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.
Benihoud
K
K
Dipartimento di Genetica e Biologia Molecolare, Universita' La Sapienza, Rome, Italy.
Salone
B
B
Esselin
S
S
Opolon
P
P
Poli
V
V
Di Giovine
M
M
Perricaudet
M
M
Saggio
I
I
D000209:Acute-Phase Proteins / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000917:Antibody Formation / Q000235:genetics*; D005822:Genetic Vectors; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout
D000209:Acute-Phase Proteins; D015850:Interleukin-6