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Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis
Open accessAbstract
Experiments were designed to test the hypothesis that chronic exposure to tumor necrosis factor alpha (TNF) alters the function of activated T lymphocytes. Pretreatment of tetanus toxoid-specific T cell clones with TNF for up to 16 d impaired rechallenge proliferative responses to antigen in a dose- and time-dependent fashion. IL-2 and PHA responses were preserved. Prolonged treatment with TNF impaired production of IL-2, IL-10, IFN gamma, TNF, and lymphotoxin (LT) following stimulation with immobilized OKT3, and resulted in suboptimal expression of the IL-2R alpha chain (Tac) but not CD3, CD4, or HLA-DR antigens, when compared to untreated control cells. By contrast, pretreatment of T cells for prolonged periods in vitro with neutralizing anti-TNF monoclonal antibodies (mAb) enhanced proliferative responses, increased lymphokine production, and upregulated Tac expression following stimulation with OKT3. To determine whether TNF exerts immunosuppressive effects on T cells in vivo, we studied cell-mediated immunity in patients with active rheumatoid arthritis (RA), before and after treatment with a chimeric anti-TNF mAb. Treatment with anti-TNF restored the diminished proliferative responses of PBMC to mitogens and recall antigens towards normal in all patients tested. These data demonstrate that persistent expression of TNF in vitro and in vivo impairs cell-mediated immune responses.
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“Since inflammatory cytokines that direct T cell subtype production are altered in depressed patients (12–14)”
From Inflammatory T helper 17 cells promote depression-like behavior in mice (2013) · cites this paper as [14]
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Metadata
- Authors
- Cope, A. P., Londei, M., Chu, N. R., Cohen, S. B., Elliott, M. J., Brennan, F. M., Maini, R. N., & Feldmann, M.
- Affiliations
- Kennedy Institute of Rheumatology (GB)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 1994-08-01
- Volume
- 94
- Issue
- 2
- Pages
- 749-760
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC296155
- OpenAlex
- W1985680749
- Cited by
- 243
- References
- 60
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2019: 9 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 5 · 2014: 7 · 2013: 7 · 2012: 10
- FWCI
- 9.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- TNF-α, T cell activation, T cell receptor/CD3 complex, anti-TNF monoclonal antibody, rheumatoid arthritis, cell-mediated immunity, immunosuppression, IL-2 receptor alpha chain, OKT3, lymphokine production, T cell clones
- MeSH terms
- Antibodies, Monoclonal, Antigen-Presenting Cells, Arthritis, Rheumatoid, Cells, Cultured, Dose-Response Relationship, Drug, HLA-DR Antigens, Humans, Interleukin-2, Lymphocyte Activation, Lymphokines, T-Lymphocytes, Tumor Necrosis Factor-alpha, CD4 Antigens, Receptor-CD3 Complex, Antigen, T-Cell
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