatory mechanism for the establishment of the immune phenotype obser ved in mutant mice. Conclusions IL-6 plays a role in the acute phase response to adenoviral vec tors. Nevertheless, possibly due to a compensatory mechanism exerted by oth er cytokines, the antibody and cellular responses to adenoviruses are very similar in wild type and IL-6-/- mice. Copyright (C) 2000 John Wiley & Sons , Ltd.