Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients.
The anti-α4 monoclonal antibody natalizumab inhibits lymphocyte extravasation into the central nervous system and increases peripheral T and B lymphocytes in multiple sclerosis patients. To investigate whether the lymphocyte accumulation was due to a higher lymphocyte production, an altered homeostasis, or a differential transmigration of lymphocyte subsets through endothelia, T-cell receptor excision circles and kappa-deleting recombination excision circles were quantified before and after treatment, T-cell receptor repertoire was analyzed by spectratyping, and T- and B-lymphocyte subset migration was studied using transwell coated with vascular and lymphatic endothelial cells. We found that the number of newly produced T and B lymphocytes is increased because of a high release and of a low propensity of naïve subsets to migrate across endothelial cells. In some patients this resulted in an enlargement of T-cell heterogeneity. Because new lymphocyte production ensures the integrity of immune surveillance, its quantification could be used to monitor natalizumab therapy safety.
Biotechnology Laboratory, Diagnostics Department, Spedali Civili di Brescia, P.le Spedali Civili 1, 25123 Brescia, Italy. zanotti.cinzia@gmail.com
Cinzia
C
Zanotti
Marco
M
Chiarini
Federico
F
Serana
Alessandra
A
Sottini
Emirena
E
Garrafa
Fabio
F
Torri
Luigi
L
Caimi
Sarah
S
Rasia
Ruggero
R
Capra
Luisa
L
Imberti
D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002464:Cell Migration Inhibition / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002648:Child; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D000069442:Natalizumab; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000276:immunology*
D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab; D020033:Protein Isoforms; D011948:Receptors, Antigen, T-Cell