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

Abstract

ObjectivesTumour necrosis factor alpha (TNFα) blockade is an effective therapy for rheumatoid arthritis (RA). The immunomodulatory effects of TNFα antagonists are thought to contribute to their therapeutic action. This study investigated whether anti-TNFα therapeutics exerted their immunoregulatory effects through modulation of dendritic cell (DC) function.MethodsTwo complementary approaches were taken: in the first ‘in vitro’ approach monocyte-derived DC from healthy donors were matured with lipopolysaccharide and treated with TNFα 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-TNFα treatment. DC were analysed for survival, phenotype, cytokine production and T-cell stimulatory capacity.ResultsTNFα 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 TNFα antagonists. Furthermore, anti-TNFα-treated DC were poor stimulators of T-cell proliferation and polarised T-cell development towards a higher IL-10/lower IFNγ cytokine profile. Similarly, DC derived from RA patients after anti-TNFα treatment showed impaired upregulation of CD80 and CD86 upon lipopolysaccharide activation and displayed poor T-cell stimulatory activity.ConclusionsThe 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.