Document Detail


Tumour necrosis factor alpha blockade impairs dendritic cell survival and function in rheumatoid arthritis.
MedLine Citation:
PMID:  19773288     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: 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.
Authors:
Helen M Baldwin; Toshiko Ito-Ihara; John D Isaacs; Catharien M U Hilkens
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-09-22
Journal Detail:
Title:  Annals of the rheumatic diseases     Volume:  69     ISSN:  1468-2060     ISO Abbreviation:  Ann. Rheum. Dis.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-25     Completed Date:  2010-07-16     Revised Date:  2013-05-27    
Medline Journal Info:
Nlm Unique ID:  0372355     Medline TA:  Ann Rheum Dis     Country:  England    
Other Details:
Languages:  eng     Pagination:  1200-7     Citation Subset:  IM    
Affiliation:
Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, Newcastle-upon-Tyne, UK.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Antibodies, Monoclonal / pharmacology,  therapeutic use
Antibodies, Monoclonal, Humanized
Antirheumatic Agents / pharmacology*,  therapeutic use
Apoptosis / drug effects
Arthritis, Rheumatoid / drug therapy,  immunology,  pathology*
Cell Survival / drug effects
Cells, Cultured
Cytokines / biosynthesis
Dendritic Cells / drug effects*,  immunology
Female
Humans
Immunoglobulin G / therapeutic use
Immunophenotyping
Lipopolysaccharides / immunology
Lymphocyte Activation / drug effects
Male
Middle Aged
Receptors, Tumor Necrosis Factor / therapeutic use
T-Lymphocyte Subsets / immunology
Tumor Necrosis Factor-alpha / antagonists & inhibitors*
Grant Support
ID/Acronym/Agency:
16361//Arthritis Research UK
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Antirheumatic Agents; 0/Cytokines; 0/Immunoglobulin G; 0/Lipopolysaccharides; 0/Receptors, Tumor Necrosis Factor; 0/Tumor Necrosis Factor-alpha; 0/infliximab; 185243-69-0/TNFR-Fc fusion protein; FYS6T7F842/adalimumab
Comments/Corrections
Comment In:
Nat Rev Rheumatol. 2010 Jul;6(7):383   [PMID:  20614506 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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