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* Institut National de la Santé et de la Recherche Médicale, Unité 563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France;
Université Toulouse III, Paul-Sabatier, Toulouse, France;
Brain Research Institute, University of Vienna, Vienna, Austria;
Genethon, Evry, France;
¶ Unité d’Immunite Cellulaire Antivirale, Pasteur Institute, Paris, France;
|| Institut de Pharmacologie et de Biologie Structurale, Unité Mixte de Recherche 5089, Toulouse, France; and
# Vaxon Biotech, Genopole, Evry, France
Multiple sclerosis (MS) is a demyelinating inflammatory disease of the CNS. Though originally believed to be CD4-mediated, additional immune effector mechanisms, including myelin-specific CD8+ T cells, are now proposed to participate in the pathophysiology of MS. To study the immunologic and encephalitogenic behavior of HLA-A*0201-binding myelin-derived epitopes in vivo, we used a humanized HLA-A*0201-transgenic mouse model. Eight HLA-A*0201-binding peptides derived from myelin oligodendrocyte glycoprotein (MOG), an immunodominant myelin self-Ag, were identified in silico. After establishing their relative affinity for HLA-A*0201 and their capacity to form stable complexes with HLA-A*0201 in vitro, their immunological characteristics were studied in HLA-A*0201-transgenic mice. Five MOG peptides, which bound stably to HLA-A*0201 exhibited strong immunogenicity by inducing a sizeable MOG-specific HLA-A*0201-restricted CD8+ T cell response in vivo. Of these five candidate epitopes, four were processed by MOG-transfected RMA target cells and two peptides proved immunodominant in vivo in response to a plasmid-encoding native full-length MOG. One of the immunodominant MOG peptides (MOG181) generated a cytotoxic CD8+ T cell response able to aggravate CD4+-mediated EAE. Therefore, this detailed in vivo characterization provides a hierarchy of candidate epitopes for MOG-specific CD8+ T cell responses in HLA-A*0201 MS patients identifying the encephalitogenic MOG181 epitope as a primary candidate.
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1 This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Association pour la Recherche sur la Sclerose en Plaques, and the European Union (Neuropromise). L.T.M. was supported by a postdoctoral fellowship from the European Union (Neuropromise).
2 Address correspondence and reprint requests to Dr. Roland S. Liblau, Institut National de la Santé et de la Recherche Médicale, Unité 563, Centre de Physiopathologie de Toulouse Purpan, Centre Hospitalo Universitaire, Purpan, BP 3028, 31024 Toulouse Cedex 3, France. E-mail address: rolandliblau{at}hotmail.com
3 Abbreviations used in this paper: MS, multiple sclerosis; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; EAE, experimental autoimmune encephalomyelitis; RA, relative affinity; DT50, dissociation complex 50; HBV, hepatitis B virus; SFC, spot-forming cell.
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