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TNFα blockade impairs dendritic cell survival and function in rheumatoid arthritis
  1. Helen M Baldwin (helen.baldwin{at}ncl.ac.uk)
  1. Newcastle University, United Kingdom
    1. Toshiko Ito-Ihara (itoshi{at}kuhp.kyoto-u.ac.jp)
    1. Newcastle University, United Kingdom
      1. John D Isaacs (j.d.isaacs{at}ncl.ac.uk)
      1. Newcastle University, United Kingdom
        1. Catharien M U Hilkens (catharien.hilkens{at}ncl.ac.uk)
        1. Newcastle University, United Kingdom

          Abstract

          Objectives: TNFα blockade is an effective therapy for rheumatoid arthritis (RA). Immunomodulatory effects of TNFα antagonists are thought to contribute to their therapeutic action. Here, we investigated whether anti-TNFα therapeutics exerted their immunoregulatory effects through modulation of dendritic cell (DC) function.

          Methods: Two complementary approaches were taken: In the first 'in vitro' approach monocyte-derived DC from healthy donors were matured with LPS and treated with TNFα antagonists in vitro for 48 hours. In the second 'ex vivo' approach monocyte-derived DC were generated from RA patients before and 8-12 weeks into anti-TNFα treatment. DC were analysed for survival, phenotype, cytokine production and T cell stimulatory capacity.

          Results: TNFα blockade during DC maturation in vitro induced approximately 40 % of DC to undergo apoptosis. Importantly, the surviving DC displayed a semi-mature phenotype with reduced levels of HLA-DR, CD80, CD83, CD86 and CCR7, and their production of IL-10 was enhanced as compared to DC matured without TNFαƒnantagonists. Furthermore, anti-TNFα-treated DC were poor stimulators of T cell proliferation and polarised T-cell development towards a higher IL-10/lower IFN-γ cytokine profile. Similarly, DC derived from RA patients after anti-TNFα treatment showed impaired upregulation of CD80 and CD86 upon LPS activation and displayed poor T cell stimulatory activity.

          Conclusions: Our data show that TNFα blockade has profound effects on DC function with downstream, potentially immunoregulatory, effects on T-cells. These data provide an interesting new insight into the potential mechanism by which anti-TNFα drugs contribute to the restoration of immunoregulation in RA patients.

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