Down-regulation of survivin expression in T lymphocytes after interferon beta-1a treatment in patients with multiple sclerosis.
BACKGROUND
Treatment with interferon beta reduces clinical exacerbations in multiple sclerosis (MS) through several immunomodulatory mechanisms that involve the augmentation of programmed cell death (apoptosis) of peripheral T lymphocytes. The expression of survivin, a cell cycle-regulated antiapoptosis protein, is up-regulated in mitogen-stimulated T lymphocytes from patients with MS, and this expression correlates with MS disease activity.


OBJECTIVE
To evaluate the effect of interferon beta on the expression of survivin and other apoptosis regulatory molecules in peripheral T lymphocytes from patients with MS.


METHODS
In a prospective, combined clinical and immunologic study, we evaluated the expression of survivin, Bcl-2 protein, and the death receptor Fas in mitogen-stimulated T lymphocytes from 26 patients with MS, before and serially after treatment with interferon beta-1a. We also investigated the long-term effects of interferon beta-1a on cellular expression of these proteins and T-lymphocyte apoptosis in a cross-sectional study of 19 patients with MS receiving long-term interferon beta-1a therapy.


RESULTS
Treatment with interferon beta-1a reduced the expression of survivin in in vitro stimulated T lymphocytes. This reduced expression correlated with augmented T-cell susceptibility to apoptosis and with clinical response to treatment. In contrast, interferon beta-1a therapy did not significantly alter cellular expression of Bcl-2 protein or Fas. This down-regulatory effect of interferon beta-1a on cellular expression of survivin was maintained after long-term therapy.


CONCLUSIONS
Our observations suggest that interferon beta exerts a regulatory effect on peripheral T lymphocytes through an antiapoptosis mechanism that involves the down-regulation of cellular survivin expression.
Department of Neuroimmunology, Guy's, King's and St. Thiomas' School of Medicine, Guy's Hospital, London SE1 1UL, England. m.k.sharief@kcl.ac.uk
Moad K
MK
Sharief
Yemane K
YK
Semra
D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D002868:Chromosomal Proteins, Non-Histone / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000494:pharmacology* / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D008869:Microtubule-Associated Proteins; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology*; D009363:Neoplasm Proteins; D011446:Prospective Studies; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000077022:Survivin; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; D002868:Chromosomal Proteins, Non-Histone; C421307:FAIM protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D016899:Interferon-beta; D000068556:Interferon beta-1a