Tumour necrosis factor alpha blockade impairs dendritic cell survival and function in rheumatoid arthritis

Objectives Tumour necrosis factor alpha (TNF alpha) blockade is an effective therapy for rheumatoid arthritis (RA). The immunomodulatory effects of TNF alpha antagonists are thought to contribute to their therapeutic action. This study investigated whether anti-TNF alpha 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 lipopolysaccharide and treated with TNF alpha antagonists in vitro for 48 h. In the second 'ex vivo' approach monocyte-derived DC were generated from RA patients before and 8-12 weeks into anti-TNF alpha treatment. DC were analysed for survival, phenotype, cytokine production and T-cell stimulatory capacity. Results TNF alpha blockade during DC maturation in vitro induced approximately 40% of DC to undergo apoptosis. Importantly, the surviving DC displayed a semimature phenotype with reduced levels of HLA-DR, CD80, CD83, CD86 and CCR7, and their production of IL-10 was enhanced compared with DC matured without TNF alpha antagonists. Furthermore, anti-TNF alpha-treated DC were poor stimulators of T-cell proliferation and polarised T-cell development towards a higher IL-10/lower IFN gamma cytokine profile. Similarly, DC derived from RA patients after anti-TNF alpha treatment showed impaired upregulation of CD80 and CD86 upon lipopolysaccharide activation and displayed poor T-cell stimulatory activity. Conclusions The data show that TNF alpha 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 alpha drugs contribute to the restoration of immunoregulation in RA patients.