title: Fingolimod does not impair T-cell release from the thymus and beneficially affects Treg function in patients with multiple sclerosis.
abstract: BACKGROUND
  In multiple sclerosis (MS), disturbed T-cell homeostasis affects both conventional CD4(+) T cells (Tcon) and regulatory T cells (Treg). Functionally, this is linked to a loss of Treg-suppressive properties. Concerns exist as to whether fingolimod might further aggravate Treg dysfunction by inhibiting thymic egress and, thus, promoting premature immunosenescence.
  
  
  OBJECTIVE
  The objective of this paper is to investigate whether fingolimod, by sequestration of developing cells in the thymus, might deteriorate numeric and/or functional disequilibrium of T-cell subtypes.
  
  
  METHODS
  We assessed numbers and phenotypes of blood Tcon and Treg in 74 MS patients treated with fingolimod and in 37 healthy donors. Treg and Tcon were also analyzed for immunoreactivity, suppressive function, sphingosine-1-phosphate-triggered (S1P) trafficking, and S1P-receptor expression. This was complemented by assessing surrogate markers of thymic T-cell development, including frequencies of cells expressing T-cell receptors (TCR) of dual specificity, and TCR diversity in Treg.
  
  
  RESULTS
  Fingolimod did not negatively affect naive T-cell phenotypes or markers of thymic T-cell development. By reducing CCR7-expressing Tcon, fingolimod increased relative proportions of Treg. As a result of this shift, fewer proliferative CCR7(-) Tcon became enriched and Treg-dysfunction was indirectly reversed.
  
  
  CONCLUSIONS
  These observations argue against harmful interference of fingolimod with thymic T-cell output that, particularly in pediatric MS, might possibly counteract its beneficial effects.
authors.affiliation: Department of Neurology, University Hospital of Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Haas
authors.affiliation: Department of Neurology, University Hospital of Heidelberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schwarz
authors.affiliation: Department of Neurology, University Hospital of Heidelberg, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Korporal-Kunke
authors.affiliation: Department of Neurology, University Hospital of Heidelberg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Jarius
authors.affiliation: Department of Neurology - Inflammatory Disorders of the Nervous System and Neurooncology, University of Münster, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.affiliation: Department of Neurology, University of Düsseldorf, Germany.
authors.forename: Bernd C
authors.initials: BC
authors.lastname: Kieseier
authors.affiliation: Department of Neurology, University Hospital of Heidelberg, Germany brigitte.wildemann@med.uni-heidelberg.de.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wildemann
mesh_terms: D000328:Adult; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000188:drug therapy*; D054400:Receptors, CCR7 / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D013950:Thymus Gland / Q000187:drug effects*; D055815:Young Adult
chemical_list: C515370:CCR7 protein, human; D007166:Immunosuppressive Agents; D054400:Receptors, CCR7; D000068876:Fingolimod Hydrochloride
keywords: Neuroimmunology; T-cell homeostasis; fingolimod; multiple sclerosis; regulatory T cells