Preclinical evaluation of innate immunity to baculovirus gene therapy vectors in whole human blood
2009 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 46, no 15, 2911-2917 p.Article in journal (Refereed) Published
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.
Autographa californica, Baculovirus, C5a receptor antagonist, Complement, Compstatin, Gene therapy
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-124322DOI: 10.1016/j.molimm.2009.07.008ISI: 000270489800006PubMedID: 19665799OAI: oai:DiVA.org:uu-124322DiVA: diva2:317342