title: Dysregulation of sphingosine 1 phosphate receptor-1 (S1P1) signaling and regulatory lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound.
abstract: Fingolimod affords protection from MS by sequestering lymphocytes in secondary lymphoid organs via down regulation of their sphingosine 1 phosphate receptor (S1P1). Unexpectedly, accumulating evidence indicates that patients who discontinue fingolimod treatment may be at risk of rehearsal of magnetic resonance (MR) and clinical disease activity, sometimes featuring dramatic rebound. We therefore developed in vivo and in vitro models of post-fingolimod MS rebound to unravel its cellular and molecular mechanisms. The impact of fingolimod withdrawal on T regulatory lymphocytes was also investigated by means of cytofluorimetric analysis and antigen-specific lymphocyte proliferation assays. We show that mice with relapsing-remitting experimental autoimmune encephalomyelitis (EAE) undergo extremely severe, chronic disease rebound upon discontinuation of fingolimod. Remarkably, rebound is preceded by a burst of S1P1 overexpression in lymph node-entrapped lymphocytes that correlates with subsequent massive lymphocyte egress and widespread CNS immune infiltration. Also, consistent with the ability of S1P1 to counteract polarization and function of T regulatory lymphocytes their number and suppression of effector T cells is reduced by fingolimod suspension. Data disclose the first pathogenic mechanisms of post-fingolimod rebound that may be targeted for therapeutic intervention.
authors.affiliation: Headache Center and Clinical Pharmacology Unit, Department of Health Sciences, Careggi University Hospital, Italy; Pharmacology and Oncology Unit, Department of Health Sciences, University of Florence, Italy. Electronic address: leonardo.cavone@unifi.it.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Cavone
authors.affiliation: Pharmacology and Oncology Unit, Department of Health Sciences, University of Florence, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Felici
authors.affiliation: Pharmacology and Oncology Unit, Department of Health Sciences, University of Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lapucci
authors.affiliation: Pharmacology and Oncology Unit, Department of Health Sciences, University of Florence, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Buonvicino
authors.affiliation: Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence 50134, Italy; Regenerative Medicine Unit of Azienda Ospedaliera Careggi, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pratesi
authors.affiliation: Pharmacology and Oncology Unit, Department of Health Sciences, University of Florence, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Muzzi
authors.affiliation: Department NEUROFARBA, Section Neurosciences, University of Florence, Italy.
authors.forename: Bahia
authors.initials: B
authors.lastname: Hakiki
authors.affiliation: Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence 50134, Italy; Regenerative Medicine Unit of Azienda Ospedaliera Careggi, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Maggi
authors.affiliation: General Laboratory Unit (Microscopy and Clinical Cytometry Unit), Careggi University Hospital, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Peruzzi
authors.affiliation: General Laboratory Unit (Microscopy and Clinical Cytometry Unit), Careggi University Hospital, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Caporale
authors.affiliation: Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence 50134, Italy; Regenerative Medicine Unit of Azienda Ospedaliera Careggi, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Annunziato
authors.affiliation: Department NEUROFARBA, Section Neurosciences, University of Florence, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Amato
authors.affiliation: Headache Center and Clinical Pharmacology Unit, Department of Health Sciences, Careggi University Hospital, Italy; Pharmacology and Oncology Unit, Department of Health Sciences, University of Florence, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarugi
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage* / Q000009:adverse effects*; D007165:Immunosuppression Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride
keywords: EAE; Fingolimod withdrawal; MS rebound; Treg