Randomized study of antibodies to IFN-g and TNF-a in secondary progressive multiple sclerosis

Abstract

Studies of cytokines in multiple sclerosis (MS) have shown that immune mechanisms connected with disturbance of the synthesis of cytokines probably play critical roles in the initiation and prolongation of MS. In a double-blind, placebo-controlled trial, 45 patients with active secondary progressive MS were randomized to three groups of 15 patients, each receiving a short course of antibodies to IFN-g, to tumor necrosis factor (TNF)-a, or a placebo. After 12 months with analysis of disability (Expanded Disability Status Scale scores), accompanied by interval determinations of lymphocyte subpopulations, cytokine production levels, MRI, and evoked potentials, it was found that only patients who received antibodies to IFN-g showed statistically significant improvement compared to the placebo group-a significant increase in the number of patients without confirmed disability progression. This was supported by MRI data (a decrease in the number of active lesions) and systemic changes in cytokine status (a decrease in IL-1b, TNF-a, and IFN-g concentrations in supernatants of activated blood cells of these MS patients and an increase in TGF-b production). Neutralization of IFN-g could be a new approach to treating secondary progressive MS. Long-term administration of humanized monoclonal antibodies to IFN-g and simultaneous use of antibodies to IFN-g together with IFN-b products are planned.

Keywords

multiple sclerosis anti-interferon-γ anti-tumor necrosis factor-α cytokines

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References

Link H. (1998) The cytokine storm in multiple sclerosis . Multiple Sclerosis 4: 12-15 .

Skurkovich SV , Klinova EG , Eremkina EI , Levina NV. (1974) Immunosuppressive effect of an anti-interferon serum . Nature 22: 551-552 .

Skurkovich SV , Eremkina EI. (1975) Probable role of interferon in allergy . Ann Allergy 35: 356-360 .

Skurkovich SV et al. (1977) Lymphocytes' cytotoxicity towards cells of human lymphoblastoid lines in patients with rheumatoid arthritis and systemic lupus erythematosus . Ann Allergy 39: 344-350 .

Chofflon M. (2000) Recombinant human interferon beta in relapsing-remitting multiple sclerosis: a review of the major clinical trials . Eur J Neurol 7: 369-380 .

Kappos L , and the European Study Group on interferon beta-1b in secondary progressive .MS (1998) Placebo controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis . Lancet 352: 1498-1504 .

Cavallo MG , Pozzilli P , Thorpe R. (1994) Cytokines and autoimmunity . Clin Exp Immunol 96: 1-7 .

Christensen T , Sorensen PD , Hansen HJ , Moller-Larsen A. (2001) Endogenous retroviruses in multiple sclerosis . Ugeskr Laeger 163: 297-301 .

Karlsson H et al. (2001) Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia . Proc Natl Acad Sci USA 98: 4634-4639 .

10.

Revel M et al. (1995) Antagonism of interferon beta on interferon gamma: inhibition of signal transduction in vitro and reduction of serum levels in multiple sclerosis patients . Multiple Sclerosis 1 (Suppl): S5-S11 .

11.

Gusev EI et al. (1997) Anticytokine therapy of secondary progressive MS . Nevrologicheskiy Vestnik 29: 55-58 .

12.

Poser CM et al. (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols . Ann Neurol 13: 227-231 .

13.

Deomina T et al. (1997) A three-month pilot trial of antibodies to cytokines (Interferon-alpha, Interferon-gamma, TNF-alpha) in multiple sclerosis . Eur J Neurol 4 (Suppl.1): S62-S63 .

14.

Miller DH et al. (1991) Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: concerted action guidelines . J Neurol Neurosurg Psychiatry 54: 683-688 .

15.

Comi G et al. (1989) Correlation between multimodal evoked potentials and magnetic resonance imaging in multiple sclerosis . JNeurol 236: 4-8 .

16.

Giesser BS et al. (1987) Trimodal evoked potentials compared with magnetic resonance imaging in the diagnosis of multiple sclerosis . Arch Neurol 44: 281-284 .

17.

Gusev EI , Demina TL , Boiko AN , Pinegin BV. (1994) Prolonged dynamical clinico-immunological observation of 85 patients with definite multiple sclerosis . J Neurol 8: 500-510 .

18.

Stone LA et al. (1995) Blood-barrier disruption on contrast-enhanced MRI in patients with mild relapsingremitting multiple sclerosis . Neurology 45: 1122-1126 .

19.

Khoury SJ , Weiner HL. (1998) Multiple sclerosis. What have we learned from magnetic resonance imaging studies? Arch Intern Med 158: 565-573 .

20.

Kremenchutzky M et al. (1999) The natural history of multiple sclerosis: a geographically based study: 7. Progressive-relapsing and relapsing progressive multiple sclerosis re-evaluation . Brain 122: 1941-1950 .

21.

Beck J et al. (1988) Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestations in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand 78: 318-323 .

22.

Debruyne J et al. (1998) Relapse markers in multiple sclerosis: are in vitro cytokine production changes reflected by T-cell phenotype alterations . Multiple Sclerosis 4: 193-197 .

23.

Sorensen PS. (1999) Biological markers in body fluids for activity and progression in multiple sclerosis . Multiple Sclerosis 5: 287-290 .

24.

Oganezov VK et al. (1992) Production of IL1 and IL6 in multiple sclerosis . Immunologia 4: 58-61 .

25.

Beck J et al. (1991) TGF-bb-like activity produced during regression of exacerbations in multiple sclerosis . Acta Neurol Scand 84: 452-455 .

26.

Navikas V et al. (1995) Increased mRNA expression of IL- 10 in mononuclear cells in multiple sclerosis and optic neuritis . Scand J Immunol 41: 171-178 .

27.

Windhagen A et al. (1998) Cytokine secretion of myelin basic protein reactive T cells in patients with multiple sclerosis . J Neuroimmunol 91: 1-9 .

28.

Panitch HS , Hirsch RL , Schindler J , Johnson KP. (1987) Treatment of multiple sclerosis with gamma interferon: Exacerbations associated with activation of the immune system . Neurology 37: 1097-1102 .

29.

Traugott U , Lebon P. (1988) Demonstration of a, b, and g interferons in active chronic multiple sclerosis lesions . Ann NY Acad Sci 540: 309-311 .

30.

Van Oosten BW et al. (1996) Increased MRI activity and immune system activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2 . Neurology 46: 1531-1534 .

31.

The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group . (1999) TNF neutralization in MS. Results of a randomized, placebo-controlled multicenter study . Neurology 53: 457-465 .

32.

Klinkert WE et al. (1997) TNF-alpha receptor fusion protein prevents experimental autoimmune encephalomyelitis and demyelination in Lewis rats: an overview . J Neuroimmunol 72: 163-168 .

33.

Liu J et al. (1998) TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination . Nat Med 4: 78-83 .

34.

Berger S et al. (1997) Immune complexes are potent inhibitors of interleukin-12 secretion by human monocytes . Eur J Immunol 27: 2994-3000 .