title: Natalizumab Affects T-Cell Phenotype in Multiple Sclerosis: Implications for JCV Reactivation.
abstract: The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects.
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.|Inserm, U1016, Institut Cochin, Paris, France.
authors.forename: Marco
authors.initials: M
authors.lastname: Iannetta
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.
authors.forename: Maria Antonella
authors.initials: MA
authors.lastname: Zingaropoli
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.|Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bellizzi
authors.affiliation: Department of Medical and Surgical Sciences and Biotechnology, Neurovascular Diagnosis Unit, Section of Neurology, Sapienza University, Rome, Italy.|Department of Neurology and Psychiatry, Multiple Sclerosis Center, Sapienza University, Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Morreale
authors.affiliation: Department of Neurology and Psychiatry, Multiple Sclerosis Center, Sapienza University, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Pontecorvo
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: D'Abramo
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Oliva
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Anzivino
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lo Menzo
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: D'Agostino
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.
authors.forename: Claudio Maria
authors.initials: CM
authors.lastname: Mastroianni
authors.affiliation: Department of Neurology and Psychiatry, Multiple Sclerosis Center, Sapienza University, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Millefiorini
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pietropaolo
authors.affiliation: Department of Neurology and Psychiatry, Multiple Sclerosis Center, Sapienza University, Rome, Italy.
authors.forename: Ada
authors.initials: A
authors.lastname: Francia
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Vullo
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Ciardi
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D004279:DNA, Viral / Q000032:analysis / Q000097:blood; D005260:Female; D006801:Humans; D007577:JC Virus / Q000187:drug effects* / Q000502:physiology; D007968:Leukoencephalopathy, Progressive Multifocal / Q000150:complications / Q000276:immunology / Q000821:virology; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000150:complications / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D000069442:Natalizumab / Q000009:adverse effects / Q000494:pharmacology*; D010641:Phenotype; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016896:Treatment Outcome; D014775:Virus Activation / Q000187:drug effects*
chemical_list: D000914:Antibodies, Viral; D004279:DNA, Viral; D000069442:Natalizumab