title: Abatacept (CTLA-4Ig) treatment reduces T cell apoptosis and regulatory T cell suppression in patients with rheumatoid arthritis.
abstract: OBJECTIVE
  Abatacept (CTLA-4Ig) blocks CD28-mediated T cell activation by binding to the costimulatory B7 ligands CD80/CD86 on antigen presenting cells. Costimulatory molecules, however, can also be expressed on T cells upon activation. Therefore, the aim of our study was to investigate direct effects of CTLA-4Ig on distinct T cell subsets in RA patients.
  
  
  METHODS
  Phenotypic and functional analyses of CD4(+) T cells, including CD4(+) FoxP3(+) CD25(+) regulatory T cells (Treg), from RA patients were performed before and during CTLA-4Ig therapy. In addition T cells from healthy volunteers were analysed on in vitro culture with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. Apoptotic DNA fragmentation in CD4(+) and CD4(+) FoxP3(+) T cells was measured by TUNEL staining.
  
  
  RESULTS
  We observed an increase in T cells, including Treg cells, after initiation of CTLA-4Ig therapy, which was linked to a downregulation of activation-associated marker molecules and CD95 on CD4(+) T cells and Treg cells. CTLA-4Ig decreased CD95-mediated cell death in vitro in a dose-dependent manner. Functional analysis of isolated Treg cells from RA patients further revealed a diminished suppression of responder T cell proliferation. This was found to be due to CTLA-4Ig-mediated blocking of CD80 and CD86 on responder T cells that led to a diminished susceptibility for Treg cell suppression.
  
  
  CONCLUSIONS
  CTLA-4Ig therapy in RA patients exerts effects beyond the suppression of T cell activation, which has to be taken into account as an additional mechanism of CTLA-4Ig treatment.
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria and.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonelli
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Göschl
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria and.
authors.forename: Stephan
authors.initials: S
authors.lastname: Blüml
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Karonitsch
authors.affiliation: Department of Advanced Allergology of the Airway, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hirahara
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria and.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ferner
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria and.
authors.forename: Carl-Walter
authors.initials: CW
authors.lastname: Steiner
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria and.
authors.forename: Günter
authors.initials: G
authors.lastname: Steiner
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria and.
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria and clemens.scheinecker@meduniwien.ac.at.
authors.forename: Clemens
authors.initials: C
authors.lastname: Scheinecker
mesh_terms: D000069594:Abatacept / Q000494:pharmacology* / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000187:drug effects*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D019014:fas Receptor / Q000276:immunology
chemical_list: D018501:Antirheumatic Agents; C491901:FAS protein, human; D019014:fas Receptor; D000069594:Abatacept
keywords: CTLA-4Ig; Foxp3; abatacept; regulatory T cells; rheumatoid arthritis