title: Preliminary study: treatment with intramuscular interferon beta-1a results in increased levels of IL-12Rβ2+ and decreased levels of IL23R+ CD4+ T - Lymphocytes in multiple sclerosis.
abstract: BACKGROUND
  There are a lack of biomarkers which can be used to predict clinical outcomes for multiple sclerosis (MS) patients receiving interferon beta (IFN-β). Thus the objective of this study was to characterize changes in CD4+ T-lymphocyte expression in an unbiased manner following initiation of intramuscular (IM) IFN-β-1a treatment, and then to verify those findings using marker-specific assays.
  
  
  METHODS
  Peripheral blood specimens were collected from twenty MS patients before and after treatment with intramuscular (IM) IFN-β-1a and were used for isolation of mononuclear cells (PBMCs). mRNA expression patterns of negatively-selected CD4+ T-cells from the PBMCs were analyzed using microarray gene expression technology. IL-12 and IL-23 receptor levels on PBMC-derived CD4+ T-cells were analyzed by flow cytometry. The phosphorylation status of Stat4 was measured by performing densitometry on western blots.
  
  
  RESULTS
  Microarray analyses demonstrated that mRNA expression of the IL-12Rβ2 gene was uniformly up-regulated in response to IFN-β-1a treatment and was associated with an increased number of IL-12Rβ2+ CD4+ T-cells by flow cytometry in 4 of 6 patients. This finding was substantiated by demonstrating that Stat4 phosphorylation, a transcription factor for IL-12, was increased after treatment. Conversely, the number of IL-23R+ CD4+ T-cells was decreased following treatment.
  
  
  CONCLUSIONS
  The IL-12 receptor shares a common subunit, the IL-12Rβ2, with the IL-23 receptor. Both of these receptors have a probable role in regulating IL-17 and TH-17 cells, important mediators of inflammation in multiple sclerosis (MS). Thus, the changes in the numbers of CD4+ T-cells expressing these receptors in response to IFN-β-1a treatment may point to an important mechanism of action for this drug, but further large scale studies are needed to confirm these preliminary observations.
authors.affiliation: Center for Genomic Sciences, Allegheny-Singer Research Institute, Pittsburgh, PA 15212, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kress-Bennett
authors.forename: Garth D
authors.initials: GD
authors.lastname: Ehrlich
authors.forename: Ashley
authors.initials: A
authors.lastname: Bruno
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Post
authors.forename: Fen Z
authors.initials: FZ
authors.lastname: Hu
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Scott
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000328:Adult; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007273:Injections, Intramuscular; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000008:administration & dosage*; D053712:Interleukin-12 Receptor beta 2 Subunit / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology*; D018123:Receptors, Interleukin / Q000187:drug effects* / Q000276:immunology; D053707:Receptors, Interleukin-12 / Q000187:drug effects* / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C515500:IL23R protein, human; D053712:Interleukin-12 Receptor beta 2 Subunit; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D016899:Interferon-beta; D000068556:Interferon beta-1a