Journal
MOLECULAR IMMUNOLOGY
Volume 46, Issue 15, Pages 2911-2917Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2009.07.008
Keywords
Baculovirus; Autographa californica; Gene therapy; Complement; Compstatin; C5a receptor antagonist
Categories
Funding
- European Union, National Institute of Health [5-R01-EB-003968, GM-62134, GM069736]
- Swedish Research Council [K2007-65X05647-28-3, K2004-71 P-15244-01A]
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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 Ob 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 4 h was prevented by both complement inhibitors. Pro- and anti-inflammatory cytokines Il-1 beta, 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. (C) 2009 Elsevier Ltd. All rights reserved.
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