RESEARCH - TNF blockade impairs dendritic cell survival and function in RA

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Ann Rheum Dis. 2009 Sep 23.

TNF{alpha} blockade impairs dendritic cell survival and function in

rheumatoid arthritis.

Baldwin HM, Ito-Ihara T, Isaacs JD, Hilkens CM.

Newcastle University, United Kingdom.

OBJECTIVES: TNFalpha blockade is an effective therapy for rheumatoid

arthritis (RA). Immunomodulatory effects of TNFalpha antagonists are

thought to contribute to their therapeutic action. Here, we

investigated whether anti-TNFalpha 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 TNFalpha 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-TNFalpha treatment.

DC were analysed for survival, phenotype, cytokine production and T

cell stimulatory capacity.

RESULTS: TNFalpha 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 TNFalphafnantagonists.

Furthermore, anti-TNFalpha-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-TNFalpha treatment showed impaired upregulation of

CD80 and CD86 upon LPS activation and displayed poor T cell

stimulatory activity.

CONCLUSIONS: Our data show that TNFalpha 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-TNFalpha drugs contribute to the

restoration of immunoregulation in RA patients.

PMID: 19773288

http://www.ncbi.nlm.nih.gov/pubmed/19773288

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