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Abstract

Objective: To define the in vitro effects of interferon beta 1a (IFN-β1a) on myelin basic protein (MBP)-reactive T cells and to determine its regulatory mechanism on cytokine networks in patients with MS.
Methods: The proliferation and cytokine production of MBP-reactive T-cell clones were measured in thymidine uptake assays and ELISA respectively. The precursor frequency of MBP-reactive T cells was estimated in a microwell culture system.
Results: IFN-β inhibited the proliferation of established MBP-reactive T-cell clones, which correlated with enhanced production of anti-inflammatory interleukin (IL)-4 and IL-10, and a decrease in tumor necrosis factor alpha (TNF-α) and IFN-γ. When examined with peripheral blood mononuclear cells (PBMCs), IFN-β was found to reduce the in vitro T-cell responses to MBP, as indicated by the significantly decreased frequency of MBP-reactive T cells. The decreased frequency of MBP-reactive T cells corresponded to an augmented production of IL-4 and IL-10. Although the level of TNF-α and IFN-γ was generally unaltered or decreased, IFN-β appeared to enhance the production of IFN-γ in PBMCs derived from some individuals with MS.
Conclusion: Interferon beta 1a (IFN-β) suppresses myelin basic protein (MBP)-reactive T cells and induces immune deviation toward the production of T-helper 2 cytokines, which may contribute to its therapeutic benefit in MS. The study also suggests some heterogeneity in MBP-reactive T-cell responses to IFN-β in different individuals with MS.

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References

1.
Stinissen P, Raus J, Zhang J. Autoimmune pathogenesis of multiple sclerosis: role of autoreactive T lymphocytes and new immunotherapeutic strategies. Crit Rev Immunol 1997;17:33–75.
2.
Zamvil S, Nelson P, Trotter J, et al. T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination. Nature 1985;317:355–358.
3.
Zhang J, Markovic–Plese S, Lacet B, Raus J, Weiner HL, Hafler DA. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 1994;179:973–984.
4.
Chou YK, Bourdette DN, Offner H, et al. Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis. J Neuroimmunol 1992;38:105–113.
5.
van der Veen RC, Stohlman SA. Encephalitogenic Th1 cells are inhibited by Th2 cells with related peptide specificity: relative roles of interleukin (IL)-4 and IL-10. J Neuroimmunol 1993;48:213–220.
6.
Sharief MK, Hentges R. Association between tumor necrosis factor-α and disease progression in patients with multiple sclerosis. N Engl J Med 1991;325:467–472.
7.
Selmaj K, Raine CS, Cannella B, Brosnan CF. Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J Clin Invest 1991;87:949–954.
8.
Panitch HS, Hirsch RL, Schindler J, Johnson KP. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 1987;37:1097–1102.
9.
Moreau T, Coles A, Wing M, et al. Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain 1996;119:225–237.
10.
Horsfall AC, Butler DM, Marinova L, et al. Suppression of collagen-induced arthritis by continuous administration of IL-4. J Immunol 1997;159:5687–5696.
11.
Bai XF, Zhu J, Zhang GX, et al. IL-10 suppresses experimental autoimmune neuritis and down-regulates TH1-type immune responses. Clin Immunol Immunopathol 1997;83:117–126.
12.
Rott O, Fleischer B, Cash E. Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur J Immunol 1994;24:1434–1440.
13.
Lider O, Reshef T, Beraud E, Ben-Nun A, Cohen IR. Anti-idiotypic network induced by T cell vaccination against experimental autoimmune encephalomyelitis. Science 1988;239:181–183.
14.
Cannella B, Gao YL, Brosnan C, Raine CS. IL-10 fails to abrogate experimental autoimmune encephalomyelitis. J Neurosci Res 1996;45:735–746.
15.
Khoruts A, Miller SD, Jenkins MK. Neuroantigen-specific Th2 cells are inefficient suppressors of experimental autoimmune encephalomyelitis induced by effector Th1 cells. J Immunol 1995;155:5011–5017.
16.
Lafaille JJ, Keere FV, Hsu Al, et al. Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease. J Exp Med 1997;186:307–312.
17.
Hermans G, Stinissen P, Hauben L, Van den Berg–Loonen E, Raus J, Zhang J. Cytokine profile of myelin basic protein-reactive T cells in multiple sclerosis and healthy individuals. Ann Neurol 1997;42:18–27.
18.
Vandenbark AA, Chou YK, Whitham R, et al. Treatment of multiple sclerosis with T-cell receptor peptides: results of a double-blind pilot trial. Nat Med 1996;2:1109–1115.
19.
Waisman A, Ruiz PJ, Hirschberg DL, et al. Suppressive vaccination with DNA encoding a variable region gene of the T-cell receptor prevents autoimmune encephalomyelitis and activates Th2 immunity. Nat Med 1996;2:899–905.
20.
Kagawa Y, Takasaki S, Utsumi J, et al. Comparative study of the asparagine-linked sugar chains of natural human interferon-β1 and recombinant human interferon-β1 produced by three different mammalian cells. J Biol Chem 1988;263:17508–17515.
21.
Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285–294.
22.
The IFNβ Multiple Sclerosis Study Group.Interferon-beta-1b is effective in relapsing–remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo controlled trial. Neurology 1993;43:655–661.
23.
Porrini AM, Gambi D, Reder AT. Interferon effects on interleukin-10 secretion: mononuclear cell response to interleukin-10 is normal in multiple sclerosis patients. J Neuroimmunol 1995;61:27–34.
24.
Noronha A, Toscas A, Jensen MA. Interferon β decreases T cell activation and interferon γ production in multiple sclerosis. J Neuroimmunol 1993;46:145–153.
25.
Rudick RA, Ransohoff RM, Peppler R, VanderBrug Medendorp S, Lehmann P, Alan J. Interferon beta induces interleukin-10 expression: relevance to multiple sclerosis. Ann Neurol 1996;40:618–627.
26.
Rudick RA, Ransohoff RM, Lee JC, et al. In vivo effects of interferon beta-1a on immunosuppressive cytokines in multiple sclerosis. Neurology 1998;50:1294–1300.
27.
Deibler GE, Martenson RE, Kies MW. Large scale preparation of myelin basic protein from central nervous tissue of several mammalian species. Prep Biochem 1972;2:139–165.
28.
Zhang J, Medaer R, Stinissen P, Hafler D, Raus J. MHC-restricted depletion of human myelin basic protein-reactive T cells by T cell vaccination. Science 1993;261:1451–1454.
29.
Khan O, Dhib-Jalbut S. Serum interferon B-1a (Avonex) levels following intramuscular injection in relapsing–remitting MS patients. Neurology 1998;51:735–742.
30.
Beck J, Rondot P, Catinot L, Falcoff E, Kirchner H, Wietzerbin J. Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand 1988;78:318–323.
31.
Arnason BGW, Toscas A, Dayal A, Qu Z, Noronha A. Role of interferons in demyelinating diseases. J Neural Transm 1997;49 (suppl):117–123.

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Published In

Neurology®
Volume 53Number 8November 1, 1999
Pages: 1692
PubMed: 10563614

Publication History

Received: January 18, 1999
Accepted: June 22, 1999
Published online: November 1, 1999
Published in print: November 1, 1999

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Authors

Affiliations & Disclosures

M.E. Kozovska, MD, PhD
From the Multiple Sclerosis Research and Neuroimmunology Laboratory (Drs. KozovskaHong, Zang, Rivera, Killian, and Zhang, and S. Li), Department of Neurology and Baylor-Methodist International Multiple Sclerosis Center; the Department of Microbiology and Immunology (Dr. Zhang), Baylor College of Medicine; and the Neurology Research Laboratory (Drs. Kozovska, Hong, Zang, and Zhang, and S. Li), Veterans Affairs Medical Center, Houston, TX.
J. Hong, MD, PhD
From the Multiple Sclerosis Research and Neuroimmunology Laboratory (Drs. KozovskaHong, Zang, Rivera, Killian, and Zhang, and S. Li), Department of Neurology and Baylor-Methodist International Multiple Sclerosis Center; the Department of Microbiology and Immunology (Dr. Zhang), Baylor College of Medicine; and the Neurology Research Laboratory (Drs. Kozovska, Hong, Zang, and Zhang, and S. Li), Veterans Affairs Medical Center, Houston, TX.
Y.C. Q. Zang, MD, PhD
From the Multiple Sclerosis Research and Neuroimmunology Laboratory (Drs. KozovskaHong, Zang, Rivera, Killian, and Zhang, and S. Li), Department of Neurology and Baylor-Methodist International Multiple Sclerosis Center; the Department of Microbiology and Immunology (Dr. Zhang), Baylor College of Medicine; and the Neurology Research Laboratory (Drs. Kozovska, Hong, Zang, and Zhang, and S. Li), Veterans Affairs Medical Center, Houston, TX.
S. Li, BS
From the Multiple Sclerosis Research and Neuroimmunology Laboratory (Drs. KozovskaHong, Zang, Rivera, Killian, and Zhang, and S. Li), Department of Neurology and Baylor-Methodist International Multiple Sclerosis Center; the Department of Microbiology and Immunology (Dr. Zhang), Baylor College of Medicine; and the Neurology Research Laboratory (Drs. Kozovska, Hong, Zang, and Zhang, and S. Li), Veterans Affairs Medical Center, Houston, TX.
V.M. Rivera, MD
From the Multiple Sclerosis Research and Neuroimmunology Laboratory (Drs. KozovskaHong, Zang, Rivera, Killian, and Zhang, and S. Li), Department of Neurology and Baylor-Methodist International Multiple Sclerosis Center; the Department of Microbiology and Immunology (Dr. Zhang), Baylor College of Medicine; and the Neurology Research Laboratory (Drs. Kozovska, Hong, Zang, and Zhang, and S. Li), Veterans Affairs Medical Center, Houston, TX.
J.M. Killian, MD
From the Multiple Sclerosis Research and Neuroimmunology Laboratory (Drs. KozovskaHong, Zang, Rivera, Killian, and Zhang, and S. Li), Department of Neurology and Baylor-Methodist International Multiple Sclerosis Center; the Department of Microbiology and Immunology (Dr. Zhang), Baylor College of Medicine; and the Neurology Research Laboratory (Drs. Kozovska, Hong, Zang, and Zhang, and S. Li), Veterans Affairs Medical Center, Houston, TX.
J.Z. Zhang, MD, PhD
From the Multiple Sclerosis Research and Neuroimmunology Laboratory (Drs. KozovskaHong, Zang, Rivera, Killian, and Zhang, and S. Li), Department of Neurology and Baylor-Methodist International Multiple Sclerosis Center; the Department of Microbiology and Immunology (Dr. Zhang), Baylor College of Medicine; and the Neurology Research Laboratory (Drs. Kozovska, Hong, Zang, and Zhang, and S. Li), Veterans Affairs Medical Center, Houston, TX.

Notes

Address correspondence and reprint requests to Dr. Jingwu Zhang, Department of Neurology, Baylor College of Medicine, 6501 Fannin Street, NB302, Houston, TX 77030.

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