| Tumour necrosis factor alpha blockade impairs dendritic cell survival and function in rheumatoid arthritis. | |
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MedLine Citation:
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PMID: 19773288 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Helen M Baldwin; Toshiko Ito-Ihara; John D Isaacs; Catharien M U Hilkens |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-09-22 |
Journal Detail:
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Title: Annals of the rheumatic diseases Volume: 69 ISSN: 1468-2060 ISO Abbreviation: Ann. Rheum. Dis. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-05-25 Completed Date: 2010-07-16 Revised Date: 2013-05-27 |
Medline Journal Info:
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Nlm Unique ID: 0372355 Medline TA: Ann Rheum Dis Country: England |
Other Details:
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Languages: eng Pagination: 1200-7 Citation Subset: IM |
Affiliation:
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Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, Newcastle-upon-Tyne, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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16361//Arthritis Research UK |
| Chemical | |
Reg. No./Substance:
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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:
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Nat Rev Rheumatol. 2010 Jul;6(7):383
[PMID:
20614506
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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