TNF blockade impairs dendritic cell survival and function in rheumatoid arthritis

Helen M Baldwin ¹, Toshiko Ito-Ihara ¹, John D Isaacs ^1* and Catharien M U Hilkens ¹

¹ Newcastle University, United Kingdom

^* To whom correspondence should be addressed. E-mail: j.d.isaacs{at}ncl.ac.uk.

Accepted 25 August 2009

Abstract

Objectives: TNF blockade is an effective therapy for rheumatoid arthritis (RA). Immunomodulatory effects of TNF antagonists are thought to contribute to their therapeutic action. Here, we investigated whether anti-TNF 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 TNF 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-TNF treatment. DC were analysed for survival, phenotype, cytokine production and T cell stimulatory capacity.

Results: TNF 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 TNFnantagonists. Furthermore, anti-TNF-treated DC were poor stimulators of T cell proliferation and polarised T-cell development towards a higher IL-10/lower IFN- cytokine profile. Similarly, DC derived from RA patients after anti-TNF treatment showed impaired upregulation of CD80 and CD86 upon LPS activation and displayed poor T cell stimulatory activity.

Conclusions: Our data show that TNF 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-TNF drugs contribute to the restoration of immunoregulation in RA patients.