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Brain Behav Immun. 2015 Nov;50:78-86. doi: 10.1016/j.bbi.2015.06.019. Epub 2015 Jun 27.

Dysregulation of sphingosine 1 phosphate receptor-1 (S1P1) signaling and regulatory lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound.

Author information

  • 1Headache 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.
  • 2Pharmacology and Oncology Unit, Department of Health Sciences, University of Florence, Italy.
  • 3Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence 50134, Italy; Regenerative Medicine Unit of Azienda Ospedaliera Careggi, Italy.
  • 4Department NEUROFARBA, Section Neurosciences, University of Florence, Italy.
  • 5General Laboratory Unit (Microscopy and Clinical Cytometry Unit), Careggi University Hospital, Italy.
  • 6Headache 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.

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.

KEYWORDS:

EAE; Fingolimod withdrawal; MS rebound; Treg

PMID:
26130058
DOI:
10.1016/j.bbi.2015.06.019
[PubMed - indexed for MEDLINE]
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