Transient blocking of both B7.1 (CD80) and B7.2 (CD86) in addition to CD40–CD40L interaction fully abrogates the immune response following systemic injection of adenovirus vector

Ziller, Christelle; Stoeckel, Fabienne; Boon, Louis; Haegel-Kronenberger, Hélène

doi:10.1038/sj.gt.3301684

Cited by 17 publications

(23 citation statements)

References 50 publications

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“…22 Recently, we studied the respective roles of CD80 and CD86 in the immune response against Ad, using antagonist anti-CD80 or anti-CD86 MAbs in combination with anti-CD40L in mice. 23 We observed that the simultaneous blockade of these three molecules upon first vector administration allowed optimal expression of the transgene after a second vector administration. 23 This prompted us to design an experiment in a nonhuman primate model, to verify whether transient costimulation blockade could facilitate readministration of an Ad vector through the systemic route.…”

Section: Introductionmentioning

confidence: 87%

“…23 We observed that the simultaneous blockade of these three molecules upon first vector administration allowed optimal expression of the transgene after a second vector administration. 23 This prompted us to design an experiment in a nonhuman primate model, to verify whether transient costimulation blockade could facilitate readministration of an Ad vector through the systemic route. The interaction between monkey CD40 and CD40L was targeted at the APC side using an antagonist anti-human CD40 MAb, 5D12.…”

Section: Introductionmentioning

confidence: 87%

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Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeys

et al. 2004

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Immunogenicity of recombinant adenoviral (Ad) vectors severely hampers the clinical development of gene therapy protocols using repeated vector administrations. Inhibition of costimulation by APCs was explored as a strategy to circumvent the immune response against Ad particles. This strategy was tested in rhesus monkeys, treated transiently with chimeric anti-human CD40 and anti-human CD86 antagonist monoclonal antibodies (MAbs) at the time of systemic administration of a recombinant Ad vector. After Ad vector administration in the absence of immunosuppressive treatment, transgene expression in the serum lasted about 3-4 weeks. All control animals developed a strong neutralizing antibody (NAb) response to the Ad particles, which totally prevented efficient administration of a second vector, as shown by the lack of transgene expression. Treatment with anti-CD40 and anti-CD86 chimeric MAbs delayed or blocked the development of a humoral response against Ad and the infiltration of CD8 þ lymphocytes into the liver. This resulted in (i) increased persistence of Ad-transduced cells after injection of a first vector encoding a nonimmunogenic transgene, and (ii) the possibility of readministering a second Ad vector with significant efficacy. In both respects, the combined blockade of CD40 and CD86 was more efficient than treatment with anti-CD40 alone. This study shows for the first time in non-human primates that blocking CD40 and CD86 costimulatory molecules represents a promising strategy to inhibit immune responses against an Ad vector injected systemically.

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Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 87%

Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeys

et al. 2004

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“…1,6,7 Other studies have compared immune-competent versus immune-compromised manipulated hosts to better understand the biologic mechanisms involved in the immune response induced by Ad vectors. [11][12][13][14][15][16][17][18][19][20][21] Although such studies are crucial to understand the effects of isolated effector molecules on persistence of the Ad transgene, these studies are usually carried out in the same strain of mice, and cannot account for the genetic variability in the immune response in different strains of mice. Therefore, these studies may not be able to represent the various contributions of genetic polymorphisms to eliminate the administered Ad vectors, and thus prevent our understanding of the precaution and limitation of adenoviral gene therapy in immune diversified hosts such as humans.…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10] Inhibition of development of CTL has been achieved by blocking the Th1 helper T-cell response by immunosuppressive therapy, 11 anti-CD4 therapy [12][13][14] anti-TNF therapy, 15 and by therapies that block B7-CD28 signaling and CD40-CD40L interactions. [16][17][18][19][20] We have previously developed cell-gene therapy utilizing either Fas ligand to delete specifically T cells responsive to Ad, or have blocked the hepatocyte to apoptosis with the soluble DR5, both of which result in prolonged gene therapy. 21,22 Therefore, it is clear that crippling of one or more of the effector pathways of the innate or adaptive immune response pathways to Ad gene therapy can greatly inhibit the elimination of Adinfected hepatocytes and greatly prolong gene therapy expression.…”

Section: Introductionmentioning

confidence: 99%

Identification of multiple genetic loci that regulate adenovirus gene therapy

et al. 2003

Gene Ther

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A key aspect of the immune response to adenovirus (Ad) gene therapy is the generation of a cytotoxic T-cell (CTL) response. To better understand the genetic network underlying these events, 20 strains of C57BL/6 Â DBA/2 (BXD) recombinant inbred (RI) mice were administered with AdLacZ and analyzed at days 7, 21, 30, and 50 for liver b-galactosidase (LacZ) expression and CTL response. Sera levels of interferon gamma (IFN-g), tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6) were analyzed at different times after AdLacZ. There was a distinct strain-dependent expression of LacZ, which was strongly correlated with the CTL response. Among the five BXD RI strains that exhibited significantly prolonged LacZ expression, four also exhibited a marked defect in the production of Ad-specific CTL. There was a strong correlation between the sera levels of IFN-g, TNF-a, and IL-6, but cytokine responses were not significantly correlated with LacZ expression or the CTL response. Quantitative trait loci regulating LacZ on day 30 were found on chromosome (Chr) 19 (33 cM) and Chr 15 (42.8 cM). Cytotoxicity mapped to Chr 7 (41.0 and 57.4-65.2 cM), Chr 15 (61.7 cM), and Chr X (27.8 cM). IFN-g production mapped to Chr 18 (22, 27, and 32 cM) and Chr 11 (64.0 cM). TNF-a and IL-6 production mapped to Chr 6 (91.5 cM) Chr 9 (42.0 cM) and Chr 8 (52 and 73.0 cM). These results indicate that different strains of mice exhibit different pathways for effective clearance of AdLacZ depending on genetic polymorphisms and interactions at multiple genetic loci.

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“…One such approach employed antibodies directed against CD40, CD80/B7.1 and CD86/B7.2. 60 This treatment reportedly fully abrogated the immune response against the Ad vector such that readministration was as effective as that in naïve animals. In addition, these authors claimed that the animals were capable of mounting a normal response to Ad.…”

Section: Readministration With Ad Vectors Remains a Challengementioning

confidence: 99%

Gene therapy progress and prospects: adenoviral vectors

George¹

2003

Gene Ther

264

165

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In September 1999, the perceptions of the use of adenoviral (Ad) vectors for gene therapy were altered when a patient exposed via the hepatic artery to a high dose of adenoviral vector succumbed to the toxicity related to vector administration. Appropriately, concerns were raised about continued use of the Ad vector system and, importantly, there were increased efforts to more fully understand the toxicity. Today it is recognized that there is no ideal vector system, and that while Ad vectors are not suitable for all applications, the significant advantages over other vector systems including efficient transduction of a variety of cell types, both quiescent and dividing, make it optimal for certain applications. These include protocols where high levels of short-term expression are sufficient to provide a therapeutic benefit. Potential target applications include therapeutic angiogenesis, administration into immune-privileged sites such as the CNS, or treatments where the adjuvant effect of adenovirus can be of benefit such as cancer vaccines. Broader applicability of Ad vectors will require resolution of toxicity issues. This review will therefore focus on studies conducted over the last 2 years that have advanced our understanding of the toxicity associated with Ad vectors, studies that have employed methods to reduce toxicity and improvements in Ad vectors themselves that will reduce toxicity by one of several mechanisms. These mechanisms include retargeting vector to the tissue of interest, minimizing or eliminating viral gene expression that is thought to result in loss of transduced cells, or by methods that seek to reduce the vector dose required for therapeutic benefit. An area where there remains significant room for improvement is when readministration of vector is required because transgene expression has decreased to background levels.

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Transient blocking of both B7.1 (CD80) and B7.2 (CD86) in addition to CD40–CD40L interaction fully abrogates the immune response following systemic injection of adenovirus vector

Abstract: Blockade of the CD40-CD40L and CD80/CD86-

Cited by 17 publications

References 50 publications

Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeys

Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeys

Identification of multiple genetic loci that regulate adenovirus gene therapy

Gene therapy progress and prospects: adenoviral vectors

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