Interferon beta promotes nerve growth factor secretion early in the course of multiple sclerosis.
BACKGROUND
Interferon beta therapy has been shown to reduce the rate of clinical relapse and the frequency of magnetic resonance imaging-defined T2- weighted lesions in patients with multiple sclerosis (MS). When given early, interferon beta also reduces the rate of development of brain atrophy and improves axonal integrity. Nerve growth factor (NGF) can retard the severity and course of experimental allergic encephalomyelitis.


OBJECTIVE
To determine whether interferon beta effects on patients with MS could be related to modulation of neurotrophin production within the central nervous system.


METHODS
We studied neurotrophin production by human glial and brain endothelial cells in response to coculture with MS patient-derived lymphocytes, and correlated levels of NGF secretion with clinical and magnetic resonance imaging-defined markers of disease.


RESULTS
We demonstrate that production of NGF by human brain microvascular endothelial cells is triggered by interaction with T lymphocytes derived from MS patients. No such response was observed using human adult microglia or human fetal astrocytes. Nerve growth factor production by endothelial cells was potentiated by pretreating lymphocytes with interferon beta in vitro, and by using lymphocytes derived from MS patients treated with interferon beta in vivo. By using this assay, we show that levels of NGF induced by lymphocytes from MS patients inversely correlate with magnetic resonance imaging measures of brain atrophy and axonal injury.


CONCLUSIONS
These findings suggest that interferon beta-mediated production of NGF at the level of the blood-brain barrier, whether acting as an immunomodulator or directly on neural cells, is another potential mechanism contributing to the magnetic resonance imaging-defined effect of interferon beta on brain atrophy when given early in the course of MS.
Biernacki
Katarzyna
K
Neuroimmunology Unit and McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University.
Antel
Jack P
JP
Blain
Manon
M
Narayanan
Sridar
S
Arnold
Douglas L
DL
Prat
Alexandre
A
D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001284:Atrophy / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D017252:CD3 Complex / Q000096:biosynthesis; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D018920:Coculture Techniques; D015331:Cohort Studies; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology* / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D020932:Nerve Growth Factor / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014855:Wallerian Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control
D017252:CD3 Complex; D001224:Aspartic Acid; D016899:Interferon-beta; D020932:Nerve Growth Factor; C000179:N-acetylaspartate