Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis.
BACKGROUND
Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an alpha4beta(1) integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection.


OBJECTIVE
To test the effect of natalizumab treatment on the CD4(+)/CD8(+) T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood.


METHODS
Prospective longitudinal study.


METHODS
Academic and private multiple sclerosis centers.


METHODS
Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus-infected patients.


METHODS
CD4(+) and CD8(+) T cells were enumerated in CSF and peripheral blood. The mean fluorescence intensity of unbound alpha4 integrin on peripheral blood CD4(+) and CD8(+) T cells was analyzed before and after natalizumab therapy.


RESULTS
Natalizumab therapy decreased the CSF CD4(+)/CD8(+) ratio of patients with MS to levels similar to those of human immunodeficiency virus-infected patients. CD4(+)/CD8(+) ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits. Six months after the cessation of natalizumab therapy, CSF CD4(+)/CD8(+) ratios normalized. The expression of unbound alpha4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4(+) vs CD8(+) T cells.


CONCLUSIONS
Natalizumab treatment alters the CSF CD4(+)/CD8(+) ratio. Lower expression of unbound alpha4 integrin on CD4(+) T cells is one possible mechanism. These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy.
Stüve
Olaf
O
Department of Neurology, University of Texas Southwestern Medical Center at Dallas, USA.
Marra
Christina M
CM
Bar-Or
Amit
A
Niino
Masaaki
M
Cravens
Petra D
PD
Cepok
Sabine
S
Frohman
Elliot M
EM
Phillips
J Theodore
JT
Arendt
Gabriele
G
Jerome
Keith R
KR
Cook
Linda
L
Grand'Maison
Francois
F
Hemmer
Bernhard
B
Monson
Nancy L
NL
Racke
Michael K
MK
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects*; D039041:Integrin alpha4beta1 / Q000187:drug effects / Q000378:metabolism; D007968:Leukoencephalopathy, Progressive Multifocal / Q000139:chemically induced / Q000276:immunology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000276:immunology*; D000069442:Natalizumab; D011446:Prospective Studies
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039041:Integrin alpha4beta1; D000069442:Natalizumab