title: Identification of anti-inflammatory drugs according to their capacity to suppress type-1 and type-2 T cell profiles.
abstract: BACKGROUND
  Down-regulation or modulation of T cell activity by immunosuppressive drugs is an effective treatment in diseases where exaggerated T cell responses play a role. A primary effect of the anti-inflammatory drugs (AIDs) is inhibition of the synthesis of growth factors, such as IL-2, thereby down-regulating T cell proliferation. However, it is still largely unknown to what extent these AIDs are able to down-regulate specifically type-1 or type-2 T cell cytokine production, and whether they can down-modulate chemokine receptor expression, thereby preventing migration of T cells to the site of inflammation.
  
  
  OBJECTIVE
  We investigated the suppressive effect of dermatologically used AID (cyclosporin A (CsA), lactoferrin (LF), 1 alpha, 25-dihydroxyvitamin D(3) (VD(3)), hydrocortisone (HC), di-methyl-fumarate (DMF), diclofenac (DF)) on both type-1 and type-2 T cells. Since allergic contact dermatitis is a skin disorder in which an exaggerated T cell response of both types of T cell subsets can be observed, we used this disorder as a model to study the capacity of AID to suppress type-1 or type-2 T cell responses.
  
  
  METHODS
  Peripheral blood mononuclear cells of nickel allergic patients were cultured in the presence of allergen and increasing concentrations of AID. Proliferation was determined by measuring (3)H thymidine incorporation; chemokine receptor (CCR10, CCR4, CXCR3) expression was studied by flow cytometric analysis and IFN-gamma or IL-5 cytokine production was measured by ELISA.
  
  
  RESULTS
  Three major patterns can be distinguished regarding the effect of AID on T cell responses. The first group, including CsA and LF, inhibited non-selectively T cell proliferation, chemokine receptor expression and cytokine production, with CsA as the most potent drug tested. A second group of AID, which included VD(3), HC and DMF, suppressed mainly type-1 T cell responses, as revealed by strong interference with IFN-gamma production and CXCR3 expression, and limited effects on either or both IL-5 and CCR4 expression. The third pattern was displayed by DF, which down-regulated IL-5 production and CCR4 expression, whereas IFN-gamma and CXCR3 were unaltered.
  
  
  CONCLUSIONS
  Using a contact allergy model, we have demonstrated that various AIDs show distinct pharmacological profiles in that either type-1 or type-2 or both T cell responses are suppressed. These results should contribute to a more rational selection of AID in treating inflammatory skin diseases mediated by either or both of these T cell subsets.
authors.affiliation: Departments of Dermatology and Pathology, VU University Medical Center Amsterdam, 1007 MB Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Moed
authors.forename: T J
authors.initials: TJ
authors.lastname: Stoof
authors.forename: D M
authors.initials: DM
authors.lastname: Boorsma
authors.forename: B M E
authors.initials: BM
authors.lastname: von Blomberg
authors.forename: S
authors.initials: S
authors.lastname: Gibbs
authors.forename: D P
authors.initials: DP
authors.lastname: Bruynzeel
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: T
authors.initials: T
authors.lastname: Rustemeyer
mesh_terms: D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy* / Q000276:immunology*; D004008:Diclofenac / Q000627:therapeutic use; D000069462:Dimethyl Fumarate; D005434:Flow Cytometry; D005650:Fumarates / Q000627:therapeutic use; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D018664:Interleukin-12 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology; D007781:Lactoferrin / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D009532:Nickel / Q000009:adverse effects; D010328:Patch Tests; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D005650:Fumarates; D015851:Interleukin-7; D004008:Diclofenac; D018664:Interleukin-12; D002762:Cholecalciferol; D015847:Interleukin-4; D009532:Nickel; D016572:Cyclosporine; D007781:Lactoferrin; D000069462:Dimethyl Fumarate; D006854:Hydrocortisone