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

Benihoud, Karim; Esselin, Stéphanie; Descamps, Delphyne; Jullienne, Betsy; Salone, B.; Bobé, Pierre; Bonardelle, Danielle; Connault, Elisabeth; Opolon, Paule; Saggio, Isabella; Perricaudet, Michel

doi:10.1038/sj.gt.3302885

Cited by 37 publications

(29 citation statements)

References 50 publications

(64 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, viral gene therapy approaches have mostly been studied in immunecompromised animal models. Tremendous effort has gone into characterizing the nature of immune responses to adenoviral vectors and modifying the genome of vectors to diminish the responses (35)(36)(37). In the current study we used unmodified adenoviral vectors and SCID mouse as an animal model.…”

Section: Discussionmentioning

confidence: 99%

Induction of angiogenesis in tissue-engineered scaffolds designed for bone repair: A combined gene therapy–cell transplantation approach

Jabbarzadeh¹,

Starnes²,

Khan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

181

View full text Add to dashboard Cite

One of the fundamental principles underlying tissue engineering approaches is that newly formed tissue must maintain sufficient vascularization to support its growth. Efforts to induce vascular growth into tissue-engineered scaffolds have recently been dedicated to developing novel strategies to deliver specific biological factors that direct the recruitment of endothelial cell (EC) progenitors and their differentiation. The challenge, however, lies in orchestration of the cells, appropriate biological factors, and optimal factor doses. This study reports an approach as a step forward to resolving this dilemma by combining an ex vivo gene transfer strategy and EC transplantation. The utility of this approach was evaluated by using 3D poly(lactide-co-glycolide) (PLAGA) sintered microsphere scaffolds for bone tissue engineering applications. Our goal was achieved by isolation and transfection of adipose-derived stromal cells (ADSCs) with adenovirus encoding the cDNA of VEGF. We demonstrated that the combination of VEGF releasing ADSCs and ECs results in marked vascular growth within PLAGA scaffolds. We thereby delineate the potential of ADSCs to promote vascular growth into biomaterials.

show abstract

Section: Discussionmentioning

confidence: 99%

Induction of angiogenesis in tissue-engineered scaffolds designed for bone repair: A combined gene therapy–cell transplantation approach

Jabbarzadeh¹,

Starnes²,

Khan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

181

View full text Add to dashboard Cite

show abstract

“…However, the increased levels were not significant (P Ͼ 0.05), and histological examination of liver sections did not reveal signs of liver toxicity (data not shown). Similarly, analysis of TNF-␣ and IL-6 levels in serum by using ELISA revealed that both were slightly elevated 6 h after injection of polyconjugate but returned to baseline by 48 h. The increases observed at 6 h would not be expected to cause significant immune stimulation and are at least four orders of magnitude lower than those observed upon stimulation with lipopolysaccharide (43,44) and one to three orders of magnitude lower than after injection of adenovirus (27,45). No significant differences in serum levels of INF-␣ were detected at any of the time points, except for a slight increase at 6 h after injection of apoB-1 siRNA polyconjugate.…”

Section: Resultsmentioning

confidence: 99%

Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes

Rozema

Lewis

Wakefield

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

616

624

View full text Add to dashboard Cite

Achieving efficient in vivo delivery of siRNA to the appropriate target cell would be a major advance in the use of RNAi in gene function studies and as a therapeutic modality. Hepatocytes, the key parenchymal cells of the liver, are a particularly attractive target cell type for siRNA delivery given their central role in several infectious and metabolic disorders. We have developed a vehicle for the delivery of siRNA to hepatocytes both in vitro and in vivo, which we have named siRNA Dynamic PolyConjugates. Key features of the Dynamic PolyConjugate technology include a membrane-active polymer, the ability to reversibly mask the activity of this polymer until it reaches the acidic environment of endosomes, and the ability to target this modified polymer and its siRNA cargo specifically to hepatocytes in vivo after simple, low-pressure i.v. injection. Using this delivery technology, we demonstrate effective knockdown of two endogenous genes in mouse liver: apolipoprotein B (apoB) and peroxisome proliferator-activated receptor alpha (ppara). Knockdown of apoB resulted in clear phenotypic changes that included a significant reduction in serum cholesterol and increased fat accumulation in the liver, consistent with the known functions of apoB. Knockdown of ppara also resulted in a phenotype consistent with its known function, although with less penetrance than observed in apoB knockdown mice. Analyses of serum liver enzyme and cytokine levels in treated mice indicated that the siRNA Dynamic PolyConjugate was nontoxic and well tolerated.pH labile bonds ͉ nonviral siRNA delivery ͉ siRNA-polymer conjugates ͉ endosomolytic polymers

show abstract

“…Such defective antibody responses to Ad vectors and an impaired recruitment of inflammatory cells to the liver were also reported in mice deficient for TNF-alone [74]. The role of TNF-in anti-Ad immune responses in mice was confirmed using different Ad vectors encoding a soluble type-I TNF receptor (TNFR1) [27,75] or etanercept [27], a drug clinically used to neutralize TNF-. Altogether, these studies showed that TNF-controls early NK cells and macrophage recruitment, and modulates the production of other pro-inflammatory cytokines, leading to a prolonged liver transgene expression and to reduced humoral responses [27,75].…”

Section: Ad Innate Immunity Influences the Development Of Adaptive Immentioning

confidence: 91%

“…Moreover, several chemokines are secreted, including macrophage inflammatory protein (MIP)-2 (CXCL2/3), monocyte chemoattractant protein (MCP)-1 (CCL2), KC (a murine IL-8 homolog, also CXCL1), RANTES (regulated on activation, normal T cells expressed and secreted; also called CCL5), MIP-1 (CCL4) and IFN--inducible protein (IP)-10 (CXCL10) [24,25]. Simultaneously, Ad vectors induce LSEC expression of leukocyte adhesion molecules, such as vascular cellular adhesion molecule (VCAM)-1 or selectins [26], which facilitate liver recruitment, and subsequent activation of neutrophils [24], monocytes/macrophages [27], natural killer (NK) cells [27][28][29][30], and T cells [31]. These innate immune cells lead to further cytokine production and stimulate the induction of anti-Ad adaptive immune responses.…”

Section: Induction Of Liver Innate Immune Responsesmentioning

confidence: 99%

Two Key Challenges for Effective Adenovirus-Mediated Liver Gene Therapy:Innate Immune Responses and Hepatocyte-Specific Transduction

Descamps

Benihoud²

2009

CGT

View full text Add to dashboard Cite

Adenovirus (Ad) are valuable vectors for liver gene therapy because of their intrinsic ability to transduce hepatocytes following intravenous administration. However, the effective application of these vectors, including helper-dependent Ad unable to trigger viral gene expression, for liver gene therapy in humans has been limited due to several obstacles. First, their high immunogenicity triggers a complex immune response, both innate and adaptive, that leads to hepatocyte destruction, reducing the duration of transgene expression. This high immunogenicity also induces a long lasting cellular and humoral immunity that impairs subsequent re-administration. Second, Ad vectors transduce not only hepatocytes but also other cell types from the liver or other organs. This Ad vector dissemination contributes to their toxicity and immunogenicity, further reducing the effective period of transgene expression. A better understanding of the interactions between Ad vectors and their host underlying the acute liver toxicity and hepatocyte transduction is required to improve the efficacy and duration of gene delivery in vivo. The aim of this review is to discuss insights into the cellular and molecular mechanisms involved in Ad vector-mediated innate immune responses. Current advances in the knowledge of Ad liver tropism and the influence of blood components on Ad vector uptake by the liver will be discussed. Finally, different approaches developed to minimize Ad vector toxicity, optimize delivery and increase transgene expression will be summarized. The full potential of Ad vectors will only be reached when their immunogenicity is abolished and hepatocyte-specific transduction achieved.

show abstract

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

Cited by 37 publications

References 50 publications

Induction of angiogenesis in tissue-engineered scaffolds designed for bone repair: A combined gene therapy–cell transplantation approach

Induction of angiogenesis in tissue-engineered scaffolds designed for bone repair: A combined gene therapy–cell transplantation approach

Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes

Two Key Challenges for Effective Adenovirus-Mediated Liver Gene Therapy:Innate Immune Responses and Hepatocyte-Specific Transduction

Contact Info

Product

Resources

About