Long-term decrease in VLA-4 expression and functional impairment of dendritic cells during natalizumab therapy in patients with multiple sclerosis

Myeloid and plasmacytoid dendritic cells (mDCs, pDCs) are central to the initiation and the regulation of immune processes in multiple sclerosis (MS). Natalizumab (NTZ) is a humanized monoclonal antibody approved for the treatment of MS that acts by blocking expression of VLA-4 integrins on the surf...

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Bibliographic Details
Published in:PloS one 2012-04, Vol.7 (4), p.e34103
Main Authors: de Andrés, Clara, Teijeiro, Roseta, Alonso, Bárbara, Sánchez-Madrid, Francisco, Martínez, M Luisa, Guzmán de Villoria, Juan, Fernández-Cruz, Eduardo, Sánchez-Ramón, Silvia
Format: Article
Language:English
Subjects:
Adult
Antibodies, Monoclonal, Humanized - therapeutic use
Antigens
B cells
Biology
Bone marrow
Care and treatment
Case-Control Studies
Cell adhesion & migration
Cell migration
Cells, Cultured
Central nervous system
Chemokines
Dendritic cells
Dendritic Cells - immunology
Dendritic Cells - metabolism
Endothelium
Evidence-based medicine
Female
Follow-Up Studies
Herpes viruses
Humans
Immunology
Immunotherapy
Impairment
Integrin alpha4beta1 - metabolism
Integrins
Leukocytes
Leukocytes (mononuclear)
Leukocytes, Mononuclear - drug effects
Leukocytes, Mononuclear - immunology
Leukocytes, Mononuclear - metabolism
Ligands
Lymphocyte Activation
Lymphocyte Function-Associated Antigen-1 - metabolism
Lymphocytes
Lymphocytes T
Magnetic Resonance Imaging
Male
Medicine
Middle Aged
Monoclonal antibodies
Multiple sclerosis
Multiple Sclerosis - drug therapy
Multiple Sclerosis - metabolism
Multiple Sclerosis, Relapsing-Remitting - drug therapy
Multiple Sclerosis, Relapsing-Remitting - metabolism
Natalizumab
Neurology
NMR
Nuclear magnetic resonance
Pathogenesis
Patients
Peripheral blood mononuclear cells
Prospective Studies
T cell receptors
T cells
T-Lymphocytes - cytology
T-Lymphocytes - metabolism
Treatment Outcome
VLA-4 antigen
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Summary:Myeloid and plasmacytoid dendritic cells (mDCs, pDCs) are central to the initiation and the regulation of immune processes in multiple sclerosis (MS). Natalizumab (NTZ) is a humanized monoclonal antibody approved for the treatment of MS that acts by blocking expression of VLA-4 integrins on the surface of leukocytes. We determined the proportions of circulating DC subsets and analyzed expression of VLA-4 expression in 6 relapsing-remitting MS patients treated with NTZ for 1 year. VLA-4 expression levels on pDCs and mDCs decreased significantly during follow-up. In vitro coculture of peripheral blood mononuclear cells and pDCs, with different doses of NTZ in healthy controls (HC) and MS patients showed dose-dependent down-regulation of VLA-4 expression levels in both MS patients and HC, and reduced functional ability to stimulate antigen-specific T-lymphocyte responses. The biological impact of NTZ may in part be attributable to inhibition of transmigration of circulating DCs into the central nervous system, but also to functional impairment of interactions between T cells and DC.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0034103