Adenovirus-based gene therapy offers a unique opportunity to target gene expression to the liver by systemic delivery. However, systemic administration of a first generation adenoviral construct elicits an inflammatory response leading to TNF-α-dependent liver injury. The aim of this study was to evaluate whether the systemic administration of recombinant adenovirus exacerbates a subsequent TNF-α-dependent liver injury induced by D-galactosamine and lipopolysaccharide. Surprisingly, low-dose adenovirus administration (105 particles) protects, while high-dose adenovirus (1010 particles) is associated with an exaggerated hepatic inflammatory response from a subsequent D-galactosamine and lipopolysaccharide challenge. This exacerbation is TNF-α dependent, since treatment with a TNF inhibitor fully protects against the liver injury. Moreover, intravenous administration of an adenoviral construct expressing the anti-inflammatory protein interleukin-10 reduces TNF-α appearance and attenuates the increased hepatocyte injury. Taken together, this report demonstrates potential additive effects of TNF-α responses induced by adenovirus and other inflammatory signals, and suggests that the response can be mitigated by relative adenovirus particle dose or by inhibitors, such as TNF-binding protein or interleukin 10.
Huard J., Lochmuller H., Acsadi G., Jani A., Massie B., Karpati G.The route of administration is a major determinant of the transduction efficiency of rat tissues by adenoviral recombinants. Gene Ther1995; 2: 107—115.
2.
Peeters MJ, Patijn GA, Lieber A., Meuse L., Kay MAAdenovirus-mediated hepatic gene transfer in mice: comparison of intravascular and biliary administration. Hum Gene Ther1996; 7: 1693—1699.
3.
Biron CACytokines in the generation of immune responses to, and resolution of, virus infection. Curr Opin Immunol1994; 6: 530—538.
4.
Christ M., Lusky M., Stoeckel F. et al. Gene therapy with recombinant adenovirus vectors: evaluation of the host immune response. Immunol Lett1997; 57: 19—25.
Ginsberg HS, Horswood RL, Chanock RM, Prince GARole of early genes in pathogenesis of adenovirus pneumonia. Proc Natl Acad Sci USA1990; 87: 6191—6195.
7.
Muruve DA, Barnes MJ, Stillman IE, Libermann TAAdenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. Hum Gene Ther1999; 10: 965—976.
8.
Ginsberg HS, Moldawer LL, Sehgal PB et al. A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia. Proc Natl Acad Sci USA1991; 88: 1651—1655.
9.
Elkon KB, Liu CC, Gall JG et al. Tumor necrosis factor alpha plays a central role in immune-mediated clearance of adenoviral vectors. Proc Natl Acad Sci USA1997; 94: 9814—9819.
10.
Mignon A., Rouquet N., Fabre M. et al. LPS challenge in D-galactosamine-sensitized mice accounts for caspase-dependent fulminant hepatitis, not for septic shock. Am J Respir Crit Care Med1999; 159: 1308—1315.
11.
Nowak M., Gaines GC, Rosenberg J. et al. LPS-induced liver injury in D-galactosamine-sensitized mice requires secreted TNF-alpha and the TNF-p55 receptor. Am J Physiol2000; 278: R1202—R1209.
12.
Wang JH, Redmond HP, Watson RW, Bouchier-Hayes D.Role of lipopolysaccharide and tumor necrosis factor-alpha in induction of hepatocyte necrosis. Am J Physiol1995; 269: G297—G304.
13.
Wills KN, Maneval DC, Menzel P. et al. Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer. Hum Gene Ther1994; 5: 1079—1088.
14.
Graham FL, Prevec L.Methods for construction of adenovirus vectors. Mol Biotechnol1995; 3: 207—220.
15.
Minter RM, Rectenwald JE, Fukuzuka K. et al. TNF-alpha receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung . J Immunol2000; 164: 443—451.
16.
Minter RM, Ferry MA, Rectenwald JE et al. Extended lung expression and increased tissue localization of viral IL-10 with adenoviral gene therapy. Proc Natl Acad Sci USA2001; 98: 277—282.
17.
Solorzano CC , Kaibara A., Hess PJ et al. Pharmacokinetics, immunogenicity, and efficacy of dimeric TNFR binding proteins in healthy and bacteremic baboon . J Appl Physiol1998; 84: 1119—1130.
18.
Espevik T., Nissen-Meyer J.A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. J Immunol Methods1986; 95: 99—105.
19.
Galanos C., Freudenberg MAMechanisms of endotoxin shock and endotoxin hypersensitivity. Immunobiology1993; 187: 346—356.
20.
Leist M., Gantner F., Jilg S., Wendel A.Activation of the 55 kDa TNF receptor is necessary and sufficient for TNF-induced liver failure, hepatocyte apoptosis, and nitrite release. J Immunol1995; 154: 1307—1316.
21.
Lieber A., He CY, Meuse L. et al. The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors. J Virol1997; 71: 8798—8807.
22.
Alexander HR, Sheppard BC, Jensen JC et al. Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of Gram-negative sepsis. J Clin Invest1991; 88: 34—39.
23.
Alexander HR , Doherty GM, Block MI et al. Single-dose tumor necrosis factor protection against endotoxin-induced shock and tissue injury in rats. Infect Immun1991; 59: 3889—3894.
24.
Beg AA, Baltimore D.An essential role for NF-kappaB in preventing TNF-alpha-induced cell death . Science1996; 274: 782—784.
25.
Van Antwerp DJ, Martin SJ, Kafri T., Green DR, Verma IMSuppression of TNF-alpha-induced apoptosis by NF-kappaB. Science1996; 274: 787—789.
26.
Iimuro Y., Nishiura T., Hellerbrand C. et al. NF-kappaB prevents apoptosis and liver dysfunction during liver regeneration. J Clin Invest1998; 101: 802—811.
27.
Suzuki M., Suzuki S., Yamamoto N. et al. Immune responses against replication-deficient adenovirus inhibit ovalbuminspecific allergic reactions in mice. Hum Gene Ther2000; 11: 827—838.
28.
Balachandran S., Roberts PC, Kipperman T. et al. Alpha/beta interferons potentiate virus-induced apoptosis through activation of the FADD/Caspase-8 death signaling pathway . J Virol2000; 74: 1513—1523.
29.
Xing Z., Ohkawara Y., Jordana M., Graham FL, Gauldie J.Adenoviral vector-mediated interleukin-10 expression in vivo: intramuscular gene transfer inhibits cytokine responses in endotoxemia. Gene Ther1997; 4: 140—149.
30.
Habib NA, Hodgson HJ, Lemoine N., Pignatelli M.A phase I/II study of hepatic artery infusion with wtp53-CMV-Ad in metastatic malignant liver tumours. Hum Gene Ther1999 ; 10: 2019—2034.
