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Preclinical evaluation of innate immunity to baculovirus gene therapy vectors in whole human blood
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
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2009 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 46, no 15, 2911-2917 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2009. Vol. 46, no 15, 2911-2917 p.
Keyword [en]
Autographa californica, Baculovirus, C5a receptor antagonist, Complement, Compstatin, Gene therapy
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-124322DOI: 10.1016/j.molimm.2009.07.008ISI: 000270489800006PubMedID: 19665799OAI: oai:DiVA.org:uu-124322DiVA: diva2:317342
Available from: 2010-05-03 Created: 2010-05-03 Last updated: 2017-12-12Bibliographically approved

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Tötterman, Thomas H.Nilsson, Bo

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