Article

Respective roles of TNF-alpha and IL-6 in the immune response-elicited by adenovirus-mediated gene transfer in mice.

Univ Paris-Sud, Faculté des Sciences, Orsay, France.
Gene Therapy (Impact Factor: 4.32). 04/2007; 14(6):533-44. DOI: 10.1038/sj.gt.3302885
Source: OAI

ABSTRACT The immunogenicity of recombinant adenoviruses (Ad) constitutes a major concern for their use in gene therapy. Antibody- and cell-mediated immune responses triggered by adenoviral vectors hamper long-term transgene expression and efficient viral readministration. We previously reported that interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha play an essential role in both the acute phase and antibody response against Ad, respectively. As TNF-alpha controls the immune response and the development of the immune system, we examined here the consequence of blockade of TNF-alpha activity through Ad-mediated gene delivery of a dimeric mouse TNFR1-IgG fusion protein on transgene expression from a second Ad. Ad encoding TNFR1-IgG (AdTNFR1-Ig) was injected intravenously along with Ad encoding beta-galactosidase or alpha1-antitrypsin transgene in wild-type (IL-6(+/+)) but also in IL-6-deficient mice (IL-6(-/-)) to analyze how TNF-alpha and IL-6 diminish liver gene transfer efficacy. Blockade of TNF-alpha leads to increased transgene expression in both wild-type and IL-6(-/-) mice due to a reduced inflammatory response and to diminished recruitment of macrophages and NK cells towards the liver. Antibody responses against adenoviral particles and expressed transgenes were only delayed in AdTNFR1-Ig-treated wild-type mice, but were markedly reduced in AdTNFR1-Ig-treated IL-6(-/-) mice. Finally, treatment of mice with etanercept, a clinically approved anti-TNF-alpha drug, confirmed the importance of controlling proinflammatory cytokines during gene therapy by adenoviral vectors.

0 Bookmarks
 · 
89 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pterygium excision with conjunctival autografting is an established surgical treatment for symptomatic pterygia. Documented complications include wound dehiscence, Tenon's granuloma, inclusion cysts, graft oedema, and corneoscleral dellen. We illustrate a previously unreported complication of this technique. A 41 year old Sri Lankan man presented with selective hyperpigmentation of the conjunctival autograft approximately three months following pterygium excision. The possible biological mechanisms behind this complication are discussed.
    Contact lens & anterior eye: the journal of the British Contact Lens Association 05/2011; 34(4):196-7.
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUD: Bcl-XL, a mitochondria membrane protein, is overexpressed in colorectal cancers and promotes cell survival. We had previously showed that the adenovector expressing small hairpin RNA targeting Bcl-XL could induce significantly apoptosis in colon cancer cells. In this study we wanted to further detect the anti-cancer effect of Ad/Bcl-XL shRNA on the rectal cancer xenografts which were derived from patient tumors. METHODS: We firstly established three rectal cancer xenografts.Then these xenografts were subsequently treated with Ad/Bcl-XL shRNA alone or in combination with 5-fluouracil. Finally, the inhibition of tumor growth, survival time and induction of apoptosis were analyzed. RESULTS: Our results demonstrated that Ad/Bcl-XL shRNA could effectively suppress the tumor growth of all three rectal cancer xenografts and prolong their survival time. After combined with 5-Fu, the suppressing effect of Ad/Bcl-XL shRNA was further enhanced. In addition, our data also showed that Ad/Bcl-XL shRNA combined with 5-Fu could significantly increased the apoptotic ratio in the rectal cancer xenograft. CONCLUSIONS: These data indicated that Ad/Bcl-XL shRNA with or without 5-Fu had effective anti-tumor effects on the patient tumor-derived rectal cancer xenografts, suggesting it could be a potential strategy for rectal cancer therapy. Copyright © 2012 John Wiley & Sons, Ltd.
    The Journal of Gene Medicine 11/2012; · 2.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Helper-dependent adenoviral (HD-Ad) vectors have great potential for gene therapy applications; however, their administration induces acute toxicity that impairs safe clinical applications. We previously observed that PEGylation of HD-Ad vectors strongly reduces the acute response in murine and primate models. To evaluate whether PEGylated HD-Ad vectors combine reduced toxicity with the correction of pathological phenotypes, we administered an HD-Ad vector expressing the human apolipoprotein A-I (hApoA-I) to low-density lipoprotein (LDL)-receptor-deficient mice (a model for familial hypercholesterolemia) fed a high-cholesterol diet. Mice were treated with high doses of HD-Ad-expressing apo A-I or its PEGylated version. Twelve weeks later, LDL levels were lower and high-density lipoprotein (HDL) levels higher in mice treated with either of the vectors than in untreated mice. After terminal killing, the areas of atherosclerotic plaques were much smaller in the vector-treated mice than in the control animals. Moreover, the increase in pro-inflammatory cytokines was lower and consequently the toxicity profile better in mice treated with PEGylated vector than in mice treated with the unmodified vector. This finding indicates that the reduction in toxicity resulting from PEGylation of HD-Ad vectors does not impair the correction of pathological phenotypes. It also supports the clinical potential of these vectors for the correction of genetic diseases.Gene Therapy advance online publication, 25 July 2013; doi:10.1038/gt.2013.38.
    Gene therapy 07/2013; · 4.75 Impact Factor

Full-text (2 Sources)

View
70 Downloads
Available from
May 22, 2014