Natalizumab affects the T-cell receptor repertoire in patients with multiple sclerosis.
OBJECTIVE
To assess changes in the T-cell receptor (TCR) repertoire in peripheral venous blood and CSF of patients with multiple sclerosis (MS) treated with natalizumab and the potential implication for developing progressive multifocal leukoencephalopathy (PML) and PML-immune reconstitution inflammatory syndrome (IRIS).


METHODS
The TCR repertoire in blood and CSF was assessed by complementarity determining region 3 spectratyping in 59 patients with MS treated with natalizumab for at least 18 months, 5 cases of natalizumab-associated PML, 17 age- and sex-matched patients with MS not treated with natalizumab, and 12 healthy controls.


RESULTS
Patients with MS presented with peripheral TCR repertoire expansions in blood, which appeared less prominent during therapy with natalizumab. TCR repertoire restrictions observed in CSF were most pronounced in patients with MS treated with natalizumab. In patients who developed PML with longitudinal samples available, new identical TCR receptor length expansions in blood and CSF were observed following plasma exchange, and preceded the development of IRIS.


CONCLUSIONS
Profound TCR repertoire restrictions in CSF of patients treated with natalizumab reflect an altered immune surveillance of the CNS, which may contribute to an increased risk of developing PML. Natalizumab seems to prompt an impaired or delayed peripheral expansion of antigen-specific T cells, whereas increased reconstitution of peripheral T-cell expansion following plasma exchange may trigger PML-IRIS. Our data suggest that treatment with natalizumab results in broader changes in the T-cell immune repertoire beyond lymphocyte migration.
From the Department of Neurology (C.W., A.K.M., M.S., T.D., L.N., G.M.z.H., H.-P.H., B.C.K.) and Institute for Virology (O.A.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; and the Department of Clinical Neuroscience (C.W., A.F.-H.), Karolinska Institutet, Stockholm, Sweden.
Clemens
C
Warnke
Anne K
AK
Mausberg
Mark
M
Stettner
Thomas
T
Dehmel
Lina
L
Nekrich
Gerd
G
Meyer zu Horste
Hans-Peter
HP
Hartung
Anna
A
Fogdell-Hahn
Ortwin
O
Adams
Bernd C
BC
Kieseier
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000175:diagnosis / Q000209:etiology; D007968:Leukoencephalopathy, Progressive Multifocal / Q000139:chemically induced* / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology*; D000069442:Natalizumab; D010951:Plasma Exchange / Q000009:adverse effects; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis*; D055815:Young Adult
D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab; D011948:Receptors, Antigen, T-Cell