Rapid induction of autoantibodies against Nogo-A and MOG in the absence of an encephalitogenic T cell response: implication for immunotherapeutic approaches in neurological diseases.
Vaccinations against various antigens of the central nervous system (CNS) are gaining increasing interest as a therapeutic approach in a variety of neurological diseases such as spinal cord injury, ischemic stroke, Alzheimer disease, or spongiform encephalopathy. In the present work, the time window after spinal cord injury allowing potentially therapeutic antibody to penetrate the damaged blood-brain barrier (BBB) was measured by intravenous injection of a monoclonal anti-Nogo-A antibody. Although an influx of Nogo antibodies at the lesion site was detectable up to 2 wk after injury, a significant decrease in BBB permeability was noticed within the first week. Clearly, therefore, a vaccination protocol with a rapid antibody response is required for acute therapeutic interventions after CNS trauma. We designed a conjugate vaccine paradigm with particular focus on the safety and the kinetics of the antibody response. As antigen targets, we used Nogo-A and the strongly encephalitogenic myelin-oligodendrocyte glycoprotein (MOG). Intrasplenic autoimmunization of rats with a Nogo-A-specific region fused to the Tetanus toxin C-fragment (TTC) resulted in a fast IgM response against Nogo-A. A specific switch to IgG was observed as soon as 4-7 days after intrasplenic immunization in TTC-primed animals. In spite of the induction of a specific IgG response after intrasplenic immunization, no signs of experimental autoimmune disease (EAE) or inflammatory infiltrates on histological examinations were observable. In contrast to subcutaneous immunization with MOG, in vitro cytokine secretion assays (IL-2, IL-10, and IFN-gamma) did not reveal activation of MOG-specific T cells after intrasplenic immunization. Our findings have critical implications for future strategies in the development of safe and efficient therapeutic vaccines for neurological diseases.
Merkler
Doron
D
Brain Research Institute, University of Zurich and Department of Biology, Swiss Federal Institute of Technology Zurich, CH-8057 Zurich, Switzerland. merkler@med.uni-goettingen.de
Oertle
Thomas
T
Buss
Armin
A
Pinschewer
Daniel D
DD
Schnell
Lisa
L
Bareyre
Florence M
FM
Kerschensteiner
Martin
M
Buddeberg
Bigna S
BS
Schwab
Martin E
ME
D000818:Animals; D000918:Antibody Specificity; D000941:Antigens / Q000008:administration & dosage; D001323:Autoantibodies / Q000096:biosynthesis* / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D004660:Encephalitis / Q000175:diagnosis / Q000276:immunology; D007700:Kinetics; D008213:Lymphocyte Activation; D018448:Models, Immunological; D009185:Myelin Proteins / Q000276:immunology*; D018992:Myelin-Associated Glycoprotein / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D009422:Nervous System Diseases / Q000628:therapy; D000070798:Nogo Proteins; D010446:Peptide Fragments / Q000008:administration & dosage; D021381:Protein Transport; D051381:Rats; D013119:Spinal Cord Injuries / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013744:Tetanus Toxin / Q000008:administration & dosage; D014612:Vaccines / Q000276:immunology* / Q000633:toxicity*
D000941:Antigens; D001323:Autoantibodies; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D000070798:Nogo Proteins; D010446:Peptide Fragments; C000603197:Rtn4 protein, rat; D013744:Tetanus Toxin; D014612:Vaccines; C040635:tetanus toxin fragment C