The effects of natalizumab on inflammatory mediators in multiple sclerosis: prospects for treatment-sensitive biomarkers

• Published in: European journal of neurology Vol. 16; no. 4; pp. 528 - 536
• Main Authors: Khademi, M., Bornsen, L., Rafatnia, F., Andersson, M., Brundin, L., Piehl, F., Sellebjerg, F., Olsson, T.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2009
• Subjects: Adult; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Biomarkers - analysis; Cell Count; cerebrospinal fluid cells; cytokines; Cytokines - blood; Cytokines - cerebrospinal fluid; Cytokines - metabolism; Female; Gene Expression - drug effects; Humans; Interferon-gamma - metabolism; Interleukin-10 - cerebrospinal fluid; Interleukin-23 - cerebrospinal fluid; Leukocytes, Mononuclear - metabolism; Male; matrix metalloproteinase; Matrix Metalloproteinase 9 - cerebrospinal fluid; Medicin och hälsovetenskap; Middle Aged; Multiple Sclerosis, Relapsing-Remitting - drug therapy; Multiple Sclerosis, Relapsing-Remitting - immunology; Multiple Sclerosis, Relapsing-Remitting - physiopathology; Natalizumab; osteopontin; Osteopontin - cerebrospinal fluid; peripheral blood mononuclear cells; relapsing-remitting multiple sclerosis; RNA, Messenger - metabolism; Treatment Outcome; Tumor Necrosis Factor-alpha - metabolism; Young Adult
• ISSN: 1351-5101; 1468-1331; 1468-1331; 1471-0552
• DOI: 10.1111/j.1468-1331.2009.02532.x

Background:  Natalizumab affects systemic cytokine expressions and clinical course in relapsing–remitting multiple sclerosis (RRMS). We analyzed levels of inflammatory cytokines in cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs), levels of matrix metalloproteinase (MMP)‐9 and osteopontin (OPN) in CSF, and clinical outcome measures in 22 natalizumab‐treated RRMS patients. Methods:  mRNA levels of cytokines in cells were detected with real‐time RT‐PCR. Protein levels of OPN and MMP‐9 were measured by ELISA. Results:  Natalizumab reduced CSF cell counts (P < 0.0001). Tumor necrosis factor (TNF) and interferon‐γ (IFN‐γ) mRNAs were significantly increased in PBMCs. In contrast, expressions of IFN‐γ and interleukin (IL)‐23 were decreased but IL‐10 increased in the CSF cells. OPN and MMP‐9 were reduced in the CSF. Patients being in remission at baseline showed the same deviations of mediators as those in relapse after natalizumab treatment. The open label clinical outcome measures were either stable or improved during therapy. Conclusions:  Natalizumab attenuates pro‐inflammatory mediators intrathecally and the reduced pro‐inflammatory milieu may allow increased production of the anti‐inflammatory mediator IL‐10. The increased systemic cytokines may impede the improvement of certain clinical measures like fatigue. The affected mediators seem to be sensitive to an immune‐modifying treatment which could be used as biomarkers for this therapy.