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*Department of Immunology, Dipartimento di Scienze Precliniche LITA Vialba, University of Milano, Milan, Italy;
Laboratory of Molecular Medicine and Biotechnology and
Multiple Sclerosis Unit, Don C. Gnocchi Organizzazione Non Lucrativa di Utilità Sociale Foundation Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; and
Chair of Immunology, Department of Biomedical Sciences and Technologies, University of Milano, Milan, Italy
T lymphocytes costimulatory molecules, including CD80, CD86, CD28, CTLA4, PD-1, PD-L1, and B7-H3, are associated with the preferential production of pro- or anti-inflammatory cytokines. We analyzed the expression of these molecules and myelin basic protein (MBP)-specific IL-10 and IFN-
production in patients with multiple sclerosis (MS) with relapsing-remitting acute (AMS, n = 40) or stable (SMS, n = 38). Twenty-two patients successfully undergoing therapy with glatimer acetate (n = 12) or IFNβ (n = 10) were also analyzed. MBP-specific and PD-1-expressing T lymphocytes, PD-L1-expressing CD19+ cells, and PD-L1+/IL-10+/CD14+ and CD19+ cells were significantly augmented in SMS patients. Additionally, MBP-specific and annexin V-expressing CD4+ and CD8+ (apoptotic) T lymphocytes were augmented and pAkt-positive (proliferating) cells were decreased in SMS compared with AMS patients. PD-1 ligation resulted in the increase of pAkt+ lymphocytes in AMS patients alone. B7-H3 expression and IFN- production were comparable in all individuals but the PD-L1+/IL-10+ over B7-H3+/IFN-+ ratio was significantly lower in AMS compared with SMS patients. Finally, PD-L1 expression on immune cells was reduced in treated patients, suggesting that therapy-induced disease remission is not associated with the modulation of the expression of this molecule. The PD-1/PD-L1 pathway plays an important role in modulating immune functions in MS patients; monitoring and targeting these proteins could offer diagnostic and therapeutic advantages.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by grants from the Istituto Superiore di Sanita’ Programma Nazionale di Ricerca sull’ AIDS, the European Microbicides Project and AIDS Vaccine Integrated Project, the Next Generation HIV-1 Immunogens Inducing Broadly Reactive Neutralising Antibodies Project, the Japan Health Science Foundation, 2008 Ricerca Finalizzata (Italian Ministry of Health), 2008 Ricerca Corrente (Italian Ministry of Health), Progetto Fondo per gli Investimenti della Ricerca di Base: Rete Italiana Chimica Farmaceutica Ricerca e Sviluppo del Farmaco (Grant RBPR05NWWC), and Fondazione Cassa di Risparmio delle Provincie Lombarde.
2 D.T. and M.S. contributed equally to this project.
3 Address correspondence and reprint requests to Prof. Mario Clerici, Chair of Immunology, University of Milano, Department of Biomedical Sciences and Technologies, Via F.lli Cervi 93, 20090 Segrate-Milano, Italy. E-mail address: mario.clerici{at}unimi.it
4 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; AMS, acute MS; COPA, Copaxone; EDSS, Expanded Disability Status Scale; MBP, myelin basic protein; MFI, mean fluorescence intensity; MOG, myelin oligodendrocyte glycoprotein; MRI, magnetic resonance imaging; MS, multiple sclerosis; RR, relapsing remitting; SMS, stable MS.
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