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IFN-ß treatment in multiple sclerosis: Longitudinal effects on secretion of IFN-γ, IL-4, IL-10, IL-13 and IL-17
Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-3993-9985
Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Department of Neuroscience and Locomotion, Neurophysiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Proinflammatory cytokines like IFN-γ and TNF-α seem to have disease-promoting roles in multiple sclerosis (MS) whereas anti-inflammatory cytokines like IL-10 and TGF-ß may downregulate the disease. IFN-ß treatment reduces the frequency and severity of relapses, however, the mechanisms of action for IFN-ß are only partly understood and modulation of cytokine secretion could be one possible explanation for the therapeutic effects. The IFN-ß products approved for the treatment of MS differ in their composition and effects, and recently differences in effects on cytokine secretion were reported. Peripheral blood was collected from 25 patients with MS, both IFN-ß1a and IFN-ß1b treated, before onset of treatment and after 6 weeks, 3 months, 6 months and one year. Spontaneous as well as myelin specific secretion of IL-4, IFN-γ and IL-10 was analysed with the ELISPOT technique. PHA stimulated secretion of IL-13 and IL-17 was analysed in cell supernatants with ELISA. A general finding was that surprisingly few changes occurred, and that most changes occurred early (6 weeks - 3 months). We found a shift in the cytokine balance towards more IL-4 and IL-10 secretion and/or less IFN-γ secretion during the treatment as the ratios of IL-4!IFN-y as well as of IL-10/IFN-γ were increased. The interesting pro-inflammatory cytokine IL-17, that has been associated with T-cell mediated autoimmunity, has not been previously investigated during IFN-ß treatment in MS. Our findings of decreased IL-17 levels after one year of treatment, following an increase in early treatment, could be a beneficial result of the IFN-ß treatment. Further we noticed differences in effects on cytokines of IFN-ß1a and IFN-ß1b respectively; the latter seemed to have more effects on cytokine secretion.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-84278OAI: oai:DiVA.org:liu-84278DiVA: diva2:558436
Available from: 2012-10-03 Created: 2012-10-03 Last updated: 2013-08-29Bibliographically approved
In thesis
1. Mechanisms in inflammatory demyelinating diseases of the nervous system: immunological and methodological aspects
Open this publication in new window or tab >>Mechanisms in inflammatory demyelinating diseases of the nervous system: immunological and methodological aspects
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The diseases studied in this thesis, Guillain-Barré Syndrome (GBS), Multiple Sclerosis (MS) and Polyneuropathy associated with monoclonal gammopathy of uncertain significance (PNMGUS), are of autoimmune origin with myelin components as putative auto antigens. T cells are important for the pathogenesis, as well as the cytokine network and autoantibodies. For all of these diseases, the immunopathogenisis is not fully understood and even if there are treatments available, none of them are curative and there are side effects. Thus there is a need for further clues in the immune mechanisms. Contrary to PNMGUS and MS, GBS is generally self-limiting. The mechanisms of the beneficial effect of interferon-beta (IFN-ß) treatment in MS are not fully understood, (although alterations in the cytokine levels are subject to many reports). In PNMGUS, the proliferation of a monoclonal B cell clone and its antibody production are of great significance, however additional immune mechanisms are also of interest like the role of T cells and the role of B cells as antigen presenting cells.

In studies of cytokines, frozen cells are often used, sometimes for practical reasons, so also in this thesis. Therefore effects of cryopreservation on cellular expression/secretion of cytokines were studied. The expression before compared to after cryopreservation of IFN-γ, IL-4, IL-5, IL-9, IL-10 and IL-13 was analysed with ELISA, ELISPOT and/or real time RT-PCR We found that the process of cryopreservation and thawing does affect the expression of cytokines, both at the protein and the mRNA level. The most consistent fmding was that expression of IL-4 was generally decreased in spontaneous and auto-antigen/allergen induced expression in cryopreserved cells. Thus, this study points out the importance of investigation of the effects of freezing for each cytokine, stimuli and patient group before using frozen cells in studies of in vitro cytokine secretion.

The secretion of IL-4, IFN-γ, TGF-ß, IL-6, and TNF-α during the course of GBS was analysed with ELISPOT and cell-ELISA. Our findings indicate a down-regulatory role for TGF-ß and IL-4 in GBS.

The longitudinal effects over one year of IFN-ß treatment on secretion of IL-4, IFN-γ and IL-10 was analysed with the ELISPOT technique and IL-13 and IL-17 was analysed in cell supernatants with ELISA. A general finding was that surprisingly few changes occurred, and that most changes occurred early (6 weeks - 3 months). However, we found a shift in the cytokine balance towards more IL-4 and IL-10 secretion and/or less IFN-γ secretion during the treatment as the ratios of IL-4/IFN-γ as well as of IL-10/IFN-γ were increased. The interesting pro-inflammatory cytokine IL-17, associated with T cell mediated autoimmunity, has not been previously investigated during IFN-ß treatment in MS and our findings of decreased IL-17 levels after one year of treatment could be a beneficial result of the IFN-ß treatment.

B cell clones from a patient with PNMGUS were successfully established by isolating B cells with myelin protein zero (P0) coated magnetic beads and subsequently transforming with Epstein-Barr virus (EBV). The clones were characterised and for instance they strongly expressed HLA-DR and CD80, compatible with antigen-presenting properties. The cell lines may provide useful tools in studies of PNMGUS.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2005. 86 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 892
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24541 (URN)6700 (Local ID)91-85299-02-2 (ISBN)6700 (Archive number)6700 (OAI)
Public defence
2005-05-04, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-03Bibliographically approved

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Kvarnström, MariaEkerfelt, ChristinaVrethem, MagnusErnerudh, Jan

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