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

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

Research output: Contribution to journalArticlepeer-review

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.

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

Keywords

  • 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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