Dangerous liaisons: the role of “danger” signals in the immune response to gene therapy

Brown, Brian D.; Lillicrap, David

doi:10.1182/blood-2001-11-0067

Cited by 89 publications

(75 citation statements)

References 109 publications

(94 reference statements)

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“…The Danger Model of immune tolerance suggests that the potential for activation of T cells may persist, if FIX is subsequently presented in the context of any of a number of inflammatory proteins or signals that can provide co-stimulation of antigen presenting cells and naïve T cells. 51,52 Loss of transgenic FIX expression in a recent clinical trial underscores this concern. 13 In summary, our studies of the R333Q-hFIX mouse using a host of potential protein and gene therapeutic strategies suggest that the presence of a missense mutation, with some level of circulating protein (CRM+), results in very low risk of inhibitor antibody formation or CTL response.…”

Section: Anti-factor IX Antibodies After Aav1 and Aav2 Fix T-p Zhang mentioning

confidence: 99%

Transgene expression levels and kinetics determine risk of humoral immune response modeled in factor IX knockout and missense mutant mice

et al. 2006

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Immune responses leading to antibody-mediated elimination of the transgenic protein are a concern in gene replacement for congenital protein deficiencies, for which hemophilia is an important model. Although most hemophilia B patients have circulating non-functional but immunologically crossreactive factor IX (FIX) protein (CRM+ phenotype), inciting factors for FIX neutralizing antibody (inhibitor) development have been studied in crossreactive material-negative (CRMÀ) animal models. For this study, determinants of FIX inhibitor development were compared in hemophilia B mice, in which circulating FIX protein is absent (CRMÀ factor IX knockout (FIXKO) model) or present (CRM+ missense R333Q-hFIX model) modeling multiple potential therapies. The investigations compare for the first time different serotypes of adenoassociated virus (AAV) vectors (AAV2 and AAV1), each at multiple doses, in the setting of two different FIX mutations. The comparisons demonstrate in the FIXKO background (CRMÀ phenotype) that neither vector serotype nor vector particle number independently determine the inhibitor trigger, which is influenced primarily by the level and kinetics of transgene expression. In the CRM+ missense background, inhibitor development was never stimulated by AAV gene therapy or protein therapy, despite the persistence of lymphocytes capable of responding to FIX with non-inhibitory antibodies. This genotype/phenotype is strongly protective against antibody formation in response to FIX therapy.

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Section: Anti-factor IX Antibodies After Aav1 and Aav2 Fix T-p Zhang mentioning

confidence: 99%

Transgene expression levels and kinetics determine risk of humoral immune response modeled in factor IX knockout and missense mutant mice

et al. 2006

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“…The most widely used vectors for gene delivery are genetically engineered viruses, because they, in the long-term evolution of nature, are equipped with specific machineries that facilitate DNA transport into the nucleus of cells (Baranowski et al, 2001). However, a main drawback of viral vectors is the toxicity caused by undesirable acute immune response to viral proteins (Brown and Lillicrap, 2002;Bowers et al, 2003;Chen et al, 2003;Jooss and Chirmule, 2003;Lowenstein, 2003). Moreover, proteins from transgene expression may also exert adverse effects on normal cells either directly or indirectly through conversion of prodrugs to cytotoxic agents (Freeman et al, 1993;Rosenfeld et al, 1995;Alvarez and Curiel, 1997;Pope et al, 1997;Chada et al, 2003).…”

mentioning

confidence: 99%

Characterisation of systemic dissemination of nonreplicating adenoviral vectors from tumours in local gene delivery

Wang

Yang

et al. 2005

Br J Cancer

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Systemic virus dissemination is a potential problem during local gene delivery in solid tumours. However, the kinetics and pathways of the dissemination have not been well characterised during the first 24 h after the infusion is started. To this end, we infused adenoviral vectors for luciferase or enhanced green fluorescence protein into three different tumour models in mice. During and/or after the infusion, we determined the amount of adenoviruses in the tumour, blood, and liver, and examined the transgene expression in the liver, lung, blood, and tumour. In addition, we intravenously injected tumour cells expressing luciferase and examined the biodistribution of these cells in the body. We observed transgene expression in the liver and tumour at 24 h after the infusion, but could not detect transgene expression in the blood and lung. The peak concentration of viral vectors in the plasma occurred during the intratumoral infusion. At 10 min after the infusion, few viral vectors remained in the blood and the ratio of copy numbers of adenoviruses between liver and tumour was 42 in 80% and X10 in 40% of the mice. Most tumour cells injected intravenously accumulated in the lung within the first 24 h. Taken together, these data indicated that systemic virus dissemination occurred mainly during the first 10 min after the intratumoral infusion was started, and that the dissemination was due to infusion-induced convective transport of viral vectors into leaky tumour microvessels.

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“…In addition, the cellular immune response, mediated through adenoviral specific CD8 positive T cells, eliminate the cells' expressing viral and transgene products (24). Overall the undesirable acute immune response to viral proteins was considered the main drawback of virus-based gene therapy (13,14,16).…”

Section: Gene Deliverymentioning

confidence: 99%

Evolving gene therapy approaches for osteosarcoma using viral vectors: Review

Witlox

Lamfers

Wuisman

et al. 2007

Bone

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Dangerous liaisons: the role of “danger” signals in the immune response to gene therapy

Cited by 89 publications

References 109 publications

Transgene expression levels and kinetics determine risk of humoral immune response modeled in factor IX knockout and missense mutant mice

Transgene expression levels and kinetics determine risk of humoral immune response modeled in factor IX knockout and missense mutant mice

Characterisation of systemic dissemination of nonreplicating adenoviral vectors from tumours in local gene delivery

Evolving gene therapy approaches for osteosarcoma using viral vectors: Review

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