Toxic effects of intracerebral PrP antibody administration during the course of BSE infection in mice.
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.
Lefebvre-Roque
Maxime
M
Department of Infectology, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Kremmer
Elisabeth
E
Gilch
Sabine
S
Zou
Wen-Quan
WQ
Féraudet
Cécile
C
Gilles
Chantal Mourton
CM
Salès
Nicole
N
Grassi
Jacques
J
Gambetti
Pierluigi
P
Baron
Thierry
T
Schätzl
Hermann
H
Lasmézas
Corinne Ida
CI
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
D000906:Antibodies; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D011328:Prions