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Natalizumab treatment in multiple sclerosis: marked decline of chemokines and cytokines in cerebrospinal fluid
Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
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2010 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 16, no 2, 208-217 p.Article in journal (Refereed) Published
Abstract [en]

Natalizumab exerts impressive therapeutic effects in patients with multiple sclerosis (MS). The proposed main mode of action is reducing transmigration of leukocytes into the CNS, but other immunological effects may also be operative. Cytokines and chemokines are involved in the regulation of inflammatory responses and may reflect the disease process in MS. The objective of this study was to evaluate the effects of natalizumab treatment on cytokine and chemokine profiles systemically and intrathecally in multiple sclerosis. We used luminex to analyse a panel of cytokines (IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma, GM-CSF) and chemokines (CXCL9, CXCL10, CXCL11, CCL17, CCL22) in blood and cerebrospinal fluid (CSF) from 31 patients with relapsing MS before and after one year of natalizumab treatment. There was a marked decline in CSF levels of cytokines and chemokines, thus including pro-inflammatory cytokines (IL-1 beta, IL-6 and IL-8) as well as chemokines associated with both Th1 (CXCL9, CXCL10, CXCL11) and Th2 (CCL22). Circulating plasma levels of some cytokines (GM-CSF, TNF-alpha, IL-6 and IL-10) also decreased after one year of treatment. This is the first study to show that natalizumab treatment is associated with a global decline in cytokine and chemokine levels at a protein level. This finding was most pronounced in CSF, in line with the reduced transmigration of cells into CNS, whereas reduction in plasma levels indicates other possible mechanisms of natalizumab treatment.

Place, publisher, year, edition, pages
2010. Vol. 16, no 2, 208-217 p.
Keyword [en]
cerebrospinal fluid, chemokines, cytokines, luminex, multiple sclerosis, natalizumab, peripheral blood
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-54061DOI: 10.1177/1352458509355068ISI: 000274326500010OAI: oai:DiVA.org:liu-54061DiVA: diva2:298311
Note

Original Publication: Johan Mellergård, Måns Edström, Magnus Vrethem, Jan Ernerudh and Charlotte Dahle, Natalizumab treatment in multiple sclerosis: marked decline of chemokines and cytokines in cerebrospinal fluid, 2010, MULTIPLE SCLEROSIS, (16), 2, 208-217. http://dx.doi.org/10.1177/1352458509355068 Copyright: SAGE Publications http://www.uk.sagepub.com/

Available from: 2010-02-22 Created: 2010-02-22 Last updated: 2013-11-07
In thesis
1. Immunological Mechanisms and Natalizumab Treatment in Multiple Sclerosis: Studies on lymphocytes, inflammatory markers and magnetic resonance spectroscopy
Open this publication in new window or tab >>Immunological Mechanisms and Natalizumab Treatment in Multiple Sclerosis: Studies on lymphocytes, inflammatory markers and magnetic resonance spectroscopy
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system (CNS), and a frequent cause of neurological disability among young adults. In addition to focal inflammatory demyelinated lesions, diffuse white matter pathology as well as a neurodegenerative component with accumulating axonal damage and gliosis have been demonstrated and contribute to MS disease characteristics. The inflammatory component is considered autoimmune and mediated by auto-reactive T lymphocytes together with other cell populations of the immune system and their respective products like cytokines and chemokines. Treatment with natalizumab, a monoclonal antibody directed against the α4β1-integrin (VLA-4), reduces migration of potential disease-promoting cells to the CNS. The efficacy of natalizumab in reducing relapses and MRI activity is evident, however associated effects on the immune response and the neurodegenerative component in MS are not clear.

Methods: In total 72 MS patients were included, distributed among paper I-IV. We investigated effects associated with one-year natalizumab treatment in 31 MS patients regarding cytokine and chemokine levels in CSF and blood using multiplex bead assay analyses (paper I), as well as treatment effects on blood lymphocyte composition in 40 patients using flow cytometry, including functional assays of lymphocyte activation (paper II). Normal appearing white matter (NAWM) metabolite concentrations were assessed with proton magnetic resonance spectroscopy (1H-MRS) in 27 MS patients before and after one year of treatment (paper III). We also evaluated the balance between circulating T helper (Th) subsets in 33 MS patients using gene expression analyses of the CD4+ T cell related transcription factors in whole blood (paper IV).

Results: One-year natalizumab treatment was associated with a marked decline in pro-inflammatory cytokines (IL-1β and IL-6) and chemokines (CXCL8, CXCL9, CXCL10 and CXCL11) intrathecally. Circulating plasma levels of some cytokines (GM-CSF, TNF, IL-6 and IL-10) also decreased after treatment. Natalizumab treatment was further associated with an increase in lymphocyte numbers of major populations in blood (total lymphocytes, T cells, T helper cells, cytotoxic T cells, NK cells and B cells). In addition, T cell responsiveness to recall antigens and mitogens was restored after treatment. As to 1H-MRS metabolite concentrations in NAWM, no change in levels were detected post-to pretreatment on a group level. However, correlation analyses between one-year change in metabolite levels (total creatine and total choline) and levels of pro-inflammatory IL-1β and CXCL8 showed a pattern of high magnitude correlation coefficients (r=0.43-0.67). Gene expression analyses demonstrated a systemically reduced expression of transcription factors related to immunoregulatory T cell populations (regulatory T cells and Th2) in relapsing MS compared with controls.

Conclusions: Our findings support that an important mode of action of natalizumab is reducing lymphocyte extravasation, although cell-signalling effects through VLA-4 also may be operative. Correlation analyses between changes 1H-MRS metabolite concentrations and inflammatory markers possibly point towards an association between intrathecal inflammation and gliosis development in NAWM. Finally, gene expression analyses indicate a systemic defect at the mRNA level in relapsing MS, involving downregulation of beneficial CD4+ phenotypes.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 83 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1332
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84274 (URN)978-91-7519-787-6 (ISBN)
Public defence
2012-11-02, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
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Available from: 2012-10-03 Created: 2012-10-03 Last updated: 2012-10-24Bibliographically approved

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Mellergård, JohanEdström, MånsVrethem, MagnusErnerudh, JanDahle, Charlotte

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