title: Dopaminergic modulation of CD4+CD25(high) regulatory T lymphocytes in multiple sclerosis patients during interferon-β therapy.
abstract: OBJECTIVE
  We investigated dopaminergic inhibition of CD4+CD25(high) regulatory T lymphocytes (Treg) in relapsing-remitting multiple sclerosis (MS) patients treated with interferon (IFN)-β.
  
  
  METHODS
  MS patients were prospectively studied at baseline and during 1 year of IFN-β, and compared with healthy controls (HCs). Treg were separated by immunomagnetic sorting and the effect of dopamine (DA) on Treg was assessed in coculture experiments with homologous effector T lymphocytes (Teff). Tyrosine hydroxylase (TH), dopaminergic receptors (DR) D3 and D5, and forkhead box protein P3 (FoxP3) mRNA were assessed by real-time PCR. Circulating CD4+ T cell subsets were assessed by flow cytometry.
  
  
  RESULTS
  In coculture experiments, Treg inhibition of Teff proliferation was reduced by DA in HCs and completely abolished in MS patients at baseline. However, in patients after 12 months of IFN-β, Teff proliferation was impaired and DA had no more effect on Treg. In comparison to cells from HCs, Treg from MS patients at baseline had increased mRNA for DR D5 and TH (but not for DR D3). During treatment with IFN-β, both DR D5 and TH mRNA decreased down to values lower than those of cells from HCs. In comparison to HCs, MS patients had a higher frequency of circulating Treg, both at baseline and after IFN-β, while FoxP3 mRNA levels in Treg were similar in patients and HCs and did not show major changes during IFN-β.
  
  
  CONCLUSIONS
  Dopaminergic inhibition of Treg in MS patients is suppressed during IFN-β treatment. Treg play a key role in the suppression of autoimmunity, thus the effect may have a therapeutic repercussion.
authors.affiliation: Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy. marco.cosentino@uninsubria.it
authors.forename: Marco
authors.initials: M
authors.lastname: Cosentino
authors.forename: Mauro
authors.initials: M
authors.lastname: Zaffaroni
authors.forename: Maria
authors.initials: M
authors.lastname: Trojano
authors.forename: Maurizio
authors.initials: M
authors.lastname: Giorelli
authors.forename: Carmela
authors.initials: C
authors.lastname: Pica
authors.forename: Emanuela
authors.initials: E
authors.lastname: Rasini
authors.forename: Raffaella
authors.initials: R
authors.lastname: Bombelli
authors.forename: Marco
authors.initials: M
authors.lastname: Ferrari
authors.forename: Angelo
authors.initials: A
authors.lastname: Ghezzi
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Paolo
authors.initials: P
authors.lastname: Livrea
authors.forename: Sergio
authors.initials: S
authors.lastname: Lecchini
authors.forename: Franca
authors.initials: F
authors.lastname: Marino
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D015704:CD4 Antigens / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004185:Disability Evaluation; D004298:Dopamine / Q000494:pharmacology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D016899:Interferon-beta / Q000627:therapeutic use; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000473:pathology*; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D050637:Receptors, Dopamine D3 / Q000235:genetics / Q000378:metabolism; D050641:Receptors, Dopamine D5 / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007155:Immunologic Factors; D053645:Interleukin-2 Receptor alpha Subunit; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D050637:Receptors, Dopamine D3; D050641:Receptors, Dopamine D5; D016899:Interferon-beta; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine