Tumour necrosis factor alpha blockade impairs dendritic cell survival and function in rheumatoid arthritis.
OBJECTIVE
Tumour necrosis factor alpha (TNFalpha) blockade is an effective therapy for rheumatoid arthritis (RA). The immunomodulatory effects of TNFalpha antagonists are thought to contribute to their therapeutic action. This study 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 lipopolysaccharide and treated with TNFalpha 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-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 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 TNFalpha antagonists. Furthermore, anti-TNFalpha-treated DC were poor stimulators of T-cell proliferation and polarised T-cell development towards a higher IL-10/lower IFNgamma cytokine profile. Similarly, DC derived from RA patients after anti-TNFalpha treatment showed impaired upregulation of CD80 and CD86 upon lipopolysaccharide activation and displayed poor T-cell stimulatory activity.


CONCLUSIONS
The 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.
Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, Newcastle-upon-Tyne, UK.
Helen M
HM
Baldwin
Toshiko
T
Ito-Ihara
John D
JD
Isaacs
Catharien M U
CM
Hilkens
D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D016130:Immunophenotyping; D000069285:Infliximab; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D016207:Cytokines; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept