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3. Neuraxial analgesia is not associated with an increased risk of post-partum relapses in MS

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Caroline Lavie, Fabien Rollot, Françoise Durand-Dubief, Romain Marignier, Iuliana Ionescu, Romain Casey, Thibault Moreau, Patricia Tourniaire, Michael Hutchinson, Marie Béatrice D’Hooghe, David-Axel Laplaud, Pierre Clavelou, Jérôme De Sèze, Marc Debouverie, David Brassat, Jean Pelletier, Christine Lebrun-Frenay, Emmanuelle Le Page, Giovanni Castelnovo, Eric Berger, Patrick Hautecoeur, Olivier Heinzlef, Luca Durelli, Marinella Clerico, Maria Trojano, Francesco Patti, Sandra Vukusic, A. Alpérovitch, H. Carton, M.B. d’Hooghe, O. Hommes, M. Hutchinson, P. Adeleine, A. Biron, P. Cortinovis-Tourniaire, J. Grimaud, M. Hours, T. Moreau, S. Vukusic, C. Confavreux, G. Chauplannaz, D. Latombe, M. Clanet, G. Lau, L. Rumbach, J.Y. Goas, F. Rouhart, A. Mazingue, E. Roullet, M. Madigand, P. Hautecoeur, P. Brunet, G. Edan, C. Allaire, G. Riffault, J. Leche, T. Benoit, C. Simonin, F. Ziegler, J.C. Baron, Y. Rivrain, R. Dumas, D. Loche, J.C. Bourrin, B. Huttin, B. Delisse, I. Gibert, C. Boulay, M. Verceletto, G. Durand, G. Bonneviot, R. Gil, M.A. Hedreville, C. Belair, R.J. Poitevin, J.L. Devoize, P. Wyremblewski, F. Delestre, A. Setiey, G. Comi, M. Filippi, A. Ghezzi, V. Martinelli, P. Rossi, M. Zaffaroni, M.R. Tola, M.P. Amato, C. Fioretti, G. Meucci, M. Inglese, G.L. Mancardi, D. Gambi, A. Thomas, M. Cavazzuti, A. Citterio, A. Heltberg, H.J. Hansen, O. Fernandez, F. Romero, T. Arbizu, J.J. Hernandez, C. De Andres de Frutos, D. Geffner Sclarky, Y. Aladro Benito, P. Reyes Yanes, M Aguilar, J.A. Burguera, R. Yaya, W. Bonakim Dib, D. Arzua-Mouronte, C.J.M. Sindic, R. Medaer, H. Roose, K.M.J. Geens, D. Guillaume, M. Van Zandycke, J. Janssens, M. Cornette, L. Mol, F. Weilbach, P. Flachenecker, H.P. Hartung, J. Haas, I. Tendolkar, E. Sindrn, H.W. Kölmel, D. Reichel, M. Rauch, S. Preuss, S. Poser, E. Mauch, S. Strausser-Fuchs, H. Kolleger, S. Hawkins, S.J.L. Howell, J.E. Rees, A. Thompson, M. Johnson, M. Boggild, R.P. Gregory, D. Bates, I. Bone, C. Polman, S. Frequin, P. Jongen, J. Correia de Sa, M.E. Rio, S. Huber, J. Lechner-Scott, L. Kappos, I. Ionescu, C. Cornu, M. El-Etr, E.E. Baulieu, M Schumacher, D.H. Miller, M. Pugeat, C. d’Archangues, J. Conard, J. Ménard, R. Sitruk-Ware, C. Pelissier, S. Dat, J. Belaïsch-Allard, N. Athéa, D. Büschsenschutz, O. Lyon-Caen, R. Gonsette, J.P. Boissel, P. Ffrench, F. Durand-Dubief, F. Cotton, C. Pachai, L. Bracoud, G. Androdias, R. Marignier, D.A. Laplaud, S. Wiertlewski, C. Lanctin-Garcia, G. Couvreur, G. Madinier, P. Clavelou, F. Taithe, D. Aufauvre, N. Guy, A. Ferrier, J. De Sèze, N. Collongues, M. Debouverie, F. Viala, D. Brassat, A. Gerdelat-Mas, P. Henry, J. Pelletier, A. Rico-Lamy, C. Lebrun-Frenay, E. Lepage, V. Deburghraeve, G. Castelnovo, E. Berger, M. Blondiau, O. Heinzlef, M. Coustans, C. Clerc, L. Rieu, M. Lauxerois, G. Hinzelin, J.C. Ouallet, D. Minier, P. Vion, N. Gromaire-Fayolle, N. Derache, E. Thouvenot, M. Sallansonnet-Froment, P. Tourniaire, L. Toureille, F. Borgel, B. Stankoff, C. Moroianu, A.M. Guennoc, C.L. Tournier-Gervason, S. Peysson, M. Trojano, F. Patti, E. D’Amico, L. Motti, L. Durelli, A. Tavella, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Observatoire Français de la Sclérose En Plaques [Lyon] (OFSEP), Service de neurologie fonctionnelle et d'épileptologie [Hôpital Pierre Wertheimer-HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Henri Duffaut (Avignon), National MS Center Melsbroek, Vrije Universiteit Brussel [Bruxelles] (VUB), Vrije Universiteit Brussel (VUB), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Laboratoire de Neuroimagerie in Vivo (LNV), CHU Strasbourg-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), Neurologie vasculaire, pathologie neuro-dégénérative et explorations fonctionnelles du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Neurologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL), centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Università degli studi di Torino = University of Turin (UNITO), University of Catania [Italy], Hospices Civils de Lyon, Departement de Neurologie (HCL), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Protéines membranaires transductrices d'énergie (PMTE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut des Géosciences de l’Environnement (IGE), Institut de Recherche pour le Développement (IRD)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherches sur les Macromolécules Végétales (CERMAV ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Environnement Ville Société (EVS), École normale supérieure - Lyon (ENS Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), Solvay (France), Laboratoire des Mécanismes et Transfert en Géologie (LMTG), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Institute of Evolutionary Biology, University of Edinburgh, Université de Lille, Sciences et Technologies, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Différenciation, interaction, activation et migration des sous-populations lymphocitaires humaines, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Motricité, interactions, performance EA 4334 / Movement - Interactions - Performance (MIP), Le Mans Université (UM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR des Sciences et Techniques des Activités Physiques et Sportives (UFR STAPS), Laboratoire Ecologie Fonctionnelle et Environnement (ECOLAB), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de Chimie Physique D'Orsay (LCPO), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), RMN et optique : De la mesure au biomarqueur, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Department of Neurology, CHU Lyon, Institut de Recherche de Chimie Paris (IRCP), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Hôpital de Hautepierre [Strasbourg], Laboratoire de Réactivité des Surfaces et des Interfaces (LRSI), Département de Physico-Chimie (DPC), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Empenn, Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques, European Leukodystrophies Association, PHRC National, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pierre Wertheimer, Département de Neurologie, Laboratoire de Mathématiques (LAMA), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Nottingham Scientific Limited, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Turin, Università degli studi di Torino (UNITO), University of Bari Aldo Moro (UNIBA), Department of Neurosciences, Università degli studi di Catania [Catania], Centre de recherche en neurosciences de Lyon (CRNL), Neuroépidémiologie, Institut de Physique du Globe de Paris (IPGP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Centre National de la Recherche Scientifique (CNRS), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut de Recherche pour le Développement (IRD)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École nationale supérieure d'architecture de Lyon (ENSAL)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École Nationale des Travaux Publics de l'État (ENTPE)-Université Jean Monnet [Saint-Étienne] (UJM)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ministère de la Culture (MC), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lavie, Caroline, Rollot, Fabien, Durand-Dubief, Françoise, Marignier, Romain, Ionescu, Iuliana, Casey, Romain, Moreau, Thibault, Tourniaire, Patricia, Hutchinson, Michael, D’Hooghe, Marie Béatrice, Laplaud, David-Axel, Clavelou, Pierre, De Sèze, Jérôme, Debouverie, Marc, Brassat, David, Pelletier, Jean, Lebrun-Frenay, Christine, Le Page, Emmanuelle, Castelnovo, Giovanni, Berger, Eric, Hautecoeur, Patrick, Heinzlef, Olivier, Durelli, Luca, Clerico, Marinella, Trojano, Maria, Patti, Francesco, Vukusic, Sandra, on behalf of PRIMS and POPARTMUS, Investigator, Filippi, Massimo, Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Environnement, Ville, Société (EVS), École normale supérieure de Lyon (ENS de Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Neuroimagerie: méthodes et applications (Empenn), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Laboratoire de glaciologie et géophysique de l'environnement (LGGE), Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromolécules Végétales (CERMAV), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire Motricité, Interactions, Performance, Université de Nantes (UN), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), CEA-Direction de l'Energie Nucléaire (CEA-DEN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction de l'Energie Nucléaire (CEA-DEN), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Service de neurologie [Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Service de Neurologie [CHU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Service de Neurologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Clinical sciences, Neuroprotection & Neuromodulation, and Neurology

Subjects
relapses, Neurology, [SDV]Life Sciences [q-bio], MESH: Pregnancy Complications / physiopathology, 0302 clinical medicine, MESH: Pregnancy, Anesthesia, Conduction, Recurrence, MESH: Anesthesia, Conduction / adverse effects, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, reproductive and urinary physiology, relapse, Postpartum Period, post-partum, MESH: Follow-Up Studies, MESH: Multiple Sclerosis / physiopathology, Obstetrical Analgesia, MESH: Multiple Sclerosis / chemically induced, Anesthesia, Female, pregnancy, Adult, medicine.medical_specialty, Clinical Neurology, Multiple sclerosis, MESH: Postpartum Period, 03 medical and health sciences, medicine, Humans, Multiple sclerosi, Post partum, Retrospective Studies, Pregnancy, MESH: Humans, MESH: Pregnancy Complications / chemically induced, business.industry, Neurotoxicity, MESH: Adult, MESH: Retrospective Studies, neuraxial analgesia, medicine.disease, MESH: Recurrence, Multiple sclerosis, neuraxial analgesia, post-partum, pregnancy, Pregnancy Complications, Increased risk, Neurology (clinical), [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

Background: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses. Objective: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy. Methods: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992–1995 and 2005–2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis. Results: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78). Conclusion: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.

Published
2019
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4. Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting

Author

Maria Trojano, Helmut Butzkueven, Ludwig Kappos, Heinz Wiendl, Tim Spelman, Fabio Pellegrini, Yi Chen, Qunming Dong, Harold Koendgen, Shibeshih Belachew, Jorge Correale, Alejandro Caride, Norma H. Deri, Carlos Ballario, Simon Broadley, Chris Kneebone, Michael Barnett, John Pollard, Suzanne Hodgkinson, Allan Kermode, Richard Macdonell, John King, Jeannette Lechner-Scott, Noel Saines, Mark Slee, Chris Plummer, Barbara Willekens, Ludo Vanopdenbosch, Rémy Phan-Ba, Valérie Delvaux, Veronique Bissay, Jan Debruyne, Danny Decoo, Roeland Crols, Anoek Symons, Guy Nagels, Vincent Van Pesch, Christian Sindic, Benedicte Dubois, Robert Medaer, Marie D'Hooghe, Daniel Guillaume, Eric De Smet, Pierrette Seeldrayers, Andreas Lysandropoulos, Mathieu Vokaer, Karine Geens, Christina Willems, Pierre Denayer, Michel Bureau, Cecile Retif, Michel Dupuis, Olivier Bouquiaux, Patrick Vanderdonckt, William van Landegem, Jo Caekebeke, Erwin Van Ingelghem, Katelijne Peeters, Pascale Gerard, Alain Maertens de Noordhout, Philippe Desfontaines, Etienne Urbain, Inge Declercq, Bart Van Wijmeersch, Erwin Vanroose, Alain Wibail, Emmanuel Barthomolé, Melanie Ursell, Margaret Elizabeth Sweet, David Howse, Draga Jichici, Melad Shawush, Mike Namaka, Anthony Traboulsee, Stan Hashimoto, Raymond Lo, Paul Marchetti, Yves Lapierre, Francois Jacques, Gregg MacLean, Virender Bhan, Pierre Duquette, Bradley Stewart, John Paulseth, Marcelo Kremenchutzky, Galina Vorobeychik, Paul O'Connor, François Grand'Maison, Eva Havrdova, Eva Meluzinová, Martin Valis, Radomír Talab, Pavel Stourac, Olga Zapletalová, Michal Dufek, Vladimíra Sládková, Alena Novotna, Romana Vancurová, Libuse Lhotaková, Jiri Fiedler, Marta Vachova, David Dolezil, Ivana Stetkarova, Adela Rehankova, Petr Psenica, Veronika Ulehlova, Sona Feketova, Ondrej Skoda, Markus Färkkilä, Sarasoja Taneli, Keijo Koivisto, Juha Matti Seppä, Laura Airas, Irina Elovaara, Päivi Hartikainen, Tuula Pirttila, Pierre Louchart, Olivier Ille, Jean philippe Thenint, Etienne Godet, Marcel Maillet Vioud, Renato Colamarino, Michel Gugenheim, Jerome Grimaud, Audrey Kopf, Christophe Billy, Bernard Huttin, Jean paul Borsotti, Philippe Devos, Jean bertin N Kendjuo, Albert Verier, Stephane Chapuis, Nathalie Daluzeau, Gilles Angibaud, Marie-Sylvie Artaud Uriot, François Ziegler, François Sellal, Antoine Moulignier, Isabelle Lavenu, Samir Ismail, Richard Devy, Manuel Suceveanu, Marc Wagner, Sebastien Marcel, Faycal Derouiche, Sohrab Mostoufizadehghalamfarsa, Sophie Delalande, Irene Ruggieri, Catherine Bossu Van Nieuwenhuyse, Chantal Nifle, Basile Ondze, Carmen Gurau Vasilescu, Cyrille Vongsouthi, Marc Coustans, Olivier Anne, Josephine Amevigbe, Jerome Servan, Marc Merienne, Philippe Eck, Stephane Berroir, Philippe Busson, Bruno Barroso, Jean-Marc Larrieu, Catherine Louvet Giendaj, Imad Malkoun, Patrick Hautecoeur, Arnaud Kwiatkowski, Andre Pouliquen, Guillaume Garrigues, Olivier Delerue, Pierric Giraud, Julien Gere, Jean Vaunaize, Olivier Dereeper, Nicolas Seiller, Roger Alsassa, Mihaela Vlaicu, Veronique Neuville, Jean Marc Faucheux, Patricia Bernady, Guy Fanjaud, François Viallet, Michael Schroeter, Sylke Schlemilch-Paschen, Thomas Lange, Kin-Arno Bohr, Klaus Jendroska, Elisabeth Rehkopf, Arnfin Bergmann, Christoph Kleinschnitz, Thomas Postert, Peter Scholz, Uwe Mauz, Hubert Stratmann, Veneta Siefjediers, Martin Prantl, Klaus Gehring, Ruth Zellner, Kathrin Junge, Anton Zellner, Valerina Bacay, Eugen Schlegel, Udo Polzer, Erik Strauss, Andreas Link, Christoph Stenzel, Matthias Freidel, Joachim Drews, Christian Neudert, Frank Schmitz, Joachim Jaeger, Said Masri, Wolfgang Heuberger, Beate Trausch, Oliver Ruhnke, Serena Scarel, Kathlen Bach, Michael Ernst, Harald Landefeld, Nils Richter, Stephan Schmidt, Michaela Krause, Alezander Dressel, Roland Ruth, Kerstin Anvari, Jens Gossling, Christoph Schenk, Oliver Tiedge, Lutz Bode, Hans-Thomas Eder, Oliver Pfeffer, Reinhard Krug, Christoph Lassek, Eberhard Fleischer, Sven Meuth, Luisa Hildegard Klotz, Ines Peglau, Borries Kukowski, Birgit Herting, Kersten Guthke, Jurgen Schierenbeck, Bernd Brockmeier, Holger Albrecht, Matthias Wuttke, Regine Augspach-Hofmann, Stefan Gunther, Martin Redbrake, Christian Franke, Klaus Buchner, Thomas Gratz, Rolf Horn, Frank Doemges, Martin Schreiber, Thomas Brosch, Markus Horn, Matthias Kittlitz, Gabriele Vulturius, Paul Hinse, Rolf Malessa, Stephan Wiehler, Zaza Katsarava, Oliver Kastrup, Ulrich Kausch, Martin Gullekes, Markus Fickinger, Wilhelm Wenzel, Ingolf C. Botefur, Gerd Reifschneider, Sebastian Rauer, Michael Lang, Lutz Harms, Ulrich Eckhardt, Simone Cursiefen, Ralf Linker, Klemens Angstwurm, Judith Haas, Ivo Schuetze, Eva Rohm, H. Stienker-Fisse, Michael Sailer, Johannes Bohringer, Mathias Maurer, Eberhard Bause, Ronald Wersching, Reinhardt Dachsel, Sylke Domke, Frank Hoffman, Bjorn Tackenberg, Kerstin Roch, Uwe Ziebold, Boris Kallmann, Bernhard Buehler, Judith Faiss, Juergen Faiss, Sebastian Schimrigk, Christian Menges, Karl Christian Knop, Wolfgang Koehler, Arno Siever, Johannes Bufler, Georg Gramsl, Benedicta Kuhnler, Matthias Maschke, Florian Stogbauer, Lisa Staude, Florian Bethke, Andreas Bitsch, Arndt D. Harmjanz, Jorg Windsheimer, Bernd C. Kieseier, Ralf Berkenfeld, Hayrettin Tumani, Michael Kirsch, Brigitte Wildemann, Regina Daniels, Klaus Gottwald, Wolfgang-Gerhard Elias, Olaf Hoffmann, Matthias Schwab, Christopher Pilz, Fabian Klostermann, Kerstin Hellwig, Achim Berthele, Antonios Bayas, Daniel Molitor, Christoph Grothe, Bert Wagner, Klimentini Karageorgiou, Dimosthenis Mitsikostas, Antonios Kodounis, Andreas Plaitakis, Alexandros Papadimitriou, Nikolaos Grigoriadis, Nikolaos Vlaikidis, Evaggelos Koutlas, Athanassios Kyritsis, Panagiotis Papathanassopoulos, Nikolaos Makris, Antonios Tavernarakis, Elio Scarpini, Enrico Montanari, Maria Giovanna Marrosu, Maria Pia Amato, Mariarosa Rottoli, Alessandra Lugaresi, Ciro Florio, Claudio Gasperini, Luigi Grimaldi, Enrico Millefiorini, Tatiana Koudriavtseva, Franco Perla, Renato Mantegazza, Antonio Bertolotto, Angelo Ghezzi, Sandra Quinones Aguilar, Eli Skromne Eisenberg, Leondardo Llamas Lopez, Rocio Marquez Estudillo, H.M. Schrijver, M.C. Wittebol, J.C. Baart, A.E.L. van Golde, G.J.D. Hengstman, P.H.M. Pop, M. Bos (Geldrop), R. Medaer, Angelique Schyns-Soeterboek, A. van der Zwart, A.J.H. van Diepen, G.A.M. Verheul, W.I.M. Verhagen, M. Bos (Helmond), R.J.G.M. Witjes, L.G.F. Sinnige, E.Th.L. van Munster, E.A.C.M. Sanders, Ron van Dijl, R.M.M. Hupperts, S.T.F.M. Frequin, L.H. Visser, J.M.L. Henselmans, J.W.B. Moll, Rune Midgard, Kjell Morten Myhr, Astrid Edland, Wenche Telstad, Tone Hognestad, Christian Lund, Harald Hovdal, Kaur Kamaljit, Jan Schepel, Roelfien Ida Hogenesch, Stephan Schüler, Francis Odeh, Karl B. Alstadhaug, Olav Korsgaard, Elisabeth Farbu, Teis Barclay Ingvaldsen, Diana Soares (SCO), José Rente, José Manuel Costa Guerra, Armando Morganho, António Leitão, João de Sá, Maria José Sá, Pinto Marques, Mário Veloso, Miguel Viana Baptista, Jarmila Szilasiová, Daniela Copikova-Cudrakova, Lubica Prochazkova, Eleonóra Klimová, Vladimir Donath, Miroslav Brozman, Cristina Ramo, Domingo Pérez Ruiz, Carmen Calles Hernández, María Eugenia Marzo Sola, Roberto Suarez Moro, Jose Antonio Vidal, Ana Belén Caminero Rodríguez, Gisela Martin Ozaeta, Jordi Batlle Nadal, Amaya Alvarez de Arcaya Esquide, Javier Olascoaga Urtaza, Sergio Martínez-Yélamos, Txomin Arbizu, Lluis Ramio i Torrenta, Mike Boggild, Martin Wilson, Adnan Al-Araji, Richard Nicholas, Timothy Harrower, Ian Redmond, Tilo Wolf, Michael Osei-Bonsu, Gordon Mazibrada, David Rog, David Cottrell, Cris Constantinescu, Orla Gray, Mohamed Belhag, Abdullah Shehu, Waqar Rashid, Martin Duddy, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Clinical sciences, Neurology, and UCL - (SLuc) Service de neurologie

Subjects
Adult, Male, medicine.medical_specialty, Disability worsening, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, immune system diseases, Internal medicine, Medicine, Humans, Immunologic Factors, In patient, Disability progression, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Medicine(all), Natalizumab/therapeutic use, Expanded Disability Status Scale, business.industry, Multiple sclerosis, General Medicine, Multiple Sclerosis, Relapsing-Remitting/drug therapy, medicine.disease, Immunologic Factors/therapeutic use, Clinical Practice, Treatment Outcome, Neurology, Disease Progression, Observational study, Female, Relapsing-remitting multiple sclerosis, Neurology (clinical), business, EDSS milestones, 030217 neurology & neurosurgery, medicine.drug, Follow-Up Studies
Abstract

Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

Published
2018

5. JC virus and multiple sclerosis: a refutation?

Author

J. A. M. Beekhuis-Brussee, R. H. Boerman, L. E. M. Bollen, R. Medaer, and J. J. Bax

Subjects
Adult, Male, Multiple Sclerosis, viruses, JC virus, Biology, medicine.disease_cause, Virus, Inclusion Bodies, Viral, Leukoencephalopathy, Demyelinating disease, medicine, Humans, Viral shedding, Aged, Urine cytology, Virulence, medicine.diagnostic_test, Progressive multifocal leukoencephalopathy, Multiple sclerosis, Leukoencephalopathy, Progressive Multifocal, virus diseases, General Medicine, Middle Aged, medicine.disease, JC Virus, Virology, Virus Shedding, Tumor Virus Infections, Neurology, Immunology, Female, Neurology (clinical)
Abstract

Polyomavirus JC (JCV) has been implicated in the etiology of multiple sclerosis (MS), because it causes progressive multifocal leukoencephalopathy (PML), a multifocal demyelinating disease with many microscopical similarities to MS. During childhood, the virus establishes a latent infection in the kidneys, which can be reactivated in immunocompromised patients. During reactivation, the virus is shed in the urine. The kidney is the only known site of latent infection and reactivation. Therefore, excretion of the virus in the urine of MS patients is to be expected, if reactivated JCV is involved in the etiology of MS. We studied urine samples of 53 patients with definitive MS and of 53 controls matched for age and sex. We found no evidence of active JCV infection in MS. The hypothesis of a polyomaviral etiology of MS is not supported by the results of this study.

Published
2009
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6. Use of rating scales to reflect cognitive and mental functioning in multiple sclerosis

Author

L. Smedt, R. Medaer, J. Geutjens, and M. Swerts

Subjects
Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Neurocognitive Disorders, Disease, Audiology, Disability Evaluation, Rating scale, medicine, Humans, Psychiatry, Mental functioning, Neurological deficit, Intelligence quotient, Multiple sclerosis, Wechsler Scales, Wechsler Adult Intelligence Scale, Cognition, General Medicine, Middle Aged, medicine.disease, Neurology, Female, Neurology (clinical), Cognition Disorders, Psychology
Abstract

46 patients with clinically definite multiple sclerosis were studied to compare intellectual function (Wechsler Adult Intelligence Scale) with other clinical expressions of the disease. Estimated premorbid I.Q. was compared to actual I.Q. 35% had I.Q. decrease of 0-14 points (clinically insignificant); 56% had mild to moderate I.Q. decrease of 15-29 points and 8% had more serious I.Q. decrease of 30 or more points. Decrease in I.Q. did not correlate with any other neurological deficit.

Published
2009
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7. Consensus guidelines on the neurologist's role in the management of neurogenic lower urinary tract dysfunction in multiple sclerosis

Author

Daniel Guillaume, Frank Van der Aa, Barbara Willekens, Dirk De Ridder, Pierrette Seeldrayers, R Medaer, Bénédicte Dubois, MB D'hooghe, Jan Debruyne, Marco Heerings, William van Landegem, Stefan Ilsbroukx, Anne-Françoise Zicot, Guy Nagels, Faculteit Medische Wetenschappen/UMCG, and Internal Medicine Specializations

Subjects
medicine.medical_specialty, Neurology, Consensus, Multiple Sclerosis, Urinary system, Urology, Urinary Bladder, INJECTIONS, Neurogenic, Guidelines as Topic, OVERACTIVITY, Double blind, DOUBLE-BLIND, Lower Urinary Tract Symptoms, Risk Factors, Physicians, mental disorders, medicine, Prevalence, DETRUSOR-SPHINCTER DYSSYNERGIA, Humans, Botulinum Toxins, Type A, Urinary Bladder, Neurogenic, Referral and Consultation, Gait Disorders, Neurologic, Botulinum a toxin, Urinary bladder, business.industry, Multiple sclerosis, General Medicine, medicine.disease, EFFICACY, nervous system diseases, medicine.anatomical_structure, Neuromuscular Agents, INCONTINENCE, INFECTIONS, ONABOTULINUMTOXINA, BOTULINUM-A TOXIN, BLADDER DYSFUNCTION, Urologic Surgical Procedures, Surgery, Human medicine, Neurology (clinical), Detrusor sphincter dyssynergia, business
Abstract

Objective: To review current management of neurogenic lower urinary tract dysfunction (NLUTD) in MS patients and give recommendations on the joint role of the neurologist and urologist in NLUTD management.Methods: An algorithm for evaluation and referral of MS patients to urologists was created. It is an outcome of discussions about current knowledge, existing guidelines, and key issues during two Belgian consensus meetings attended by neurologists, urologists and other stakeholders involved in MS management. At these meetings, updated information on management of NLUTD in MS was exchanged and the neurologists' opinion on how to integrate this in the other aspects of care in MS patients was explored.Results: Short evaluation of NLUTD in MS patients by neurologists and appropriate referral to urologists could accelerate proper diagnosis and treatment. Neurologists can play a central role in the interdisciplinary communication on interactions between disease manifestations of MS and their treatments.Conclusion: The coordinating role of neurologists in NLUTD management may considerably improve QoL in MS patients. More research is needed to evaluate outcomes of urological assessments and treatment. (C) 2013 Elsevier B.V. All rights reserved.

Published
2013

8. Increased frequency of gamma delta T cells in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. Reactivity, cytotoxicity, and T cell receptor V gene rearrangements

Author

P Stinissen, C Vandevyver, R Medaer, L Vandegaer, J Nies, L Tuyls, D A Hafler, J Raus, and J Zhang

Subjects
Immunology, Immunology and Allergy
Abstract

Infiltrating gamma delta T cells are potentially involved in the central nervous system demyelination in multiple sclerosis (MS). To further study this hypothesis, we analyzed the frequency and functional properties of gamma delta T cells in peripheral blood (PB) and paired cerebrospinal fluid (CSF) of patients with MS and control subjects, including patients with other neurologic diseases (OND) and healthy individuals. The frequency analysis was performed under limiting dilution condition using rIL-2 and PHA. After PHA stimulation, a significantly increased frequency of gamma delta T cells was observed in PB (14.7 x 10(-4)) and in CSF (15.8 x 10(-4)) of MS patients as compared with 4.3 x 10(-4) in PB and 3.9 x 10(-4) detected in CSF of patients with OND. The frequency was represented equally in OND patients and normal individuals. Similarly, the IL-2-responsive gamma delta T cells occurred at a higher frequency in PB of control subjects (1.1 x 10(-4)) in OND patients and 1.5 x 10(-4) in normal individuals). Forty-three percent (13 of 30) of the gamma delta T cell clones isolated from PB and CSF of MS patients responded to heat shock protein (HSP70) but not HSP65, whereas only 2 of 30 control gamma delta T cell clones reacted to the HSP. The majority of the gamma delta T cell clones were able to induce non-MHC-restricted cytolysis of Daudi cells. All clones displayed a substantial reactivity to bacterial superantigens staphylococcal enterotoxin B and toxic shock syndrome toxin-1, irrespective of their gamma delta V gene usage. Furthermore, the gamma delta T cell clones expressed predominantly TCRDV2 and GV2 genes (26 of 35 clones), whereas the clones derived from CSF of MS patients expressed either DV1 or DV2 genes. The obtained gamma delta clones, in general, represented rather heterogeneous clonal origins, even though a predominant clonal origin was found in a set of 10 gamma delta clones derived from one patient with MS. The present study provides new evidence supporting a possible role of gamma delta T cells in the secondary inflammatory processes in MS.

Published
1995
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9. HLA and T-cell receptor polymorphisms in Belgian multiple sclerosis patients: No evidence for disease association with the T-cell receptor

Author

Jean-Jacques Cassiman, Z Ghabanbasani, L Philippaerts, Inge Buyse, Herwig Carton, R Medaer, Caroline Vandevyver, and Jef Raus

Subjects
Multiple Sclerosis, Genotype, Receptors, Antigen, T-Cell, alpha-beta, Immunology, chemical and pharmacologic phenomena, Human leukocyte antigen, Biology, medicine, Humans, Immunology and Allergy, HLA-DR2 Antigen, Allele, Gene, Alleles, Genetics, Multiple sclerosis, Haplotype, T-cell receptor, medicine.disease, Haplotypes, Neurology, Neurology (clinical), Restriction fragment length polymorphism, Polymorphism, Restriction Fragment Length
Abstract

There are compelling data to indicate that the susceptibility to multiple sclerosis (MS) is inherited, at least in part. Particular HLA genotypes may be associated with MS and recently also polymorphisms in the T-cell receptor (TCR) genes have been reported to correlate with the disease; however, these data have been difficult to confirm. We investigated the TCRA and TCRB chain genes of HLA-typed Belgian CP MS patients employing four DNA restriction fragment length polymorphisms (RFLPs) detected with TCR constant (TCRAC1, TCRBC2) and variable (TCRBV8, TCRBV11) gene segments. Similar frequencies in patients and controls were observed for all RFLPs studied. Although the HLA DR2 genotype was significantly associated with MS, no interactive effects were seen with MS, DR2, TCRAC1, TCRBC2 and TCRBV alleles. We conclude that, while a clear association with HLA DR2 is observed, little convincing evidence exists for an association of CP MS with RFLPs of the TCRA or TCRB chain genes.

Published
1994
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10. Long-term follow up of glatiramer acetate compassionate use in Belgium

Author

C J M, Sindic, P, Seeldrayers, L, Vande Gaer, E, De Smet, G, Nagels, P P, De Deyn, R, Medaer, D, Guillaume, M B, D'Hooghe, M C, Deville, D, Decoo, B, Sadzot, W, Van Landegem, T, Strauven, J, Pepin, H, Merckx, J, Caekebeke, and M A, van der Tool

Subjects
Adult, Male, Time Factors, Adolescent, Luxembourg, Glatiramer Acetate, Middle Aged, Health Surveys, Multiple Sclerosis, Relapsing-Remitting, Treatment Outcome, Belgium, Disease Progression, Secondary Prevention, Humans, Patient Compliance, Female, Peptides, Immunosuppressive Agents, Follow-Up Studies, Netherlands
Abstract

Between June 1995 and November 1998, 228 patients with relapsing-remitting Multiple Sclerosis started treatment with glatiramer acetate (Copaxone) 20 mg once daily in the frame of a "compassionate use" protocol in 15 Belgian centers. Following an average treatment period of 5.8 years, treating neurologists were requested to fill in follow-up forms indicating neurological disability status and side effects during the previous 6 months. These data were available for 134 patients. In this group, the Expanded Disability Status Scale (EDSS) improved in 26.3% of patients. An additional 36.8% of patients remained neurologically stable. The Ambulation Index (AI) showed similar results: 12.5% of patients improved, 50% of patients remained stable, and 37.5% worsened. Only 10% of patients dropped out due to several reasons. The adverse events occurring in the period preceding the follow-up survey were non-serious and consistent with the current product information of glatiramer acetate. Among the 94 patients no longer followed-up in the compassionate program, reasons for lost to follow-up were obtained for 63; most of them (41) had stopped GA treatment or switched to another disease-modifying treatment. Overall these results are very similar to the ones reported in the extension study of the pivotal trial (Johnson et al., 2000), and indicate that patients treated with glatiramer acetate have a better outcome than expected on the basis of the natural course of the disease. Despite limitations of the study design, this report confirms the sustained efficacy of glatiramer acetate in reducing the disease progression in patients with relapsing-remitting multiple sclerosis treated in day-to-day clinical practice.

Published
2005

11. T cell vaccination in multiple sclerosis patients with autologous CSF-derived activated T cells: results from a pilot study

Author

Niels Hellings, Jef Raus, Y. Palmers, R. Medaer, A. Van Der Aa, Piet Stinissen, and G. Gelin

Subjects
Adult, CD4-Positive T-Lymphocytes, Male, Multiple Sclerosis, medicine.medical_treatment, T cell, Receptors, Antigen, T-Cell, alpha-beta, Immunology, T-cell vaccination, Pilot Projects, Lymphocyte Activation, Autoantigens, Immune system, Antigen, Immunology and Allergy, Medicine, Humans, Lymphocyte Count, biology, business.industry, ELISPOT, Myelin Basic Protein, Immunotherapy, Original Articles, Middle Aged, Adoptive Transfer, Myelin basic protein, Clone Cells, medicine.anatomical_structure, Receptor-CD3 Complex, Antigen, T-Cell, Genes, T-Cell Receptor beta, biology.protein, Female, business, CD8, Cell Division
Abstract

SUMMARY Myelin-reactive T cells are considered to play an essential role in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. We have previously studied the effects of T cell vaccination (TCV), a procedure by which MS patients are immunized with attenuated autologous myelin basic protein (MBP)-reactive T cell clones. Because several myelin antigens are described as potential autoantigens for MS, T cell vaccines incorporating a broad panel of antimyelin reactivities may have therapeutic effects. Previous reports have shown an accumulation of activated T cells recognizing multiple myelin antigens in the cerebrospinal fluid (CSF) of MS patients. We conducted a pilot clinical trial of TCV with activated CD4+ T cells derived from CSF in five MS patients (four RR, one CP) to study safety, feasibility and immune effects of TCV. CSF lymphocytes were cultured in the presence of rIL-2 and depleted for CD8 cells. After 5–8 weeks CSF T cell lines (TCL) were almost pure TCRαβ+CD4+ cells of the Th1/Th0 type. The TCL showed reactivity to MBP, MOG and/or PLP as tested by Elispot and had a restricted clonality. Three immunizations with irradiated CSF vaccines (10 million cells) were administered with an interval of 2 months. The vaccinations were tolerated well and no toxicity or adverse effects were reported. The data from this small open-label study cannot be used to support efficacy. However, all patients remained clinically stable or had reduced EDSS with no relapses during or after the treatment. Proliferative responses against the CSF vaccine were observed in 3/5 patients. Anti-ergotypic responses were observed in all patients. Anti-MBP/PLP/MOG reactivities remained low or were reduced in all patients. Based on these encouraging results, we recently initiated a double-blind placebo-controlled trial with 60 MS patients to study the effects of TCV with CSF-derived vaccines in early RR MS patients.

Published
2003

12. Risks of multiple sclerosis in relatives of patients in Flanders, Belgium

Author

Robert Vlietinck, Ruth J. F. Loos, J. Debruyne, J. De Keyser, I M Yee, Herwig Carton, L. Truyen, R Medaer, A D Sadovnick, Marie B. D'hooghe, Gerontology, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, and University of Groningen

Subjects
Proband, Male, Middle Age, Belgium, Recurrence, Epidemiology, Ethnicity, Medicine, Child, Netherlands, Likelihood Functions, Netherlands/ethnology, Middle Aged, PREVALENCE, Pedigree, Psychiatry and Mental health, TWINS, familial multiple sclerosis, language, Female, Disease Susceptibility, Risk assessment, recurrence risk, Human, Research Article, Adult, medicine.medical_specialty, Canada, Multiple Sclerosis, Age adjustment, Canada/epidemiology, Ethnic Groups, Risk Assessment, Age Distribution, Confidence Intervals, Humans, First-degree relatives, Belgium/epidemiology, Multiple Sclerosis/ethnology/*genetics, Aged, business.industry, Multiple sclerosis, medicine.disease, Middle age, language.human_language, Flemish, Surgery, Neurology (clinical), business, Demography
Abstract

Objectives - To calculate age adjusted risks for multiple sclerosis in relatives of Flemish patients with multiple sclerosis. Methods - Lifetime risks were calculated using the maximum likelihood approach. Results - Vital information was obtained on 674 probands with multiple sclerosis in Flanders and a total of their 26 225 first, second, and third degree relatives. Full medical information to allow documentation of multiple sclerosis status was available for 21 351 (81.4%) relatives. The age adjusted risk for parents was 1.61 (SEM 0.35)%, for siblings 2.10 (SE 0.36)%, and for children 1.71 (SEM 0.70)%. For aunts and uncles, the risk was 0.66 (SEM 0.13)%. Conclusions - The risk for first degree relatives of patients with multiple sclerosis in Flanders is increased 10-fold to 12-fold; for second degree relatives, it is increased threefold. This information can be used for risk counselling in families and provides additional support for the role of more than one locus contributing to the susceptibility of multiple sclerosis.

Published
1997

13. Depletion of myelin-basic-protein autoreactive T cells by T-cell vaccination: pilot trial in multiple sclerosis

Author

J. Raus, Piet Stinissen, L. Truyen, R. Medaer, and J. Zhang

Subjects
Adult, Male, Multiple Sclerosis, medicine.medical_treatment, T-Lymphocytes, T-cell vaccination, Autoimmunity, Pilot Projects, Lymphocyte Depletion, Myelin, Recurrence, medicine, Humans, Chemotherapy, Vaccines, biology, business.industry, Multiple sclerosis, Vaccination, Brain, Myelin Basic Protein, General Medicine, T lymphocyte, Immunotherapy, medicine.disease, Magnetic Resonance Imaging, Myelin basic protein, medicine.anatomical_structure, Case-Control Studies, Immunology, biology.protein, Female, business, Follow-Up Studies
Abstract

In a pilot trial, eight patients with multiple sclerosis were matched to control patients and received T-cell vaccination with irradiated T cells reactive to myelin basic protein (MBP) to deplete circulating MBP-reactive T cells. In the 2 years before and after vaccination, exacerbations decreased in five vaccinated patients (numbers 1, 2, 6-8) with relapsing-remitting disease from sixteen to three, respectively, and from twelve to ten in their matched controls. Magnetic resonance imaging showed a mean 8.0% increase in brain lesion size in the vaccinated patients compared with a 39.5% increase in the controls. Lesions and/or relapses worsened in three cases after vaccination in association with reappearance of circulating MBP-reactive T cells.

Published
1995

14. Clonal expansion of myelin basic protein-reactive T cells in patients with multiple sclerosis: restricted T cell receptor V gene rearrangements and CDR3 sequence

Author

Jingwu Zhang, N. Mertens, C. Vandevyver, R. Medaer, J. Raus, and P J van der Elsen

Subjects
DNA, Complementary, Multiple Sclerosis, Sequence analysis, T cell, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, Immunology, Molecular Sequence Data, Immunoglobulin Variable Region, Epitope, Antigen, medicine, Immunology and Allergy, Humans, Amino Acid Sequence, Gene, Peptide sequence, Cells, Cultured, Genetics, biology, Base Sequence, T-cell receptor, Myelin Basic Protein, Molecular biology, Myelin basic protein, Clone Cells, medicine.anatomical_structure, biology.protein, Sequence Analysis
Abstract

Myelin basic protein (MBP)-reactive T cells are thought to play an important role in the pathogenesis of multiple sclerosis (MS). In some patients with MS, these autoreactive T cells display a limited heterogeneity in their epitope recognition and T cell receptor (TCR) variable (V) gene usage. These individual-dependent properties of MBP-reactive T cells have led to the speculation that they may represent clonal expansion in vivo in some MS patients. In the present study, 51 MBP-reactive T cell clones derived from patients with MS and healthy individuals were examined for their epitope recognition and the TCR V alpha and V beta gene rearrangements. The V gene junctional region sequences of identified alpha and beta genes were further analyzed to probe their clonal origins, as the sequences are unique for individual clones. Our data showed that 26 clones derived from nine patients with MS shared a predominant reactivity to the immunodominant regions of MBP, 84-102, 110-129 and 143-168, and used various TCR V alpha and V beta rearrangements. The V gene usage of the clones was restricted to certain V alpha V beta combination(s) in a given MS patient, but varied among different patients. The sequence analysis revealed that the clones generated from a given patient shared a limited or a single junctional region sequence pattern(s), indicating their oligoclonal or monoclonal origin(s). In contrast, 25 MBP-reactive T cell clones derived from normal individuals exhibited unfocused epitope recognition and V gene usage. Thus, the limited heterogeneity of MBP-reactive T cells in their structural and functional characteristics reflects their clonal expansion in vivo in some patients with MS.

Published
1995

15. Focal leptomeningeal MR enhancement along the chiasm as a presenting sign of multiple sclerosis

Author

Herwig Carton, Wim Robberecht, Guy Wilms, A L Baert, Ingele Casteels, R Medaer, and Philippe Demaerel

Subjects
Adult, Male, medicine.medical_specialty, Pathology, Multiple Sclerosis, genetic structures, Optic chiasm, Central nervous system disease, Meninges, Blurred vision, medicine, Humans, Radiology, Nuclear Medicine and imaging, medicine.diagnostic_test, business.industry, Multiple sclerosis, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, eye diseases, Visual field, medicine.anatomical_structure, Optic Chiasm, Optic chiasma, Radiology, medicine.symptom, business
Abstract

We demonstrate focal leptomeningeal enhancement along the chiasm on MRI in a 28-year-old man presenting with blurred vision and bitemporal visual field defects. The diagnosis of clinically definite multiple sclerosis was confirmed by laboratory investigations and brain MR findings.

Published
1995

19. Intellectual impairment in multiple sclerosis

Author

M. Swerts, R. Medaer, L. De Smedt, and J. Geutjens

Subjects
Borderline intellectual functioning, business.industry, Intellectual impairment, Multiple sclerosis, Memory span, Medicine, Progression rate, Psychometric testing, business, medicine.disease, Clinical psychology
Abstract

Intellectual impairment is hardly known or studied in multiple sclerosis (MS). For the last 3 years intellectual impairment in multiple sclerosis patients has been the subject of systematic research in the MS clinic of Overpelt. Psychometric testing in MS encounters many difficulties due to the patients’ visual and motor deficits and also their psychological problems.

Published
1984
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20. Does the history of multiple sclerosis go back as far as the 14th century?

Author

R. Medaer

Subjects
medicine.medical_specialty, Multiple Sclerosis, business.industry, Multiple sclerosis, MEDLINE, General Medicine, medicine.disease, History, Medieval, Physical medicine and rehabilitation, Neurology, Family medicine, Medicine, Humans, Female, Neurology (clinical), business, History, 15th Century, Netherlands
Abstract

A number of documents written before or shortly after the death of St. Lidwina of Schiedam (1380-1433) surprised us by their very accurate description of symptoms which for the most part correspond to the clinical criteria prevailing nowadays for the diagnosis of multiple sclerosis. These could be the oldest known documents, describing a case of multiple sclerosis.

Published
1979

21. A Comparative Study between Multiple Sclerosis Out-patients and In-patients staying at a specialized Multiple Sclerosis Clinic

Author

M. Puystjens, H. Callaert, and R. Medaer

Subjects
Pediatrics, medicine.medical_specialty, Multiple sclerosis clinic, business.industry, Multiple sclerosis, Medicine, In patient, Population subgroup, National planning, business, medicine.disease, Out patients
Abstract

Data concerning the disability and the home situation of M.S. patients are virtually non-existing. Therefore, regional and national planning of resources is difficult. There are no statistical data concerning the reasons of admission in a specialized M.S. clinic.

Published
1986
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22. A method to establish antibody secreting B cell lines and simultaneously perform frequency analysis

Author

Jef Raus, R Medaer, J W Zhang, C Ying, and P Henderikx

Subjects
Frequency analysis, B-Lymphocytes, Immunology, Cyclosporins, Biology, Molecular biology, law.invention, Cell Line, medicine.anatomical_structure, Established cell line, law, MBP - Myelin basic protein, Cell culture, medicine, biology.protein, Immunology and Allergy, Humans, CSA - Cyclosporin A, Antibody-Producing Cells, Antibody, B cell
Published
1989

23. Lymphocytapheresis therapy in multiple sclerosis, a preliminary study

Author

K. Gautama, R. Medaer, C. Eeckhout, and C. Vermijlen

Subjects
Adult, Male, medicine.medical_specialty, Multiple Sclerosis, business.industry, Neurological status, Multiple sclerosis, Follow up studies, General Medicine, Plasmapheresis, Middle Aged, medicine.disease, Surgery, Disability Evaluation, Neurology, Intensive Phase, Internal medicine, medicine, Humans, Lymphocytapheresis, Female, Neurology (clinical), Lymphocytes, business, Follow-Up Studies
Abstract

10 patients with definite multiple sclerosis (MS), most of them with the chronic progressive type, were treated with lymphocytapheresis during one year. The DSS (Disability Status Scale) improved in 4 patients during the intensive phase of treatment, remained stable in 5 patients and deteriorated in one. The NSS (Neurological Status Scale) showed a stabilisation for the majority of the neurologic functions. Using the ISS (Incapacity Status Scale), an improvement was measured in 6 patients, a stabilisation in one and a deterioration in 3. Exacerbations could not be prevented by lymphocytapheresis.

Published
1984

24. Magnetic resonance imaging and cognitive functioning in multiple sclerosis

Author

E. Nelissen, H. Callaert, M. Swerts, J. Geutjens, B. Appel, and R. Medaer

Subjects
Adult, Male, medicine.medical_specialty, Neurology, Multiple Sclerosis, Audiology, Neuropsychological Tests, medicine, Humans, Cognitive skill, Psychiatry, Neuroradiology, medicine.diagnostic_test, Multiple sclerosis, Cognitive disorder, Brain, Magnetic resonance imaging, Cognition, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Female, Neurology (clinical), Psychology, Cognition Disorders, Psychopathology
Abstract

The relationship between cognitive impairment in multiple sclerosis and brain lesions seen on magnetic resonance imaging (MRI) was studied. Three groups of 11 patients with multiple sclerosis, matched for the variables of disability, duration of illness, age and sex, were included. On the basis of neuropsychological testing, the groups were seen to differ in their level of cognitive impairment. The first group showed no cognitive impairment, the second group a moderate, and the third group a serious cognitive impairment. These differences between the groups were reflected by MRI, which revealed more abnormalities in the groups with cognitive impairment compared with the group with normal cognitive function. However, by MRI it was not possible to distinguish between the groups with moderate and that with serious cognitive impairment.

Published
1987

25. HLA-Antigens in Multiple Sclerosis Patients in the Benelux

Author

A. Bouckaert, M. De Bruyère, R. Medaer, I. Van De Putte, Dominique Latinne, J. M. Balen, Herwig Carton, P. Reekers, O. R. Hommes, and J. M. Minderhoud

Subjects
Linkage disequilibrium, Antigen, business.industry, Multiple sclerosis, Immunology, medicine, Susceptibility locus, Progression rate, Human leukocyte antigen, Negative association, medicine.disease, business, Disease course
Abstract

The association of multiple sclerosis (MS) with HLA-A3, B7 and DR2 is well established in most northern European populations suggesting the existence of an MS susceptibility locus closely linked to HLA. The demonstration of a negative association has been more problematic due to compensatory decreases in frequencies of antigens other than DR2 and antigens in linkage disequilibrium. Attempts have also been made to correlate HLA antigens and clinical characteristics including type of disease course and rate of progression (Madigand et al. 1982, Meyer-Rienecker et al. 1982).

Published
1986
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27. Safety and efficacy of natalizumab in Belgian multiple sclerosis patients: subgroup analysis of the natalizumab observational program.

Author

van Pesch V, Bartholomé E, Bissay V, Bouquiaux O, Bureau M, Caekebeke J, Debruyne J, Declercq I, Decoo D, Denayer P, De Smet E, D'hooghe M, Dubois B, Dupuis M, Sankari SE, Geens K, Guillaume D, van Landegem W, Lysandropoulos A, de Noordhout AM, Medaer R, Melin A, Peeters K, Ba RP, Retif C, Seeldrayers P, Symons A, Urbain E, Vanderdonckt P, Van Ingelghem E, Vanopdenbosch L, Vanroose E, Van Wijmeersch B, Willekens B, Willems C, and Sindic C

Subjects
Adolescent, Adult, Age Distribution, Aged, Belgium epidemiology, Cohort Studies, Disability Evaluation, Female, Humans, International Cooperation, Magnetic Resonance Imaging, Male, Middle Aged, Natalizumab, Product Surveillance, Postmarketing, Severity of Illness Index, Time Factors, Treatment Outcome, Young Adult, Antibodies, Monoclonal, Humanized therapeutic use, Immunologic Factors therapeutic use, Multiple Sclerosis drug therapy
Abstract

Natalizumab (Tysabri(®)) is highly efficacious in controlling disease activity in relapsing multiple sclerosis (MS) patients. As it is one of the more recent therapies for MS, there remains a need for long-term safety and efficacy data of natalizumab in a clinical practice setting. The Tysabri observational program (TOP) is an open-label, multicenter, multinational, prospective observational study, aiming to recruit up to 6,000 patients with relapsing-remitting MS from Europe, Canada and Australia. The objectives of this study are to collect long-term safety and efficacy data on disease activity and disability progression. We report here the interim results of the 563 patients included in TOP between December 2007 and 2012 from Belgium. This patient cohort was older at baseline, had longer disease duration, higher neurological impairment, and a higher baseline annualized relapse rate, when compared to patients included in the pivotal phase III AFFIRM trial. Nevertheless, the efficacy of natalizumab was comparable. The annualized relapse rate on treatment was reduced by 90.70 % (p < 0.0001) with a cumulative probability of relapse of 26.87 % at 24 months. The cumulative probabilities of sustained disability improvement and progression at 24 months were 25.68 and 9.01 %, respectively. There were no new safety concerns over the follow-up period. Two cases of progressive multifocal leukoencephalopathy were diagnosed. Our results are consistent with other observational studies in the post-marketing setting.

Published
2014
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28. Consensus guidelines on the neurologist's role in the management of neurogenic lower urinary tract dysfunction in multiple sclerosis.

Author

De Ridder D, Van Der Aa F, Debruyne J, D'hooghe MB, Dubois B, Guillaume D, Heerings M, Ilsbroukx S, Medaer R, Nagels G, Seeldrayers P, Van Landegem W, Willekens B, and Zicot AF

Subjects
Botulinum Toxins, Type A therapeutic use, Consensus, Gait Disorders, Neurologic etiology, Guidelines as Topic, Humans, Lower Urinary Tract Symptoms diagnosis, Lower Urinary Tract Symptoms etiology, Neurology, Neuromuscular Agents, Physicians, Prevalence, Referral and Consultation, Risk Factors, Urinary Bladder surgery, Urinary Bladder, Neurogenic diagnosis, Urinary Bladder, Neurogenic etiology, Urologic Surgical Procedures, Urology, Lower Urinary Tract Symptoms therapy, Multiple Sclerosis complications, Urinary Bladder, Neurogenic therapy
Abstract

Objective: To review current management of neurogenic lower urinary tract dysfunction (NLUTD) in MS patients and give recommendations on the joint role of the neurologist and urologist in NLUTD management., Methods: An algorithm for evaluation and referral of MS patients to urologists was created. It is an outcome of discussions about current knowledge, existing guidelines, and key issues during two Belgian consensus meetings attended by neurologists, urologists and other stakeholders involved in MS management. At these meetings, updated information on management of NLUTD in MS was exchanged and the neurologists' opinion on how to integrate this in the other aspects of care in MS patients was explored., Results: Short evaluation of NLUTD in MS patients by neurologists and appropriate referral to urologists could accelerate proper diagnosis and treatment. Neurologists can play a central role in the inter-disciplinary communication on interactions between disease manifestations of MS and their treatments., Conclusion: The coordinating role of neurologists in NLUTD management may considerably improve QoL in MS patients. More research is needed to evaluate outcomes of urological assessments and treatment., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Published
2013
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29. Boosting endogenous neuroprotection in multiple sclerosis: the ASsociation of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial.

Author

Gonsette RE, Sindic C, D'hooghe MB, De Deyn PP, Medaer R, Michotte A, Seeldrayers P, and Guillaume D

Subjects
Adult, Anti-Inflammatory Agents adverse effects, Belgium, Disability Evaluation, Disease Progression, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Inosine adverse effects, Inosine metabolism, Interferon beta-1a, Interferon beta-1b, Interferon-beta adverse effects, Kaplan-Meier Estimate, Male, Middle Aged, Multiple Sclerosis, Relapsing-Remitting blood, Multiple Sclerosis, Relapsing-Remitting diagnosis, Neuroprotective Agents adverse effects, Neuroprotective Agents metabolism, Severity of Illness Index, Time Factors, Treatment Outcome, Uric Acid blood, Anti-Inflammatory Agents therapeutic use, Inosine therapeutic use, Interferon-beta therapeutic use, Multiple Sclerosis, Relapsing-Remitting drug therapy, Neuroprotective Agents therapeutic use
Abstract

Anti-inflammatory drugs are effective on relapses, but neuroprotective agents to prevent disability are still unavailable. Uric acid has neuroprotective effects in experimental models including encephalomyelitis and appears to be involved in multiple sclerosis. Oral administration of inosine, a precursor of uric acid, increases serum uric acid levels and is well tolerated. Our objective was to test the possibility that a combination therapy associating an anti-inflammatory drug (interferon beta) and an endogenous neuroprotective molecule (uric acid) would be more effective than interferon beta alone on the accumulation of disability. Patients with relapsing-remitting multiple sclerosis on interferon beta for at least 6 months were randomized to interferon beta + inosine or interferon beta + placebo for 2 years. The dose of inosine was adjusted to maintain serum uric acid levels in the range of asymptomatic hyperuricaemia (

Published
2010
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30. The results of two multicenter, open-label studies assessing efficacy, tolerability and safety of protiramer, a high molecular weight synthetic copolymeric mixture, in patients with relapsing-remitting multiple sclerosis.

Author

De Stefano N, Filippi M, Confavreux C, Vermersch P, Simu M, Sindic C, Hupperts R, Bajenaru O, Edan G, Grimaldi L, Marginean I, Medaer R, Orefice G, Pascu I, Pelletier J, Sanders E, Scarpini E, and Mancardi GL

Subjects
Adult, Chemistry, Pharmaceutical, Dose-Response Relationship, Drug, Female, Glatiramer Acetate, Humans, Immunosuppressive Agents adverse effects, Immunosuppressive Agents chemistry, Injections, Subcutaneous, Male, Molecular Weight, Peptides adverse effects, Peptides chemistry, Pilot Projects, Treatment Outcome, Immunosuppressive Agents administration & dosage, Multiple Sclerosis, Relapsing-Remitting drug therapy, Peptides administration & dosage
Abstract

Objective: Two pilot studies were conducted to evaluate safety, tolerability, and efficacy of two doses of Protiramer (TV-5010) in patients with relapsing-remitting multiple sclerosis., Background: Both glatiramer acetate and TV-5010 are synthetic copolymers comprised the same four amino acids in a defined molar ratio. TV-5010 has higher average molecular weight than Glatiramer acetate and might be hypothesized that glatiramoids with higher molecular weight might be more immunoreactive than lower molecular weight peptides, thus increasing therapeutic potential and allowing for less frequent dosing., Methods: In the two separate studies, after a 10 week pretreatment period, TV-5010 was given subcutaneously once weekly at 15 mg and 30 mg for 36 weeks. The primary end point was a reduction in the number of magnetic resonance imaging active lesions (i.e., T1-weigthed gadolinium-enhancing and new T2-weighted lesions) between the pretreatment period and the end of study., Results: Both TV-5010 doses were generally well tolerated. The treatment with TV-5010 at a dose of 15 mg/wk did not show any significant effect. In contrast, in patients treated with at a dose of 30 mg/wk, a significant reduction in the mean number of gadolinium-enhancing (-58.8%; P = 0.0013) and new T2-W (-50%; P = 0.0002) lesions was observed. However, a large decrease in the mean number of both gadolinium-enhancing (-55%) and new T2-W (-40%) lesions during the pretreatment period made difficult the interpretation of the efficacy assessments., Conclusions: Further studies are needed to confirm these preliminary data on safety and efficacy of TV-5010 at a weekly dose of 30 mg.

Published
2009
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31. Autoantibody profiling in multiple sclerosis reveals novel antigenic candidates.

Author

Somers V, Govarts C, Somers K, Hupperts R, Medaer R, and Stinissen P

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Autoantibodies chemistry, Autoantigens isolation & purification, Binding Sites, Antibody, Biomarkers cerebrospinal fluid, Cloning, Molecular, Female, Gene Library, Humans, Male, Middle Aged, Molecular Sequence Data, Multiple Sclerosis, Relapsing-Remitting cerebrospinal fluid, Multiple Sclerosis, Relapsing-Remitting diagnosis, Multiple Sclerosis, Relapsing-Remitting metabolism, Organ Specificity genetics, Organ Specificity immunology, Peptide Fragments immunology, Peptide Fragments isolation & purification, Peptide Fragments metabolism, Recombinant Fusion Proteins immunology, Viral Fusion Proteins genetics, Viral Fusion Proteins immunology, Autoantibodies metabolism, Autoantigens immunology, Autoantigens metabolism, Multiple Sclerosis, Relapsing-Remitting immunology
Abstract

An important contribution of B cells and autoantibodies has been demonstrated in the pathogenesis of multiple sclerosis (MS), leading to interest in the use of such autoantibodies as diagnostic or prognostic biomarkers. The objective of this study was to identify novel Ab biomarkers for MS using "serological Ag selection". Using a phage display library derived from MS brain plaques, we applied serological Ag selection to identify antigenic targets specifically interacting with Abs present in the cerebrospinal fluid (CSF) of 10 relapsing-remitting MS patients. These antigenic targets were further evaluated on a large panel of CSF from 63 other MS patients, 30 patients with other inflammatory disorders, and 64 patients with noninflammatory neurological disorders. A panel of eight antigenic targets was identified that showed a 86% specificity and 45% sensitivity in discriminating MS patients and controls. Four of the antigenic targets showed exclusive reactivity (100% specificity; 23% sensitivity) in the MS group as compared with the control group. Detailed bio-informatic analyses revealed a novel Ag, SPAG16. Among the novel phage peptides identified, novel epitopes were generated from untranslated sequences and out-of-frame sequences. Of 10 relapsing-remitting patients used for serological Ag selection, Ab reactivity toward one of the eight antigenic targets was also demonstrated in serum of 38% CSF-positive patients. Autoantibody profiles against epitopes derived from MS brain tissue could serve as diagnostic markers or form the basis for the identification of a subgroup of MS patients.

Published
2008
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32. Compromised CD4+ CD25(high) regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level.

Author

Venken K, Hellings N, Thewissen M, Somers V, Hensen K, Rummens JL, Medaer R, Hupperts R, and Stinissen P

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Cells, Cultured, Female, Forkhead Transcription Factors blood, Forkhead Transcription Factors cerebrospinal fluid, Humans, Immune Tolerance immunology, Immunophenotyping, Interferon-beta therapeutic use, Lymphocyte Count, Male, Middle Aged, Multiple Sclerosis, Relapsing-Remitting drug therapy, Forkhead Transcription Factors metabolism, Multiple Sclerosis, Relapsing-Remitting immunology, T-Lymphocytes, Regulatory immunology
Abstract

CD4+ CD25(high) regulatory T cells (Tregs) of patients with relapsing-remitting (RR) multiple sclerosis (MS), in contrast to those of patients with secondary progressive (SP) MS, show a reduced suppressive function. In this study, we analysed forkhead box P3 (FOXP3) at the single-cell level in MS patients and controls (healthy individuals and patients with other neurological diseases) by means of intracellular flow cytometry. Our data revealed a reduced number of peripheral blood CD4+ CD25(high) FOXP3+ T cells and lower FOXP3 protein expression per cell in RR-MS patients than in SP-MS patients and control individuals, which was correlated with the suppressive capacity of Tregs in these patients. Interestingly, interferon (IFN)-beta-treated RR-MS patients showed restored numbers of FOXP3+ Tregs. Furthermore, a higher percentage of CD4+ CD25(high) FOXP3+ Tregs in RR-MS patients, as compared with controls and SP-MS patients, expressed CD103 and CD49d, adhesion molecules involved in T-cell recruitment towards inflamed tissues. This was consistent with a significantly increased number of CD27+ CD25(high) CD4+ T cells in the cerebrospinal fluid (CSF), as compared with peripheral blood, in RR-MS patients. Taken together, these data show aberrant FOXP3 expression at the single-cell level correlated with Treg dysfunction in RR-MS patients. Our results also suggest that Tregs accumulate in the CSF of RR-MS patients, in an attempt to down-regulate local inflammation in the central nervous system.

Published
2008
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33. Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FOXP3 expression.

Author

Venken K, Hellings N, Hensen K, Rummens JL, Medaer R, D'hooghe MB, Dubois B, Raus J, and Stinissen P

Subjects
Adult, Age Factors, Age of Onset, Aged, Cell Proliferation, Cells, Cultured, Female, Forkhead Transcription Factors biosynthesis, Forkhead Transcription Factors genetics, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Genetic Variation immunology, Humans, Immune Tolerance genetics, Interferon-gamma metabolism, Male, Middle Aged, Multiple Sclerosis, Chronic Progressive blood, Multiple Sclerosis, Chronic Progressive physiopathology, Multiple Sclerosis, Relapsing-Remitting blood, Multiple Sclerosis, Relapsing-Remitting physiopathology, RNA, Messenger metabolism, T-Lymphocytes, Regulatory immunology, CD4-Positive T-Lymphocytes immunology, Forkhead Transcription Factors metabolism, Immune Tolerance immunology, Multiple Sclerosis, Chronic Progressive immunology, Multiple Sclerosis, Relapsing-Remitting immunology, Receptors, Interleukin-2 biosynthesis
Abstract

Accumulating evidence indicates an immunosuppressive role for CD4(+)CD25(+) regulatory T cells (Tregs) in autoimmune diseases. Although an impaired Treg function in patients with relapsing-remitting multiple sclerosis (RR-MS) has been reported recently, no information is available so far about Treg function in the progressive stage of the disease. In the present study, the phenotypic and functional characteristics of CD4(+)CD25(+) T cells isolated from the peripheral blood of patients with RR-MS and secondary progressive multiple sclerosis (SP-MS) were investigated. No significant quantitative or phenotypic abnormalities in CD4(+)CD25(+) T cells from RR- and SP-MS patients were detected. However, whereas a reduced suppressor function of CD4(+)CD25(+) T cells toward proliferation and interferon-gamma production of CD4(+)CD25(-) responder T cells was found in RR-MS patients, SP-MS patients showed a normal Treg function. The suppressive capacity of MS-derived CD4(+)CD25(+) T cells was correlated with disease duration but not with age, indicating that Treg function is more affected in the early phase of the disease process. Consistently with the suppressive capacity, CD4(+)CD25(+) T cells from SP-MS patients showed normal levels of FOXP3 mRNA in contrast to RR-MS patients that had a reduced FOXP3 expression. These data are the first to demonstrate differences in function and FOXP3 expression of CD4(+)CD25(+) T cells from patients with RR- and SP-MS., ((c) 2006 Wiley-Liss, Inc.)

Published
2006
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34. Long-term follow up of glatiramer acetate compassionate use in Belgium.

Author

Sindic CJ, Seeldrayers P, Vande Gaer L, De Smet E, Nagels G, De Deyn PP, Medaer R, Guillaume D, D'Hooghe MB, Deville MC, Decoo D, Sadzot B, Van Landegem W, Strauven T, Pepin J, Merckx H, Caekebeke J, and van der Tool MA

Subjects
Adolescent, Adult, Belgium, Disease Progression, Female, Follow-Up Studies, Glatiramer Acetate, Health Surveys, Humans, Immunosuppressive Agents adverse effects, Luxembourg, Male, Middle Aged, Multiple Sclerosis, Relapsing-Remitting physiopathology, Netherlands, Patient Compliance, Peptides adverse effects, Secondary Prevention, Time Factors, Treatment Outcome, Immunosuppressive Agents administration & dosage, Multiple Sclerosis, Relapsing-Remitting drug therapy, Peptides administration & dosage
Abstract

Between June 1995 and November 1998, 228 patients with relapsing-remitting Multiple Sclerosis started treatment with glatiramer acetate (Copaxone) 20 mg once daily in the frame of a "compassionate use" protocol in 15 Belgian centers. Following an average treatment period of 5.8 years, treating neurologists were requested to fill in follow-up forms indicating neurological disability status and side effects during the previous 6 months. These data were available for 134 patients. In this group, the Expanded Disability Status Scale (EDSS) improved in 26.3% of patients. An additional 36.8% of patients remained neurologically stable. The Ambulation Index (AI) showed similar results: 12.5% of patients improved, 50% of patients remained stable, and 37.5% worsened. Only 10% of patients dropped out due to several reasons. The adverse events occurring in the period preceding the follow-up survey were non-serious and consistent with the current product information of glatiramer acetate. Among the 94 patients no longer followed-up in the compassionate program, reasons for lost to follow-up were obtained for 63; most of them (41) had stopped GA treatment or switched to another disease-modifying treatment. Overall these results are very similar to the ones reported in the extension study of the pivotal trial (Johnson et al., 2000), and indicate that patients treated with glatiramer acetate have a better outcome than expected on the basis of the natural course of the disease. Despite limitations of the study design, this report confirms the sustained efficacy of glatiramer acetate in reducing the disease progression in patients with relapsing-remitting multiple sclerosis treated in day-to-day clinical practice.

Published
2005

35. T cell vaccination in multiple sclerosis patients with autologous CSF-derived activated T cells: results from a pilot study.

Author

Van der Aa A, Hellings N, Medaer R, Gelin G, Palmers Y, Raus J, and Stinissen P

Subjects
Adult, Autoantigens immunology, Cell Division, Clone Cells, Female, Genes, T-Cell Receptor beta, Humans, Lymphocyte Count, Male, Middle Aged, Multiple Sclerosis cerebrospinal fluid, Multiple Sclerosis immunology, Pilot Projects, Receptor-CD3 Complex, Antigen, T-Cell immunology, Adoptive Transfer methods, CD4-Positive T-Lymphocytes immunology, Lymphocyte Activation, Multiple Sclerosis therapy, Myelin Basic Protein immunology, Receptors, Antigen, T-Cell, alpha-beta immunology
Abstract

Myelin-reactive T cells are considered to play an essential role in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. We have previously studied the effects of T cell vaccination (TCV), a procedure by which MS patients are immunized with attenuated autologous myelin basic protein (MBP)-reactive T cell clones. Because several myelin antigens are described as potential autoantigens for MS, T cell vaccines incorporating a broad panel of antimyelin reactivities may have therapeutic effects. Previous reports have shown an accumulation of activated T cells recognizing multiple myelin antigens in the cerebrospinal fluid (CSF) of MS patients. We conducted a pilot clinical trial of TCV with activated CD4+ T cells derived from CSF in five MS patients (four RR, one CP) to study safety, feasibility and immune effects of TCV. CSF lymphocytes were cultured in the presence of rIL-2 and depleted for CD8 cells. After 5-8 weeks CSF T cell lines (TCL) were almost pure TCR alpha beta+CD4+ cells of the Th1/Th0 type. The TCL showed reactivity to MBP, MOG and/or PLP as tested by Elispot and had a restricted clonality. Three immunizations with irradiated CSF vaccines (10 million cells) were administered with an interval of 2 months. The vaccinations were tolerated well and no toxicity or adverse effects were reported. The data from this small open-label study cannot be used to support efficacy. However, all patients remained clinically stable or had reduced EDSS with no relapses during or after the treatment. Proliferative responses against the CSF vaccine were observed in 3/5 patients. Anti-ergotypic responses were observed in all patients. Anti-MBP/PLP/MOG reactivities remained low or were reduced in all patients. Based on these encouraging results, we recently initiated a double-blind placebo-controlled trial with 60 MS patients to study the effects of TCV with CSF-derived vaccines in early RR MS patients.

Published
2003
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36. Longitudinal study of antimyelin T-cell reactivity in relapsing-remitting multiple sclerosis: association with clinical and MRI activity.

Author

Hellings N, Gelin G, Medaer R, Bruckers L, Palmers Y, Raus J, and Stinissen P

Subjects
Adult, Biomarkers, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunophenotyping, Intercellular Adhesion Molecule-1 blood, Interferon-gamma immunology, Interleukin-6 immunology, Longitudinal Studies, Male, Middle Aged, Myelin Basic Protein immunology, Myelin Basic Protein pharmacology, Myelin Proteins pharmacology, Myelin Proteolipid Protein immunology, Myelin Proteolipid Protein pharmacology, Myelin-Associated Glycoprotein immunology, Myelin-Associated Glycoprotein pharmacology, Myelin-Oligodendrocyte Glycoprotein, T-Lymphocytes cytology, T-Lymphocytes drug effects, Tumor Necrosis Factor-alpha immunology, Vascular Cell Adhesion Molecule-1 blood, Magnetic Resonance Imaging, Multiple Sclerosis, Relapsing-Remitting immunology, Multiple Sclerosis, Relapsing-Remitting pathology, Myelin Proteins immunology, T-Lymphocytes immunology
Abstract

In multiple sclerosis (MS), T-cells are considered to be critical in coordinating an immunopathological cascade that results in myelin damage. We investigated whether clinical disease activity or brain inflammatory activity as measured by magnetic resonance imaging (MRI) was associated with changes in autoreactive T-cell reactivities in MS patients. To this end, a longitudinal study was performed in which T-cell-related immune parameters and clinical parameters (including MRI) were monitored in seven relapsing-remitting (RR) MS patients and two healthy controls with bimonthly intervals over a period of 18 months. The serial evaluation of antimyelin (MBP, PLP, MOG) T-cell responses revealed highly dynamic shifts and fluctuations from one pattern to another in a patient-dependent manner. In some of the patients, changes in T-cell-related immune variables were found to concur with MRI activity and generally preceded clinical relapses. These alterations include: increased number of myelin-reactive IFN-gamma secreting T-cells, detection of clonally expanded myelin-reactive T-cells, elevated proinflammatory and decreased antiinflammatory cytokine production, upregulation of ICAM-1 membrane expression and highly increased serum levels of soluble VCAM-1. However, not all exacerbations and MRI changes were associated with changes in antimyelin reactivity. Some of the observed immune alterations were also detected in the healthy controls, indicating that additional regulatory mechanisms-which may be defective in MS-play a role in the downregulation of potentially pathological T-cell responses. In conclusion, this study provides further support for an important role of myelin-reactive T-cells in the pathogenesis of MS. In addition, the observed dynamic changes in the antimyelin T-cell reactivity pattern may be a major obstacle for the development of antigen-specific immunotherapies.

Published
2002
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37. Interferon-gamma-induced calcium influx in T lymphocytes of multiple sclerosis and rheumatoid arthritis patients: a complementary mechanism for T cell activation?

Author

Buntinx M, Ameloot M, Steels P, Janssen P, Medaer R, Geusens P, Raus J, and Stinissen P

Subjects
Adult, Calcium Signaling, Female, Humans, Intracellular Membranes metabolism, Lymphocyte Activation drug effects, Male, Middle Aged, Osmolar Concentration, Receptors, Interleukin-2 metabolism, Reference Values, T-Lymphocytes drug effects, Virus Diseases metabolism, Arthritis, Rheumatoid metabolism, Calcium metabolism, Interferon-gamma pharmacology, Multiple Sclerosis metabolism, T-Lymphocytes metabolism
Abstract

Autoreactive T lymphocytes are considered to play a crucial role in orchestrating a chronic inflammation in the central nervous system (CNS) of multiple sclerosis (MS) patients and in the joints of rheumatoid arthritis (RA) patients. However, it has been suggested that the majority of T cells in the immune infiltrate are nonspecifically recruited into the CNS and into the inflamed joint. In addition, several lines of evidence suggest an important role for interferon-gamma (IFN-gamma) in the pathogenesis of MS and RA. We have studied whether peripheral blood T cells from patients with autoimmune diseases are more susceptible to activation in the presence of IFN-gamma. The results indicate that IFN-gamma mediates a sustained elevated [Ca(2+)](i) in T cells of (active) MS and RA patients as compared to healthy controls and patients with common viral infections. No [Ca(2+)](i) increase was observed in Ca(2+)-free medium, excluding an effect of IFN-gamma on Ca(2+)-release from intracellular stores. Although the IFN-gamma-activated Ca(2+)-influx is insufficient to induce T cell proliferation in vitro, our data indicate a significantly augmented proliferation in response to suboptimal doses of PHA in the presence of IFN-gamma. This study suggests that the IFN-gamma-induced Ca(2+)-influx can act as a complementary mechanism in the activation of blood T lymphocytes from MS and RA patients.

Published
2002
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38. T-cell reactivity to multiple myelin antigens in multiple sclerosis patients and healthy controls.

Author

Hellings N, Barée M, Verhoeven C, D'hooghe MB, Medaer R, Bernard CC, Raus J, and Stinissen P

Subjects
Adult, Antigens blood, Enzyme-Linked Immunosorbent Assay, Female, Humans, Interferon-gamma blood, Interleukin-12 pharmacology, Interleukin-2 immunology, Interleukin-2 pharmacology, Interleukin-4 metabolism, Interleukin-4 pharmacology, Male, Middle Aged, Multiple Sclerosis blood, Multiple Sclerosis physiopathology, Myelin Basic Protein blood, Myelin Basic Protein immunology, Myelin Proteins blood, Myelin Proteolipid Protein blood, Myelin Proteolipid Protein immunology, Myelin-Associated Glycoprotein blood, Myelin-Associated Glycoprotein immunology, Myelin-Oligodendrocyte Glycoprotein, T-Lymphocytes, Helper-Inducer immunology, Antigens immunology, Multiple Sclerosis immunology, Myelin Proteins immunology, T-Lymphocytes immunology
Abstract

Myelin proteins, including myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) are candidate autoantigens in MS. It is not clear whether MS patients show a predominant reactivity to one or several myelin antigens. We evaluated the IFN-gamma production induced by MBP and MOG and selected MBP-, MOG- and PLP-peptides in MS patients and healthy controls using the IFN-gamma ELISPOT assay. Most MS patients and healthy controls showed a heterogeneous anti-myelin T-cell reactivity. Interestingly in MS patients a positive correlation was found between the anti-MOG and anti-MBP T-cell responses. No myelin peptide was preferentially recognized among the peptides tested (MBP 84-102, 143-168, MOG 1-22, 34-56, 64-86, 74-96, PLP 41-58, 184-199, 190-209). In addition the frequency of IL2R+ MBP reactive T-cells was significantly increased in blood of MS patients as compared with healthy subjects, indicating that MBP reactive T-cells exist in an in vivo activated state in MS patients. Most of the anti-MBP T-cells were of the Th1-type because reactivity was observed in IFN-gamma but not in IL-4 ELISPOT-assays. Using Th1 (IL-12) and Th2 (IL-4) promoting conditions we observed that the cytokine secretion pattern of anti-MBP T-cells still is susceptible to alteration. Our data further indicate that precursor frequency analysis of myelin reactive T-cells by proliferation-based assays may underestimate the true frequency of myelin specific T-cells significantly., (Copyright 2001 Wiley-Liss, Inc.)

Published
2001
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39. Myelin reactive T cells after T cell vaccination in multiple sclerosis: cytokine profile and depletion by additional immunizations.

Author

Hermans G, Medaer R, Raus J, and Stinissen P

Subjects
Clone Cells, Cytokines biosynthesis, Epitopes, Humans, Immunotherapy, Multiple Sclerosis blood, Multiple Sclerosis therapy, T-Lymphocytes metabolism, T-Lymphocytes physiology, T-Lymphocytes, Cytotoxic physiology, Time Factors, Multiple Sclerosis immunology, Myelin Basic Protein immunology, T-Lymphocytes immunology, Vaccination
Abstract

Pathogenic autoreactive T cells can be targeted by T cell vaccination (TCV), a procedure in which patients are immunized with autologous attenuated pathogenic T cells. We reported previously that TCV with myelin basic protein (MBP) reactive T cell clones in multiple sclerosis (MS) patients induced T cell immune responses, resulting in a clonal depletion of MBP reactive T cells in all patients. Five years after TCV, MBP reactive T cells were observed in five out of nine MS patients. These clones had a different clonal origin from those isolated before vaccination. We have studied the cytokine profile, cytotoxicity and epitope specificity of these reappearing clones. Our data indicate that the clones express similar effector functions as those isolated before TCV, suggesting that they also could play a pathogenic role in the disease. We demonstrated that these clones can be depleted by an additional sequence of immunizations. These findings may be relevant to other T cell targeted immunotherapies for MS and other autoimmune diseases.

Published
2000
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40. Myelin reactive T cells in the autoimmune pathogenesis of multiple sclerosis.

Author

Stinissen P, Medaer R, and Raus J

Subjects
Epitopes blood, Humans, Inflammation immunology, Lymphocyte Activation, Vaccination, Autoantibodies blood, Multiple Sclerosis immunology, Myelin Sheath immunology, T-Lymphocytes immunology
Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination. Although it is widely accepted that demyelination in MS results from an active inflammatory process, the cause of the inflammation is still not completely resolved. Findings in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and observations in human MS have led to the hypothesis that MS is an autoimmune disease mediated by autoreactive T cells with specificity for myelin antigens. The identity of the brain antigen(s) which is (are) the primary target(s) of the autoimmune process is not known, but current evidence indicates that myelin basic protein (MBP) is a likely candidate. In this paper we will overview some of the experimental evidence suggesting that MBP reactive T cells hold a central position in the pathogenesis of MS, and discuss some of the currently tested therapeutic strategies in MS which are directed towards the pathogenic MBP reactive T cells. Although there appears to be no direct correlation between anti-MBP T cell responses and clinical disease activity, some recent observations suggest that monitoring of anti-MBP T cell responses could be helpful to study immunological efficacy of experimental immunotherapies in MS.

Published
1998
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41. Risks of multiple sclerosis in relatives of patients in Flanders, Belgium.

Author

Carton H, Vlietinck R, Debruyne J, De Keyser J, D'Hooghe MB, Loos R, Medaer R, Truyen L, Yee IM, and Sadovnick AD

Subjects
Adult, Age Distribution, Aged, Belgium epidemiology, Canada epidemiology, Child, Confidence Intervals, Disease Susceptibility, Ethnicity, Female, Humans, Likelihood Functions, Male, Middle Aged, Multiple Sclerosis ethnology, Netherlands ethnology, Pedigree, Recurrence, Risk Assessment, Multiple Sclerosis genetics
Abstract

Objectives: To calculate age adjusted risks for multiple sclerosis in relatives of Flemish patients with multiple sclerosis., Methods: Lifetime risks were calculated using the maximum likelihood approach., Results: Vital information was obtained on 674 probands with multiple sclerosis in Flanders and a total of their 26225 first, second, and third degree relatives. Full medical information to allow documentation of multiple sclerosis status was available for 21351 (81.4%) relatives. The age adjusted risk for parents was 1.61 (SEM 0.35)%, for siblings 2.10 (SE 0.36)%, and for children 1.71 (SEM 0.70)%. For aunts and uncles, the risk was 0.66 (SEM 0.13)%., Conclusions: The risk for first degree relatives of patients with multiple sclerosis in Flanders is increased 10-fold to 12-fold; for second degree relatives, it is increased threefold. This information can be used for risk counselling in families and provides additional support for the role of more than one locus contributing to the susceptibility of multiple sclerosis.

Published
1997
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42. T cell vaccination: clinical application in autoimmune diseases.

Author

Zhang J, Stinissen P, Medaer R, and Raus J

Subjects
Humans, Multiple Sclerosis immunology, Multiple Sclerosis physiopathology, Myelin Basic Protein immunology, Myelin Basic Protein metabolism, Vaccines immunology, Vaccines isolation & purification, Autoimmune Diseases immunology, T-Lymphocytes immunology, Vaccination methods
Abstract

T cell responses to myelin basic protein (MBP) are implicated to play an important role in the pathogenesis of multiple sclerosis (MS). These MBP autoreactive T cells are found to undergo in vivo activation and clonal expansion in patients with MS. They accumulate in the brain compartment and may reside in the brain lesions of patients with MS. As MBP-reactive T cells potentially hold a central position in initiation and perpetuation of the brain inflammation, specific immune therapies designed to deplete them may improve the clinical course of the disease. We review here the recent application of T cell vaccination in patients with MS to deplete circulating MBP-reactive T cells. The results of our phase I clinical trial indicate that T cell vaccination with inactivated MBP autoreactive T cells induces specific regulatory T cell network of the host immune system to deplete circulating MBP-reactive T cells in a clonotype-specific fashion. The immunity induced by T cell vaccination is clonotype specific and long-lasting. Our longitudinal clinical evaluation further suggests a moderately lower rate of clinical exacerbation, disability score, and brain lesions (measured by magnetic resonance imaging) in vaccinated patients than in matched controls. Our study should encourage further investigation on the treatment efficacy of T cell vaccination and further improvement for its clinical administration in other human autoimmune diseases. This review discusses the immune regulation and therapeutic administration of T cell vaccination in human autoimmune diseases, exemplified by our recent T cell vaccination trial in MS.

Published
1996
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43. Vaccination with autoreactive T cell clones in multiple sclerosis: overview of immunological and clinical data.

Author

Stinissen P, Zhang J, Medaer R, Vandevyver C, and Raus J

Subjects
Amino Acid Sequence, Animals, Clone Cells immunology, Molecular Sequence Data, Autoimmunity immunology, Multiple Sclerosis immunology, Multiple Sclerosis prevention & control, T-Lymphocytes immunology, Vaccination
Abstract

Although the etiology and pathogenesis of Multiple Sclerosis (MS) remain elusive, accumulating evidence indicates that MS is a chronic inflammatory disease with an autoimmune component, mediated by autoreactive T lymphocytes specific for myelin antigens. The triggering T cell autoantigen has not been identified yet, but recent immunological studies in MS and parallel experiments in experimental allergic encephalomyelitis (EAE), the animal model of MS, have indicated that myelin basic protein (MBP) can be considered as one of the major candidate autoantigens in the pathogenesis of the disease. Based on these observations, several therapeutic strategies have been developed aimed at the specific elimination or inactivation of MBP reactive T cells in MS. One of these approaches involves the immunization of MS patients with autologous attenuated autoreactive T cells to induce an immune response specifically targeted at these autoreactive T cells. This method, termed T cell vaccination, has been shown to prevent and treat EAE. We have recently conducted a pilot trial of T cell vaccination in a limited group of MS patients to evaluate the immunological responses to the injected cells. The data obtained indicate that this type of vaccination induces an effective anti-clonotypic T cell response leading to a specific depletion of circulating MBP reactive T cells. Preliminary data on the clinical effects are promising, encouraging further clinical trials.

Published
1996
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44. Depletion of myelin-basic-protein autoreactive T cells by T-cell vaccination: pilot trial in multiple sclerosis.

Author

Medaer R, Stinissen P, Truyen L, Raus J, and Zhang J

Subjects
Adult, Brain pathology, Case-Control Studies, Female, Follow-Up Studies, Humans, Lymphocyte Depletion, Magnetic Resonance Imaging, Male, Multiple Sclerosis immunology, Multiple Sclerosis pathology, Pilot Projects, Recurrence, T-Lymphocytes radiation effects, Vaccines, Autoimmunity, Multiple Sclerosis therapy, Myelin Basic Protein immunology, T-Lymphocytes immunology, Vaccination
Abstract

In a pilot trial, eight patients with multiple sclerosis were matched to control patients and received T-cell vaccination with irradiated T cells reactive to myelin basic protein (MBP) to deplete circulating MBP-reactive T cells. In the 2 years before and after vaccination, exacerbations decreased in five vaccinated patients (numbers 1, 2, 6-8) with relapsing-remitting disease from sixteen to three, respectively, and from twelve to ten in their matched controls. Magnetic resonance imaging showed a mean 8.0% increase in brain lesion size in the vaccinated patients compared with a 39.5% increase in the controls. Lesions and/or relapses worsened in three cases after vaccination in association with reappearance of circulating MBP-reactive T cells.

Published
1995
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45. Increased frequency of gamma delta T cells in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. Reactivity, cytotoxicity, and T cell receptor V gene rearrangements.

Author

Stinissen P, Vandevyver C, Medaer R, Vandegaer L, Nies J, Tuyls L, Hafler DA, Raus J, and Zhang J

Subjects
Base Sequence, Cell Line, Clone Cells, Enterotoxins immunology, Flow Cytometry, Heat-Shock Proteins immunology, Humans, Lymphocyte Activation immunology, Molecular Sequence Data, Multiple Sclerosis blood, Multiple Sclerosis cerebrospinal fluid, Multiple Sclerosis genetics, Receptors, Antigen, T-Cell, gamma-delta genetics, Superantigens immunology, Gene Rearrangement, T-Lymphocyte genetics, Multiple Sclerosis immunology, Receptors, Antigen, T-Cell, gamma-delta metabolism, T-Lymphocyte Subsets immunology, T-Lymphocytes, Cytotoxic immunology
Abstract

Infiltrating gamma delta T cells are potentially involved in the central nervous system demyelination in multiple sclerosis (MS). To further study this hypothesis, we analyzed the frequency and functional properties of gamma delta T cells in peripheral blood (PB) and paired cerebrospinal fluid (CSF) of patients with MS and control subjects, including patients with other neurologic diseases (OND) and healthy individuals. The frequency analysis was performed under limiting dilution condition using rIL-2 and PHA. After PHA stimulation, a significantly increased frequency of gamma delta T cells was observed in PB (14.7 x 10(-4)) and in CSF (15.8 x 10(-4)) of MS patients as compared with 4.3 x 10(-4) in PB and 3.9 x 10(-4) detected in CSF of patients with OND. The frequency was represented equally in OND patients and normal individuals. Similarly, the IL-2-responsive gamma delta T cells occurred at a higher frequency in PB of control subjects (1.1 x 10(-4)) in OND patients and 1.5 x 10(-4) in normal individuals). Forty-three percent (13 of 30) of the gamma delta T cell clones isolated from PB and CSF of MS patients responded to heat shock protein (HSP70) but not HSP65, whereas only 2 of 30 control gamma delta T cell clones reacted to the HSP. The majority of the gamma delta T cell clones were able to induce non-MHC-restricted cytolysis of Daudi cells. All clones displayed a substantial reactivity to bacterial superantigens staphylococcal enterotoxin B and toxic shock syndrome toxin-1, irrespective of their gamma delta V gene usage. Furthermore, the gamma delta T cell clones expressed predominantly TCRDV2 and GV2 genes (26 of 35 clones), whereas the clones derived from CSF of MS patients expressed either DV1 or DV2 genes. The obtained gamma delta clones, in general, represented rather heterogeneous clonal origins, even though a predominant clonal origin was found in a set of 10 gamma delta clones derived from one patient with MS. The present study provides new evidence supporting a possible role of gamma delta T cells in the secondary inflammatory processes in MS.

Published
1995

46. Clonal expansion of myelin basic protein-reactive T cells in patients with multiple sclerosis: restricted T cell receptor V gene rearrangements and CDR3 sequence.

Author

Vandevyver C, Mertens N, van den Elsen P, Medaer R, Raus J, and Zhang J

Subjects
Amino Acid Sequence, Base Sequence, Cells, Cultured, Clone Cells, DNA, Complementary, Humans, Immunoglobulin Variable Region genetics, Molecular Sequence Data, Multiple Sclerosis metabolism, Sequence Analysis, T-Lymphocytes immunology, Multiple Sclerosis immunology, Myelin Basic Protein biosynthesis, Receptors, Antigen, T-Cell, alpha-beta genetics, T-Lymphocytes metabolism
Abstract

Myelin basic protein (MBP)-reactive T cells are thought to play an important role in the pathogenesis of multiple sclerosis (MS). In some patients with MS, these autoreactive T cells display a limited heterogeneity in their epitope recognition and T cell receptor (TCR) variable (V) gene usage. These individual-dependent properties of MBP-reactive T cells have led to the speculation that they may represent clonal expansion in vivo in some MS patients. In the present study, 51 MBP-reactive T cell clones derived from patients with MS and healthy individuals were examined for their epitope recognition and the TCR V alpha and V beta gene rearrangements. The V gene junctional region sequences of identified alpha and beta genes were further analyzed to probe their clonal origins, as the sequences are unique for individual clones. Our data showed that 26 clones derived from nine patients with MS shared a predominant reactivity to the immunodominant regions of MBP, 84-102, 110-129 and 143-168, and used various TCR V alpha and V beta rearrangements. The V gene usage of the clones was restricted to certain V alpha V beta combination(s) in a given MS patient, but varied among different patients. The sequence analysis revealed that the clones generated from a given patient shared a limited or a single junctional region sequence pattern(s), indicating their oligoclonal or monoclonal origin(s). In contrast, 25 MBP-reactive T cell clones derived from normal individuals exhibited unfocused epitope recognition and V gene usage. Thus, the limited heterogeneity of MBP-reactive T cells in their structural and functional characteristics reflects their clonal expansion in vivo in some patients with MS.

Published
1995
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47. Focal leptomeningeal MR enhancement along the chiasm as a presenting sign of multiple sclerosis.

Author

Demaerel P, Robberecht W, Casteels I, Wilms G, Medaer R, Carton H, and Baert AL

Subjects
Adult, Humans, Male, Magnetic Resonance Imaging, Meninges pathology, Multiple Sclerosis diagnosis, Optic Chiasm pathology
Abstract

We demonstrate focal leptomeningeal enhancement along the chiasm on MRI in a 28-year-old man presenting with blurred vision and bitemporal visual field defects. The diagnosis of clinically definite multiple sclerosis was confirmed by laboratory investigations and brain MR findings.

Published
1995
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48. MHC-restricted depletion of human myelin basic protein-reactive T cells by T cell vaccination.

Author

Zhang J, Medaer R, Stinissen P, Hafler D, and Raus J

Subjects
Adult, CD4 Antigens analysis, CD8 Antigens analysis, Cell Line, Epitopes immunology, Female, Humans, Lymphocyte Activation, Male, Middle Aged, Multiple Sclerosis immunology, Receptors, Antigen, T-Cell, alpha-beta immunology, Vaccination, Immunotherapy, Adoptive, Multiple Sclerosis therapy, Myelin Basic Protein immunology, T-Lymphocytes immunology
Abstract

Activated autoreactive T cells are potentially pathogenic and regulated by clonotypic networks. Experimental autoimmune diseases can be treated by inoculation with autoreactive T cells (T cell vaccination). In the present study, patients with multiple sclerosis were inoculated with irradiated myelin basic protein (MBP)-reactive T cells. T cell responses to the inoculates were induced to deplete circulating MBP-reactive T cells in the recipients. Regulatory T cell lines isolated from the recipients inhibited T cells used for vaccination. The cytotoxicity of the CD8+ T cell lines was restricted by major histocompatibility antigens. Thus, clonotypic interactions regulating autoreactive T cells in humans can be induced by T cell vaccination.

Published
1993
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49. Myelin basic protein-specific T lymphocytes in multiple sclerosis and controls: precursor frequency, fine specificity, and cytotoxicity.

Author

Jingwu Z, Medaer R, Hashim GA, Chin Y, van den Berg-Loonen E, and Raus JC

Subjects
Adult, Autoimmune Diseases blood, Autoimmune Diseases pathology, Cell Line, Cytotoxicity, Immunologic, Female, HLA Antigens analysis, Humans, Leukocyte Count, Male, Middle Aged, Multiple Sclerosis blood, Multiple Sclerosis pathology, Peptide Fragments immunology, T-Lymphocyte Subsets immunology, Autoimmune Diseases immunology, Multiple Sclerosis immunology, Myelin Basic Protein immunology, T-Lymphocytes, Cytotoxic immunology
Abstract

A panel of 90 myelin basic protein (MBP)-specific T-cell lines were derived from peripheral blood of eight patients with multiple sclerosis and four normal subjects. The precursor frequency of MBP-reactive T cells in peripheral blood mononuclear cells ranged from 10(-7) to 9 x 10(-7) (mean, 6.7 x 10(-7)) in the group of patients with multiple sclerosis and from 0.5 x 10(-7) to 9.8 x 10(-7) (mean, 5.6 x 10(-7)) in the control subjects. This difference between the two groups was not statistically significant (p greater than 0.1). These T-cell lines expressed exclusively CD3+CD4+CD8- phenotypes and were restricted predominantly by HLA-DR molecules. When tested with fragments and synthetic peptides of human MBP, these MBP-specific T-cell lines (45 lines for each group) displayed a limited heterogeneous pattern with a biased recognition to peptide 84-102 and the C-terminal peptide 149-171. The reactivity to the 84-102 region of MBP was associated with the HLA-DR2, DRw15 (DRw15,2) haplotype, whereas the recognition to peptide 149-171 did not correlate with a particular HLA-DR allele(s). Furthermore, the majority of T-cell lines (greater than 75%) were found to exhibit substantial cytotoxic activity against MBP-coated target cells, but showing no significant difference between these two groups. This MBP-dependent cytotoxicity was not associated with epitope specificities of the T-cell lines tested.

Published
1992
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50. Regulation of myelin basic protein-specific helper T cells in multiple sclerosis: generation of suppressor T cell lines.

Author

Zhang JW, Schreurs M, Medaer R, and Raus JC

Subjects
Antigens, Differentiation, T-Lymphocyte analysis, CD3 Complex, CD4-Positive T-Lymphocytes immunology, CD8 Antigens analysis, Cells, Cultured, Clone Cells, Cyclosporine pharmacology, Cytotoxicity, Immunologic, HLA-DR Antigens analysis, Humans, In Vitro Techniques, Lymphocyte Activation, Lymphokines physiology, Receptors, Antigen, T-Cell analysis, Multiple Sclerosis immunology, Myelin Basic Protein immunology, T-Lymphocyte Subsets immunology, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Regulatory immunology
Abstract

Suppressor T cell (Ts) lines specific for myelin basic protein (MBP)-reactive helper T cell (Th) clones were generated from two patients with multiple sclerosis (MS) following a primary culture of peripheral blood mononuclear cells (PBMC) with MBP and cyclosporine A (CsA). These suppressor T cell lines were maintained in culture by alternate stimulation with MBP and antigen-presenting cells (APC). The Ts lines expressed preferentially the CD4 phenotype (5/6 Ts lines tested) and exhibited potent antigen-specific suppressor activity on the proliferation of MBP-specific Th clones and not on the T cell lines with other antigen specificity. For some Ts lines, a Ts-to-Th ratio of 1 was sufficient to inhibit the proliferation of MBP-specific T cells by 90%. The suppressor T cells obtained were weakly responsive to MBP and required the presence of the autologous PBMC for proliferation. Furthermore, proliferation of these suppressor T cell lines was restricted by HLA-DR molecules (for CD4+ Ts lines) and HLA class I (for a CD8+ Ts line). The suppressor T cell lines generated and the techniques described in this study may be helpful in our understanding of the events involved in the immune regulation in MS and other autoimmune diseases.

Published
1992
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