Preclinical evaluation of innate immunity to baculovirus gene therapy vectors in whole human blood.

Autor: Georgopoulos LJ; YCR Cancer Research Unit, Department of Biology (Area 13), University of York, Heslington, York YO10 5DD, UK. ljs8@york.ac.uk, Elgue G, Sanchez J, Dussupt V, Magotti P, Lambris JD, Tötterman TH, Maitland NJ, Nilsson B
Jazyk: angličtina
Zdroj: Molecular immunology [Mol Immunol] 2009 Sep; Vol. 46 (15), pp. 2911-7. Date of Electronic Publication: 2009 Aug 08.
DOI: 10.1016/j.molimm.2009.07.008
Abstrakt: 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.
Databáze: MEDLINE
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