The effects of natalizumab on inflammatory mediators in multiple sclerosis: prospects for treatment-sensitive biomarkers.
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-gamma (IFN-gamma) mRNAs were significantly increased in PBMCs. In contrast, expressions of IFN-gamma 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.
Khademi
M
M
Neuroimmunology Unit, CMM, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. mohsen.khademi@ki.se
Bornsen
L
L
Rafatnia
F
F
Andersson
M
M
Brundin
L
L
Piehl
F
F
Sellebjerg
F
F
Olsson
T
T
D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000032:analysis; D002452:Cell Count; D016207:Cytokines / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000134:cerebrospinal fluid; D053759:Interleukin-23 / Q000134:cerebrospinal fluid; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000134:cerebrospinal fluid; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D000069442:Natalizumab; D053495:Osteopontin / Q000134:cerebrospinal fluid; D012333:RNA, Messenger / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D016207:Cytokines; C508609:IL10 protein, human; D053759:Interleukin-23; D000069442:Natalizumab; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D053495:Osteopontin; D016753:Interleukin-10; D007371:Interferon-gamma; D020780:Matrix Metalloproteinase 9