title: Impact of the CTLA-4/CD28 axis on the processes of joint inflammation in rheumatoid arthritis.
abstract: OBJECTIVE
  The importance of the costimulatory molecules CD28 and CTLA-4 in the pathologic mechanism of rheumatoid arthritis (RA) has been demonstrated by genetic associations and the successful clinical application of CTLA-4Ig for the treatment of RA. This study was undertaken to investigate the role of the CTLA-4/CD28 axis in the local application of CTLA-4Ig in the synovial fluid (SF) of RA patients.
  
  
  METHODS
  Quantitative polymerase chain reaction was used to analyze the expression of proinflammatory and antiinflammatory cytokines in ex vivo fluorescence-activated cell sorted CTLA-4+ and CTLA-4- T helper cells from the peripheral blood and SF of RA patients. T helper cells were also analyzed for cytokine expression in vitro after the blockade of CTLA-4 by anti-CTLA-4 Fab fragments or of B7 (CD80/CD86) molecules by CTLA-4Ig.
  
  
  RESULTS
  CTLA-4+ T helper cells were unambiguously present in the SF of all RA patients examined, and they expressed increased amounts of interferon-γ (IFNγ), interleukin-17 (IL-17), and IL-10 as compared to CTLA-4- T helper cells. The selective blockade of CTLA-4 in T helper cells from the SF in vitro led to increased levels of IFNγ, IL-2, and IL-17. The concomitant blockade of CD28 and CTLA-4 in T helper cells from RA SF by CTLA-4Ig in vitro resulted in reduced levels of the proinflammatory cytokines IFNγ and IL-2 and increased levels of the antiinflammatory cytokines IL-10 and transforming growth factor β.
  
  
  CONCLUSIONS
  Our ex vivo and in vitro results demonstrate that the CTLA-4/CD28 axis constitutes a drug target for not only the systemic, but potentially also the local, application of the costimulation blocking agent CTLA-4Ig for the treatment of RA.
authors.affiliation: Charité Universitätsmedizin Berlin and Deutsches Rheumaforschungszentrum Berlin, Berlin, Germany.
authors.forename: Dezsö
authors.initials: D
authors.lastname: Körmendy
authors.forename: Holger
authors.initials: H
authors.lastname: Hoff
authors.forename: Paula
authors.initials: P
authors.lastname: Hoff
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bröker
authors.forename: Gerd-Rüdiger
authors.initials: GR
authors.lastname: Burmester
authors.forename: Monika C
authors.initials: MC
authors.lastname: Brunner-Weinzierl
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D018106:CD28 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D058990:Molecular Targeted Therapy; D060888:Real-Time Polymerase Chain Reaction; D013582:Synovial Fluid / Q000276:immunology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D016207:Cytokines