Elimination of innate immune responses and liver inflammation by PEGylation of adenoviral vectors and methylprednisolone.
Improvement of the therapeutic index of adenoviral gene transfer requires the development of strategies to abrogate adenoviral capsid-induced inflammation and cytokine production. The effect of monomethoxypolyethylene glycol (MPEG) conjugation to adenoviral vectors and of methylprednisolone (MP) on innate immunity, liver inflammation, and thrombocyte counts was evaluated after transfer of 1011 particles of E1/E3/E4- deleted adenoviral vector expressing human apolipoprotein A-I (apoA-I). Gene transfer with unPEGylated vectors induced peak interleukin-6 (IL-6) plasma levels that were 66-fold above baseline levels in C57BL/6 mice. PEGylation combined with 4 mg of MP 6 hr before and at the time of gene transfer suppressed IL-6 plasma levels to baseline values at all time points. This combination resulted in 24-, 28-, 5.9-, 42-, 26-, and 2.5- fold reduced mRNA expression in the liver of monocyte chemoattractant protein-1, macrophage inflammatory protein-2, interferon-inducible protein-10, macrophage inflammatory protein-1 beta, lipopolysaccharide-induced CXC chemokine, and keratinocyte-derived chemokine, respectively; abrogated neutrophil infiltration in the liver; and reduced alanine aminotransferase levels. PEGylation reduced vector uptake in the spleen and in nonparenchymal liver cells. PEGylation also inhibited the development of thrombocytopenia. In conclusion, PEGylation of adenoviral vectors combined with MP administration improves the therapeutic index of adenoviral gene transfer.
De Geest
Bart
B
Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium. bart.degeest@med.kuleuven.de
Snoeys
Jan
J
Van Linthout
Sophie
S
Lievens
Joke
J
Collen
Désiré
D
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000276:immunology*; D000818:Animals; D003227:Conjugation, Genetic; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008775:Methylprednisolone / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology; D011092:Polyethylene Glycols / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D016207:Cytokines; D015850:Interleukin-6; D012333:RNA, Messenger; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D008775:Methylprednisolone