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

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Published copy (DOI)

Author(s)

  • Lindsay J Georgopoulos
  • Graciela Elgue
  • Javier Sanchez
  • Vincent Dussupt
  • Paola Magotti
  • John D Lambris
  • Thomas H Tötterman
  • Norman J Maitland
  • Bo Nilsson

Department/unit(s)

Publication details

JournalMolecular immunology
DatePublished - Sep 2009
Issue number15
Volume46
Number of pages7
Pages (from-to)2911-2917
Original languageEnglish

Abstract

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.

    Research areas

  • Baculoviridae, Complement C3b, Complement C5a, Complement Membrane Attack Complex, Cytokines, Gene Therapy, Genetic Vectors, Humans, Immunity, Innate, Immunoassay, Immunoglobulin M, Peptides, Cyclic

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