title: Toxic effects of intracerebral PrP antibody administration during the course of BSE infection in mice.
abstract: The absence of specific immune response is a hallmark of prion diseases. However, in vitro and in vivo experiments have provided evidence that an anti-PrP humoral response could have beneficial effects. Prophylactic passive immunization performed at the time of infection delayed or prevented disease. Nonetheless, the potential therapeutic effect of PrP antibodies administered shortly before the clinical signs has never been tested in vivo. Moreover, a recent study showed the potential toxicity of PrP antibodies administered intracerebrally. We aimed at evaluating the effect of a prolonged intracerebral anti-PrP antibody administration at the time of neuroinvasion in BSE infected Tg20 mice. Unexpectedly, despite a good penetration of the antibodies in the brain parenchyma, the treatment was not protective against the development of BSE. Instead, it led to an extensive neuronal loss, strong astrogliosis and microglial activation. Since this effect was observed after injection of anti-PrP antibodies as whole IgGs, F(ab')(2) or Fab fragments, the toxicity was directly related to the ability of the antibodies to recognize native PrP and to the intracerebral concentration achieved, and not to the Fc portion or the divalence of the antibodies. This experiment shows that a prolonged treatment with anti-PrP antibodies by the intracerebral route can induce severe side-effects and calls for caution with regard to the use of similar approaches for late therapeutic interventions in humans.
authors.affiliation: Department of Infectology, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Maxime
authors.initials: M
authors.lastname: Lefebvre-Roque
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Sabine
authors.initials: S
authors.lastname: Gilch
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Zou
authors.forename: Cécile
authors.initials: C
authors.lastname: Féraudet
authors.forename: Chantal Mourton
authors.initials: CM
authors.lastname: Gilles
authors.forename: Nicole
authors.initials: N
authors.lastname: Salès
authors.forename: Jacques
authors.initials: J
authors.lastname: Grassi
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.forename: Thierry
authors.initials: T
authors.lastname: Baron
authors.forename: Hermann
authors.initials: H
authors.lastname: Schätzl
authors.forename: Corinne Ida
authors.initials: CI
authors.lastname: Lasmézas
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D000917:Antibody Formation / Q000276:immunology; D001921:Brain / Q000276:immunology; D002417:Cattle; D016643:Encephalopathy, Bovine Spongiform / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D007116:Immunization, Passive / Q000379:methods; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D011328:Prions / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000906:Antibodies; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D011328:Prions