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Changes in chemokines and their receptors in blood during treatment with the TNF inhibitor infliximab in patients with rheumatoid arthritis
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
2013 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, Vol. 42, no 4, 260-265 p.Article in journal (Refereed) Published
Abstract [en]

Background. Chemokines are involved in leucocyte recruitment into inflammatory sites, such as the synovial tissue of patients with rheumatoid arthritis (RA). The release of certain chemokines is augmented by pro-inflammatory cytokines, such as tumor necrosis factor (TNF). Infliximab, a monoclonal antibody against TNF that blocks the biological effects of TNF, is used in the treatment of chronic inflammatory diseases. The effect of blocking TNF activity on chemokines is not fully understood.

Aim. The aim of this study was to analyse the effects on chemokines and their receptors on peripheral mononuclear cells of anti-TNF treatment in RA-patients.

Material and methods. Twelve patients with established RA who began treatment with infliximab, and nine patients with early RA treated with traditional disease-modifying anti-rheumatic drugs, were followed clinically for 30 weeks and chemokine levels in blood samples and chemokine receptor expression on the surface of T-cells and monocytes analysed. Three SLE-patients, as a small control group of another inflammatory disease, and nine healthy subjects were also included in the study.

Result. CXCL10/IP-10 was significantly higher in RA-patients compared with healthy controls and decreased significantly two weeks after infliximab infusion. CCL2/MCP-1 and CCL4/MIP-1β decreased significantly after infliximab treatment although the concentrations were not significantly elevated at baseline compared with controls. There was an inverse correlation between the chemokine cleaving molecule dipeptidyl peptidase-IV/CD26 and CCL5/RANTES. Several chemokine receptors on T-cells were elevated in RA patients at inclusion into the study. The CCR2 expression on T-cells decreased significantly after infliximab treatment.

Conclusion. The chemokines CXCL10/IP-10, CCL2/MCP-1 and CCL4/MIP-1β, mainly targeting the Th1 immune response, decreased after treatment with anti-TNF suggesting a more pronounced effect onTh1 activity than on the Th2 mediated response. Several chemokine receptors on blood T-cells were elevated in RA-patients, suggesting that they may be involved in the recruitment of T-lymphocytes from the blood to affected tissues.

Place, publisher, year, edition, pages
2013. Vol. 42, no 4, 260-265 p.
National Category
Immunology in the medical area Rheumatology and Autoimmunity
Research subject
Clinical Immunology; Medicine, rheumatology
URN: urn:nbn:se:umu:diva-39809DOI: 10.3109/03009742.2012.754937ISBN: 978-91-7459-143-9OAI: diva2:410817
Available from: 2011-04-15 Created: 2011-02-09 Last updated: 2013-08-20Bibliographically approved
In thesis
1. Immunological mechanisms in systemic autoimmunity: autoantibodies and chemokines in systemic lupus erythematosus and during treatment with TNF inhibitors in rheumatoid arthritis
Open this publication in new window or tab >>Immunological mechanisms in systemic autoimmunity: autoantibodies and chemokines in systemic lupus erythematosus and during treatment with TNF inhibitors in rheumatoid arthritis
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background. Rheumatoid Arthritis (RA) is an autoimmune inflammatory disease that, without powerful treatment, may lead to irreversible joint damage. During the past decade, anti-cytokine therapy has become available, e.g., infliximab, a chimeric antibody targeting the pro-inflammatory cytokine TNF that has a central role in the inflammatory process in RA patients. Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that may affect all organs and is characterized by a massive antibody production. Chemokines, chemokine receptors and lipoprotein receptor-related protein 1(CD91) are regulators of inflammation in autoimmune diseases and T-cell migration.

Objectives. The aim of this study was to get a deeper understanding how TNF blocking treatment influences inflammatory mechanisms and autoantibody formation in RA with special reference to similarities and differences with SLE.

Methods. In patients with RA treated with anti-TNF, and in SLE patients (ACR criteria) clinical evaluation was performed and blood samples analyzed. Autoantibodies were analyzed using indirect immunofluorescence, ELISA and multiplex flow cytometry in samples from anti-TNF treated RA patients (n=59) followed longitudinally for 54 weeks, in pre-diseased samples from SLE patients (n=38) and matched population-based controls (n=152). T-cell expression of chemokine receptors and CD91 was analyzed by flow cytometry, whilst serum levels of chemokines were determined using ELISA in anti-TNF treated RA-patients (n=24) followed longitudinally (30 weeks), and cross-sectionally in SLE-patients (n=23). Expression of mRNA for chemokines was analyzed in T-cells from SLE-patients (n=10) using PCR.

Results. After treatment with infliximab, RA patients produced ANA, anti-dsDNA and anti-nucleosome antibodies, but not anti-ENA antibodies. Although these antibodies are considered typical for SLE only one patient developed a transient lupus-syndrome. Antibodies against cell nuclear antigens, including ENA, were detected several years before the first clinical symptom of SLE; anti-SSA was the earliest detectable antibody.

In RA-patients before infliximab treatment, the T-cell expression of several chemokine receptors was elevated compared with healthy controls. In contrast, only one soluble chemokine, IP-10 was elevated. After treatment the levels of soluble MIP-1β, MCP-1 and IP-10, and the T-cell expression of CCR2 were decreased. In SLE-patients MIP-1β, MCP-1, SDF-1, IP-10 and RANTES in blood were elevated, whilst expression of CXCR5 and CCR6 on T-cells was lower than in healthy controls. T-cell expression of CXCR2 and CCR1 was elevated in active disease (measured as SLEDAI index), whereas the CXCR5 and CCR2 expression was lower in inactive SLE. In SLE patients with nephritis IP-10 was lower and T-cell expression of CXCR3 and CCR3 elevated compared with patients without nephritis. The expression of CD91 was higher on T-cells from patients not responsive to infliximab treatment compared with responders.

Conclusion. These findings indicate that anti-TNF (infliximab) treatment in RA-patients has a major impact on the production of autoantibodies and chemokines. The autoantibody profile in infliximab-treated patients was similar to that predating disease onset in SLE patients with the exception of anti-ENA being detectable in SLE, but the development of lupus-syndromes was rare. The expression of CD91 on T-cells may predict responsiveness to infliximab. The expression of chemokine receptors in SLE- patients seemed to be related to disease activity. Anti-nuclear antibodies were detectable years before clinical disease onset in patients who developed SLE suggesting a gradual pathogenic process.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2011. 68 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1401
autoimmunity, chemokines, T-cells, autoantibodies, CD91
National Category
Immunology in the medical area Rheumatology and Autoimmunity
Research subject
Clinical Immunology; Medicine, rheumatology
urn:nbn:se:umu:diva-42954 (URN)978-91-7459-143-9 (ISBN)
Public defence
2011-05-12, Betula, Norrlands universitetssjukhus, by 6M, Umeå, 09:00 (Swedish)
Available from: 2011-04-20 Created: 2011-04-15 Last updated: 2011-04-20Bibliographically approved

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