title: Modulation of the central memory and Tr1-like regulatory T cells in multiple sclerosis patients responsive to interferon-beta therapy.
abstract: BACKGROUND
  Interferon-beta is used to reduce disease activity in multiple sclerosis, but its action is incompletely understood, individual treatment response varies among patients, and biological markers predicting clinical benefits have yet to be identified. Since it is known that multiple sclerosis patients have a deficit of the regulatory T-cell subsets, we investigated whether interferon-beta therapy induced modifications of the two main categories of regulatory T cells (Tregs), natural and IL-10-secreting inducible Tr1 subset, in patients who are biologically responsive to the therapy.
  
  
  METHODS
  T-cell phenotype was determined by flow cytometry, while real-time PCR was used to evaluate interferon-beta bioactivity through MxA determination, and to measure the RNA for IL-10 and CD46 molecule in peripheral blood mononuclear cells stimulated with anti-CD46 and anti-CD3 monoclonal antibodies, which are known to expand a Tr1-like population.
  
  
  RESULTS
  Interferon-beta induced a redistribution of natural Treg subsets with a shift of naive Tregs towards the 'central memory-like' Treg population that expresses the CCR7 molecule required for the in vivo suppressive activity. Furthermore, in a subgroup of treated patients, the CD46/CD3 co-stimulation, probably through the Tr1-like subset modulation, increased the production of RNA for IL-10 and CD46. The same group showed a lower median EDSS score after two years of therapy.
  
  
  CONCLUSIONS
  The selective increase of 'central memory-like' subset and the involvement of the Tr1-like population may be two of the mechanisms by which interferon-beta achieves its beneficial effects. The quantification of RNA for IL-10 and CD46 could be used to identify patients with a different response to interferon-beta therapy.
authors.affiliation: Diagnostics Department, Spedali Civili of Brescia, Brescia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Chiarini
authors.forename: F
authors.initials: F
authors.lastname: Serana
authors.forename: C
authors.initials: C
authors.lastname: Zanotti
authors.forename: R
authors.initials: R
authors.lastname: Capra
authors.forename: S
authors.initials: S
authors.lastname: Rasia
authors.forename: M
authors.initials: M
authors.lastname: Rottoli
authors.forename: M
authors.initials: M
authors.lastname: Rovaris
authors.forename: D
authors.initials: D
authors.lastname: Caputo
authors.forename: G
authors.initials: G
authors.lastname: Cavaletti
authors.forename: M
authors.initials: M
authors.lastname: Frigo
authors.forename: B
authors.initials: B
authors.lastname: Frigeni
authors.forename: R
authors.initials: R
authors.lastname: Clerici
authors.forename: M
authors.initials: M
authors.lastname: Rezzonico
authors.forename: L
authors.initials: L
authors.lastname: Caimi
authors.forename: L
authors.initials: L
authors.lastname: Imberti
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D017252:CD3 Complex / Q000097:blood; D016022:Case-Control Studies; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007156:Immunologic Memory / Q000187:drug effects*; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics; D007558:Italy; D051916:Membrane Cofactor Protein / Q000235:genetics; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D012333:RNA, Messenger / Q000097:blood; D060888:Real-Time Polymerase Chain Reaction; D054400:Receptors, CCR7 / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; C515370:CCR7 protein, human; D017252:CD3 Complex; C497857:CD46 protein, human; C508609:IL10 protein, human; D007155:Immunologic Factors; D051916:Membrane Cofactor Protein; D012333:RNA, Messenger; D054400:Receptors, CCR7; D016753:Interleukin-10; D016899:Interferon-beta; D000068556:Interferon beta-1a