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Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 1994 Nov;57(Suppl):11–14. doi: 10.1136/jnnp.57.suppl.11

Intravenous immunoglobulin therapy in multiple sclerosis: progress from remyelination in the Theiler's virus model to a randomised, double-blind, placebo-controlled clinical trial.

J H Noseworthy 1, P C O'Brien 1, B G van Engelen 1, M Rodriguez 1
PMCID: PMC1016715  PMID: 7964842

Abstract

No treatment has been found which reverses long-standing neurological dysfunction in patients with multiple sclerosis (MS). Observations in animal models of MS show that immunoglobulins directed against CNS components promote oligodendroglial proliferation and new myelin synthesis. Preliminary studies in inflammatory-demyelinating diseases of the human peripheral and central nervous system suggest that the repeated intravenous administration of polyclonal human immunoglobulin (IVIg) is sometimes followed by clinical improvement. A randomised, placebo-controlled, double-blind, clinical trial was designed to test the hypothesis that repeated administration of IVIg will result in a meaningful degree of recovery of apparently irreversibly lost neurological function (weakness). A total of 76 patients with MS will participate in the study. These patients had developed a fixed, apparently permanent weakness that had not improved in the preceding four to 18 months. If effective, IVIg administration may benefit the large proportion of patients with MS who have active disease by enhancing the potential for myelin repair in the evolution of the inflammatory-demyelinating lesion.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Brar S. P., Smith M. B., Nelson L. M., Franklin G. M., Cobble N. D. Evaluation of treatment protocols on minimal to moderate spasticity in multiple sclerosis. Arch Phys Med Rehabil. 1991 Mar;72(3):186–189. [PubMed] [Google Scholar]
  2. Dal Canto M. C., Lipton H. L. Multiple sclerosis. Animal model:Theiler's virus infection in mice. Am J Pathol. 1977 Aug;88(2):497–500. [PMC free article] [PubMed] [Google Scholar]
  3. Dal Canto M. C., Lipton H. L. Recurrent demyelination in chronic central nervous system infection produced by Theiler's murine encephalomyelitis virus. J Neurol Sci. 1979 Aug;42(3):391–405. doi: 10.1016/0022-510x(79)90172-2. [DOI] [PubMed] [Google Scholar]
  4. Dobi S., Lenkey B. Role of a secretagogue immunoglobulin in gastric acid secretion. Acta Physiol Acad Sci Hung. 1982;60(1-2):9–25. [PubMed] [Google Scholar]
  5. Dwyer J. M. Intravenous therapy with gamma globulin. Adv Intern Med. 1987;32:111–135. [PubMed] [Google Scholar]
  6. Engelhard D., Waner J. L., Kapoor N., Good R. A. Effect of intravenous immune globulin on natural killer cell activity: possible association with autoimmune neutropenia and idiopathic thrombocytopenia. J Pediatr. 1986 Jan;108(1):77–81. doi: 10.1016/s0022-3476(86)80772-7. [DOI] [PubMed] [Google Scholar]
  7. Friedmann A., Frankel G., Lorch Y., Steinman L. Monoclonal anti-I-A antibody reverses chronic paralysis and demyelination in Theiler's virus-infected mice: critical importance of timing of treatment. J Virol. 1987 Mar;61(3):898–903. doi: 10.1128/jvi.61.3.898-903.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Frohman L. P., Cook S. D., Bielory L. Dysgammaglobulinemia in steroid-dependent optic neuritis: response to gammaglobulin treatment. J Clin Neuroophthalmol. 1991 Dec;11(4):241–245. [PubMed] [Google Scholar]
  9. Fukue Y., Uchimura H., Mitsuhashi T., Okano S., Kanaji Y., Takaku F. Thyroglobulin release-stimulating activity in immunoglobulin G from patients with Graves' disease studied by human thyroid cells in vitro. J Clin Endocrinol Metab. 1987 Feb;64(2):261–265. doi: 10.1210/jcem-64-2-261. [DOI] [PubMed] [Google Scholar]
  10. Ghatak N. R., Leshner R. T., Price A. C., Felton W. L., 3rd Remyelination in the human central nervous system. J Neuropathol Exp Neurol. 1989 Sep;48(5):507–518. doi: 10.1097/00005072-198909000-00002. [DOI] [PubMed] [Google Scholar]
  11. Hirano A., Zimmerman H. M., Levine S. Electron microscopic observations of peripheral myelin in a central nervous system lesion. Acta Neuropathol. 1969;12(4):348–365. doi: 10.1007/BF00809131. [DOI] [PubMed] [Google Scholar]
  12. Hirsch R., Gress R. E., Pluznik D. H., Eckhaus M., Bluestone J. A. Effects of in vivo administration of anti-CD3 monoclonal antibody on T cell function in mice. II. In vivo activation of T cells. J Immunol. 1989 Feb 1;142(3):737–743. [PubMed] [Google Scholar]
  13. Huizinga T. W., van der Schoot C. E., Jost C., Klaassen R., Kleijer M., von dem Borne A. E., Roos D., Tetteroo P. A. The PI-linked receptor FcRIII is released on stimulation of neutrophils. Nature. 1988 Jun 16;333(6174):667–669. doi: 10.1038/333667a0. [DOI] [PubMed] [Google Scholar]
  14. Hunziker W., Koch T., Whitney J. A., Mellman I. Fc receptor phosphorylation during receptor-mediated control of B-cell activation. Nature. 1990 Jun 14;345(6276):628–632. doi: 10.1038/345628a0. [DOI] [PubMed] [Google Scholar]
  15. Itoyama Y., Webster H. D., Richardson E. P., Jr, Trapp B. D. Schwann cell remyelination of demyelinated axons in spinal cord multiple sclerosis lesions. Ann Neurol. 1983 Sep;14(3):339–346. doi: 10.1002/ana.410140313. [DOI] [PubMed] [Google Scholar]
  16. Kurtzke J. F., Beebe G. W., Nagler B., Auth T. L., Kurland L. T., Nefzger M. D. Studies on the natural history of multiple sclerosis. 7. Correlates of clinical change in an early bout. Acta Neurol Scand. 1973;49(3):379–395. doi: 10.1111/j.1600-0404.1973.tb01311.x. [DOI] [PubMed] [Google Scholar]
  17. Lang W., Rodriguez M., Lennon V. A., Lampert P. W. Demyelination and remyelination in murine viral encephalomyelitis. Ann N Y Acad Sci. 1984;436:98–102. doi: 10.1111/j.1749-6632.1984.tb14779.x. [DOI] [PubMed] [Google Scholar]
  18. Lehrich J. R., Arnason B. G., Hochberg F. H. Demyelinative myelopathy in mice induced by the DA virus. J Neurol Sci. 1976 Oct;29(2-4):149–160. doi: 10.1016/0022-510x(76)90167-2. [DOI] [PubMed] [Google Scholar]
  19. Lipton H. L., Canto C. D. Contrasting effects of immunosuppression on Theiler's virus infection in mice. Infect Immun. 1977 Mar;15(3):903–909. doi: 10.1128/iai.15.3.903-909.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ohta Y., Tamura S., Tezuka E., Sugawara M., Imai S., Tanaka H. Autoimmune MRL/lpr mice sera contain IgG with interleukin 3-like activity. J Immunol. 1988 Jan 15;140(2):520–525. [PubMed] [Google Scholar]
  21. Penn R. D. Intrathecal baclofen for spasticity of spinal origin: seven years of experience. J Neurosurg. 1992 Aug;77(2):236–240. doi: 10.3171/jns.1992.77.2.0236. [DOI] [PubMed] [Google Scholar]
  22. Poser C. M., Paty D. W., Scheinberg L., McDonald W. I., Davis F. A., Ebers G. C., Johnson K. P., Sibley W. A., Silberberg D. H., Tourtellotte W. W. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983 Mar;13(3):227–231. doi: 10.1002/ana.410130302. [DOI] [PubMed] [Google Scholar]
  23. Prineas J. W., Barnard R. O., Kwon E. E., Sharer L. R., Cho E. S. Multiple sclerosis: remyelination of nascent lesions. Ann Neurol. 1993 Feb;33(2):137–151. doi: 10.1002/ana.410330203. [DOI] [PubMed] [Google Scholar]
  24. Prineas J. W., Connell F. Remyelination in multiple sclerosis. Ann Neurol. 1979 Jan;5(1):22–31. doi: 10.1002/ana.410050105. [DOI] [PubMed] [Google Scholar]
  25. Prineas J. W., Kwon E. E., Goldenberg P. Z., Ilyas A. A., Quarles R. H., Benjamins J. A., Sprinkle T. J. Multiple sclerosis. Oligodendrocyte proliferation and differentiation in fresh lesions. Lab Invest. 1989 Nov;61(5):489–503. [PubMed] [Google Scholar]
  26. Raine C. S., Hintzen R., Traugott U., Moore G. R. Oligodendrocyte proliferation and enhanced CNS remyelination after therapeutic manipulation of chronic relapsing EAE. Ann N Y Acad Sci. 1988;540:712–714. doi: 10.1111/j.1749-6632.1988.tb27222.x. [DOI] [PubMed] [Google Scholar]
  27. Raine C. S., Scheinberg L., Waltz J. M. Multiple sclerosis. Oligodendrocyte survival and proliferation in an active established lesion. Lab Invest. 1981 Dec;45(6):534–546. [PubMed] [Google Scholar]
  28. Raine C. S., Traugott U. Chronic relapsing experimental autoimmune encephalomyelitis. Ultrastructure of the central nervous system of animals treated with combinations of myelin components. Lab Invest. 1983 Mar;48(3):275–284. [PubMed] [Google Scholar]
  29. Rault R., Piraino B., Johnston J. R., Oral A. Pulmonary and renal toxicity of intravenous immunoglobulin. Clin Nephrol. 1991 Aug;36(2):83–86. [PubMed] [Google Scholar]
  30. Rodriguez M. Immunoglobulins stimulate central nervous system remyelination: electron microscopic and morphometric analysis of proliferating cells. Lab Invest. 1991 Mar;64(3):358–370. [PubMed] [Google Scholar]
  31. Rodriguez M., Lafuse W. P., Leibowitz J., David C. S. Partial suppression of Theiler's virus-induced demyelination in vivo by administration of monoclonal antibodies to immune-response gene products (Ia antigens). Neurology. 1986 Jul;36(7):964–970. doi: 10.1212/wnl.36.7.964. [DOI] [PubMed] [Google Scholar]
  32. Rodriguez M., Leibowitz J. L., Lampert P. W. Persistent infection of oligodendrocytes in Theiler's virus-induced encephalomyelitis. Ann Neurol. 1983 Apr;13(4):426–433. doi: 10.1002/ana.410130409. [DOI] [PubMed] [Google Scholar]
  33. Rodriguez M., Lennon V. A., Benveniste E. N., Merrill J. E. Remyelination by oligodendrocytes stimulated by antiserum to spinal cord. J Neuropathol Exp Neurol. 1987 Jan;46(1):84–95. doi: 10.1097/00005072-198701000-00008. [DOI] [PubMed] [Google Scholar]
  34. Rodriguez M., Lennon V. A. Immunoglobulins promote remyelination in the central nervous system. Ann Neurol. 1990 Jan;27(1):12–17. doi: 10.1002/ana.410270104. [DOI] [PubMed] [Google Scholar]
  35. Rodriguez M., Oleszak E., Leibowitz J. Theiler's murine encephalomyelitis: a model of demyelination and persistence of virus. Crit Rev Immunol. 1987;7(4):325–365. [PubMed] [Google Scholar]
  36. Rodriguez M., Quddus J. Effect of cyclosporin A, silica quartz dust, and protease inhibitors on virus-induced demyelination. J Neuroimmunol. 1986 Dec;13(2):159–174. doi: 10.1016/0165-5728(86)90062-7. [DOI] [PubMed] [Google Scholar]
  37. Rodriguez M., Scheithauer B. W., Forbes G., Kelly P. J. Oligodendrocyte injury is an early event in lesions of multiple sclerosis. Mayo Clin Proc. 1993 Jul;68(7):627–636. doi: 10.1016/s0025-6196(12)60597-7. [DOI] [PubMed] [Google Scholar]
  38. Rodriguez M., Siegel L. M., Hovanec-Burns D., Bologa L., Graves M. C. Theiler's virus-associated antigens on the surfaces of cultured glial cells. Virology. 1988 Oct;166(2):463–474. doi: 10.1016/0042-6822(88)90517-x. [DOI] [PubMed] [Google Scholar]
  39. Rodriguez M., Sriram S. Successful therapy of Theiler's virus-induced demyelination (DA strain) with monoclonal anti-Lyt-2 antibody. J Immunol. 1988 May 1;140(9):2950–2955. [PubMed] [Google Scholar]
  40. Roos R. P., Wollmann R. DA strain of Theiler's murine encephalomyelitis virus induces demyelination in nude mice. Ann Neurol. 1984 May;15(5):494–499. doi: 10.1002/ana.410150516. [DOI] [PubMed] [Google Scholar]
  41. SCHUMACHER G. A., BEEBE G., KIBLER R. F., KURLAND L. T., KURTZKE J. F., MCDOWELL F., NAGLER B., SIBLEY W. A., TOURTELLOTTE W. W., WILLMON T. L. PROBLEMS OF EXPERIMENTAL TRIALS OF THERAPY IN MULTIPLE SCLEROSIS: REPORT BY THE PANEL ON THE EVALUATION OF EXPERIMENTAL TRIALS OF THERAPY IN MULTIPLE SCLEROSIS. Ann N Y Acad Sci. 1965 Mar 31;122:552–568. doi: 10.1111/j.1749-6632.1965.tb20235.x. [DOI] [PubMed] [Google Scholar]
  42. Salama A., Mueller-Eckhardt C., Kiefel V. Effect of intravenous immunoglobulin in immune thrombocytopenia. Lancet. 1983 Jul 23;2(8343):193–195. doi: 10.1016/s0140-6736(83)90175-7. [DOI] [PubMed] [Google Scholar]
  43. Sultan Y., Kazatchkine M. D., Maisonneuve P., Nydegger U. E. Anti-idiotypic suppression of autoantibodies to factor VIII (antihaemophilic factor) by high-dose intravenous gammaglobulin. Lancet. 1984 Oct 6;2(8406):765–768. doi: 10.1016/s0140-6736(84)90701-3. [DOI] [PubMed] [Google Scholar]
  44. Tan E., Hajinazarian M., Bay W., Neff J., Mendell J. R. Acute renal failure resulting from intravenous immunoglobulin therapy. Arch Neurol. 1993 Feb;50(2):137–139. doi: 10.1001/archneur.1993.00540020015010. [DOI] [PubMed] [Google Scholar]
  45. Traugott U., Stone S. H., Raine C. S. Chronic relapsing experimental autoimmune encephalomyelitis. treatment with combinations of myelin components promotes clinical and structural recovery. J Neurol Sci. 1982 Oct;56(1):65–73. doi: 10.1016/0022-510x(82)90061-2. [DOI] [PubMed] [Google Scholar]
  46. Welsh C. J., Tonks P., Nash A. A., Blakemore W. F. The effect of L3T4 T cell depletion on the pathogenesis of Theiler's murine encephalomyelitis virus infection in CBA mice. J Gen Virol. 1987 Jun;68(Pt 6):1659–1667. doi: 10.1099/0022-1317-68-6-1659. [DOI] [PubMed] [Google Scholar]
  47. van Doorn P. A., Rossi F., Brand A., van Lint M., Vermeulen M., Kazatchkine M. D. On the mechanism of high-dose intravenous immunoglobulin treatment of patients with chronic inflammatory demyelinating polyneuropathy. J Neuroimmunol. 1990 Sep-Oct;29(1-3):57–64. doi: 10.1016/0165-5728(90)90147-f. [DOI] [PubMed] [Google Scholar]
  48. van Engelen B. G., Hommes O. R., Pinckers A., Cruysberg J. R., Barkhof F., Rodriguez M. Improved vision after intravenous immunoglobulin in stable demyelinating optic neuritis. Ann Neurol. 1992 Dec;32(6):834–835. doi: 10.1002/ana.410320624. [DOI] [PubMed] [Google Scholar]

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