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Preclinical evaluat...
Preclinical evaluation of innate immunity to baculovirus gene therapy vectors in whole human blood
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Georgopoulos, Lindsay J. (författare)
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- Elgue, Graciela (författare)
- Uppsala universitet,Enheten för klinisk immunologi
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- Sanchez, Javier (författare)
- Uppsala universitet,Enheten för klinisk immunologi
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Dussupt, Vincent (författare)
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Magotti, Paola (författare)
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Lambris, John D. (författare)
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- Tötterman, Thomas H. (författare)
- Uppsala universitet,Enheten för klinisk immunologi
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Maitland, Norman J. (författare)
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- Nilsson, Bo (författare)
- Uppsala universitet,Enheten för klinisk immunologi
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(creator_code:org_t)
- Elsevier BV, 2009
- 2009
- Engelska.
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Ingår i: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 46:15, s. 2911-2917
- Relaterad länk:
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https://europepmc.or...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Interactions of gene therapy vectors with human blood components upon intravenous administration have a significant effect on vector efficacy and patient safety. Here we describe methods to evaluate these interactions and their effects in whole human blood, using baculovirus vectors as a model. Opsonisation of baculovirus particles by binding of IgM and C3b was demonstrated, which is likely to be the cause of the significant blood cell-associated virus that was detected. Preventing formation of the complement C5b-9 (membrane attack) complex maintained infectivity of baculovirus particles as shown by studying the effects of two specific complement inhibitors, Compstatin and a C5a receptor antagonist. Formation of macroscopic blood clots after 4h was prevented by both complement inhibitors. Pro- and anti-inflammatory cytokines Il-1beta, IL-6, IL-8 and TNF-alpha were produced at variable levels between volunteers and complement inhibitors showed patient-specific effects on cytokine levels. Whilst both complement inhibitors could play a role in protecting patients from aggressive inflammatory reactions, only Compstatin maintained virus infectivity. We conclude that this ex vivo model, used here for the first time with infectious agents, is a valuable tool in evaluating human innate immune responses to gene therapy vectors or to predict the response of individual patients as part of a clinical trial or treatment. The use of complement inhibitors for therapeutic viruses should be considered on a patient-specific basis.
Nyckelord
- Autographa californica
- Baculovirus
- C5a receptor antagonist
- Complement
- Compstatin
- Gene therapy
- MEDICINE
- MEDICIN
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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