Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand

An Erratum to this article was published on 01 December 2000

Abstract

Myelin-specific T lymphocytes are considered essential in the pathogenesis of multiple sclerosis. The myelin basic protein peptide (a.a. 83–99) represents one candidate antigen; therefore, it was chosen to design an altered peptide ligand, CGP77116, for specific immunotherapy of multiple sclerosis. A magnetic resonance imaging-controlled phase II clinical trial with this altered peptide ligand documented that it was poorly tolerated at the dose tested, and the trial had therefore to be halted. Improvement or worsening of clinical or magnetic resonance imaging parameters could not be demonstrated in this small group of individuals because of the short treatment duration. Three patients developed exacerbations of multiple sclerosis, and in two this could be linked to altered peptide ligand treatment by immunological studies demonstrating the encephalitogenic potential of the myelin basic protein peptide (a.a. 83–99) in a subgroup of patients. These data raise important considerations for the use of specific immunotherapies in general.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Changes in clinical, MRI and immunological parameters during therapy with CGP77116.
Figure 2: Cytokine profile and cross-reactivity of TCL specific for MBP(83–99) and CGP77116
Figure 3: Axial brain MRI images before and during exacerbations of MS.
Figure 4: T-cell reactivity to multiple myelin epitopes in patients MS502 (left) and MS601 (right).
Figure 5: Cross-reactivity patterns between MBP(83–99) and CGP77116 and delineation of the fine specificity of autoreactive T cells from patients MS502 and MS601.

References

  1. Martin, R., McFarland, H.F. & McFarlin, D.E. Immunological aspects of demyelinating diseases. Annu. Rev. Immunol. 10, 153–187 (1992).

    CAS  Article  PubMed  Google Scholar 

  2. Lassmann, H. Neuropathology in multiple sclerosis: new concepts. Mult. Scler. 4, 93–98 (1998 ).

    CAS  Article  PubMed  Google Scholar 

  3. Raine, C.S. in Multiple Sclerosis (eds. Hallpike, J.F., Adams, C.W. & Tourtellotte, W.W.) 413–478 (Williams & Wilkins, Baltimore, 1983).

    Google Scholar 

  4. Trapp, B.D. et al. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278–285 (1998).

    CAS  Article  PubMed  Google Scholar 

  5. Steinman, L. Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 85, 299– 302 (1996).

    CAS  Article  PubMed  Google Scholar 

  6. Hafler, D.A. & Weiner, H.L. MS: a CNS and systemic autoimmune disease. Immunol. Today 10, 104– 107 (1989).

    CAS  Article  PubMed  Google Scholar 

  7. Wekerle, H., Linington, C., Lassmann, H. & Meyermann, R. Cellular immune reactivity within the CNS. Trends. Neuro. Sci. 9, 271–277 ( 1986).

    Article  Google Scholar 

  8. Madsen, L.S. et al. A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nature Genet. 23, 343–347 (1999).

    CAS  Article  PubMed  Google Scholar 

  9. Lassmann, H., Raine, C.S., Antel, J. & Prineas, J.W. Immunopathology of multiple sclerosis: report on an international meeting held at the Institute of Neurology of the University of Vienna. J. Neuroimmunol. 86, 213–217 (1998).

    CAS  Article  PubMed  Google Scholar 

  10. Lucchinetti, C.F., Brueck, W., Rodriguez, M. & Lassmann, H. Multiple sclerosis: lessons from neuropathology. Semin. Neurol. 18, 337–349 ( 1998).

    CAS  Article  PubMed  Google Scholar 

  11. Zamvil, S.S. & Steinman, L. The T lymphocyte in experimental allergic encephalomyelitis. Annu. Rev. Immunol. 8, 579–621 (1990).

    CAS  Article  PubMed  Google Scholar 

  12. Ota, K. et al. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 346, 183– 187 (1990).

    CAS  Article  PubMed  Google Scholar 

  13. Martin, R. et al. Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals . J. Immunol. 145, 540– 548 (1990).

    CAS  PubMed  Google Scholar 

  14. Fritz, R.B. & McFarlin, D.E. in Antigenic Determinants and Immune Response. Chem. Immunol. Vol 46 (ed. Sercarz, E.E.) 101–125 (Karger, Basel, 1989).

    Google Scholar 

  15. Pette, M. et al. Myelin autoreactivity in multiple sclerosis: recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of multiple sclerosis patients and healthy donors. Proc. Natl. Acad. Sci. USA 87, 7968–7972 ( 1990).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Valli, A. et al. Binding of myelin basic protein peptides to human histocompatibility leukocyte antigen class II molecules and their recognition by T cells from multiple sclerosis patients. J. Clin. Invest. 91, 616–628 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Martin, R. et al. A myelin basic protein peptide is recognized by cytotoxic T cells in the context of four HLA-DR types associated with multiple sclerosis . J. Exp. Med. 173, 19– 24 (1991).

    CAS  Article  PubMed  Google Scholar 

  18. Krogsgaard, M. et al. Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85–99 complex . J. Exp. Med. 191, 1395– 1412 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Vandenbark, A.A., Hashim, G. & Offner, H. Immunization with a synthetic T-cell receptor V-region peptide against experimental autoimmune encephalomyelitis. Nature 341, 541–544 ( 1989).

    CAS  Article  PubMed  Google Scholar 

  20. Howell, M.D. et al. Vaccination against experimental allergic autoimmune encephalomyelitis with T cell receptor peptides. Science 246, 668–670 (1989).

    CAS  Article  PubMed  Google Scholar 

  21. Wraith, D.C., McDevitt, H.O., Steinman, L. & Acha-Orbea, H. T cell recognition as the target for immune intervention in autoimmune disease . Cell 57, 709–715 (1989).

    CAS  Article  PubMed  Google Scholar 

  22. Acha-Orbea, H. et al. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention . Cell 54, 263–273 (1988).

    CAS  Article  PubMed  Google Scholar 

  23. Hohlfeld, R. Biotechnological agents of the immunotherapy of multiple sclerosis. Principles, problems and perspectives. Brain 120, 865 –916 (1997).

    Article  PubMed  Google Scholar 

  24. Nicholson, L.B., Greer, J.M., Sobel, R.A., Lees, M.B. & Kuchroo, V.K. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 3, 397–405 (1995).

    CAS  Article  PubMed  Google Scholar 

  25. Karin, N., Mitchell, D.J., Brocke, S., Ling, N. & Steinman, L. Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon γ and tumor necrosis factor α production. J. Exp. Med. 180, 2227–2237 (1994).

    CAS  Article  PubMed  Google Scholar 

  26. Brocke, S. et al. Dynamics of autoimmune T cell infiltration: reversal of paralysis and disappearance of inflammation following treatment of experimental encephalomyelitis with a myelin basic protein peptide analog. Nature 379, 343–346 (1996).

    CAS  Article  PubMed  Google Scholar 

  27. De Magistris, M.T. et al. Antigen analog-major histocompatibility complexes act as antagonists of the T cell receptor. Cell 68, 625– 634 (1992).

    CAS  Article  PubMed  Google Scholar 

  28. Sloan-Lancaster, J., Shaw, A.S., Rothbard, J.B. & Allen, P.M. Partial T cell signaling: Altered phospho-ζ and lack of zap70 recruitment in APL-induced T cell anergy. Cell 79, 913 –922 (1994).

    CAS  Article  PubMed  Google Scholar 

  29. Madrenas, J. et al. ζ phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Science 167, 515–518 (1995).

    Article  Google Scholar 

  30. Windhagen, A. et al. Modulation of cytokine patterns of human autoreactive T cell clones by a single amino acid substitution of their peptide ligand. Immunity 2, 373–380 ( 1995).

    CAS  Article  PubMed  Google Scholar 

  31. Kurtzke, J.F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33, 1444– 52 (1983).

    CAS  Article  PubMed  Google Scholar 

  32. Sharrack, B. & Hughes, R.A. Clinical scales for multiple sclerosis . J. Neurol. Sci. 135, 1– 9 (1996).

    CAS  Article  PubMed  Google Scholar 

  33. Stone, L.A. et al. Characterization of MRI response to treatment with interferon beta-1b: contrast-enhancing MRI lesion frequency as a primary outcome measure . Neurology 49, 862–869 (1997).

    CAS  Article  PubMed  Google Scholar 

  34. Bielekova, B. et al. Preferential expansion of autoreactive T lymphocytes from the memory T-cell pool by IL-7. J. Neuroimmunol. 100 , 115–123 (1999).

    CAS  Article  PubMed  Google Scholar 

  35. Germain, R.N. & Stefanova, I. The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation . Annu. Rev. Immunol. 17, 467– 522 (1999).

    CAS  Article  PubMed  Google Scholar 

  36. Hemmer, B., Stefanova, I., Vergelli, M., Germain, R.N. & Martin, R. Relationships among TCR ligand potency, thresholds for effector function elicitation, and the quality of early signaling events in human T cells. J. Immunol. 160, 5807–5814 (1998).

    CAS  PubMed  Google Scholar 

  37. Sturniolo, T. et al. Generation of tissue-specific and promiscuous HLA ligand databases using DNA microarrays and virtual HLA class II matrices. Nature Biotechnol. 17, 555–561 (1999).

    CAS  Article  Google Scholar 

  38. Vergelli, M. et al. Differential activation of human autoreactive T cell clones by altered peptide ligands derived from myelin basic protein peptide (87-99) . Eur. J. Immunol. 26, 2624– 2634 (1996).

    CAS  Article  PubMed  Google Scholar 

  39. Mason, D. A very high level of crossreactivity is an essential feature of the T- cell receptor. Immunol. Today 19, 395– 404 (1998).

    CAS  Article  PubMed  Google Scholar 

  40. Lucas, B., Stefanova, I., Yasutomo, K., Dautigny, N. & Germain, R.N. Divergent changes in the sensitivity of maturing T cells to structurally related ligands underlies formation of a useful T cell repertoire. Immunity 10, 367–376 (1999).

    CAS  Article  PubMed  Google Scholar 

  41. Nicholson, L.B., Anderson, A.C. & Kuchroo, V.K. Tuning T cell activation threshold and effector function with cross-reactive peptide ligands. Int. Immunol. 12, 205–213 (2000).

    CAS  Article  PubMed  Google Scholar 

  42. Hemmer, B. et al. Human T-cell response to myelin basic protein peptide (83–99): Extensive heterogeneity in antigen recognition, function, and phenotype. Neurology 49, 1116–1126 (1997).

    CAS  Article  PubMed  Google Scholar 

  43. Constant, S.L. & Bottomly, K. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu. Rev. Immunol. 15, 297–322 (1997).

    CAS  Article  PubMed  Google Scholar 

  44. Tuohy, V.K., Sobel, R.A. & Lees, M.B. Myelin proteolipid protein-induced experimental allergic encephalomyelitis. Variations of disease expression in different strains of mice. J. Immunol. 140, 1868– 1873 (1988).

    CAS  PubMed  Google Scholar 

  45. Remlinger, J. Accidents paralytiques au cours du traitment antirabique. Ann. Inst. Pasteur 19, 625–646 (1905).

    Google Scholar 

  46. Rivers, T.M., Sprunt, D.H. & Berry, G.P. Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J. Exp. Med. 58, 39–53 (1933).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Paterson, P.Y. Transfer of allergic encephalomyelitis in rats by means of lymph node cells . J. Exp. Med. 111, 119– 133 (1960).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Pettinelli, C.B. & McFarlin, D.E. Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vivo activation of lymph node cells by myelin basic protein: requirement for Lyt-1+2- T lymphocytes . J. Immunol. 127, 1420– 1423 (1981).

    CAS  PubMed  Google Scholar 

  49. Fujinami, R.S. & Oldstone, M.B.A. Amino Acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 230, 1043–1045 (1985).

    CAS  Article  PubMed  Google Scholar 

  50. Schumacher, G.A. Problems of experimental trials of therapy in multiple sclerosis: Report by the panel on the evaluation of experimental trials in multiple sclerosis. Ann. New York Acad. Sci. 112, 552– 568 (1965).

    Google Scholar 

  51. DeCarli, C. et al. Method for quantification of brain, ventricular, and subarachnoid CSF volumes from MR images. J. Comput. Assist. Tomogr. 16, 274–284 (1992).

    CAS  Article  PubMed  Google Scholar 

  52. Deibler, G.E., Martenson, R.E. & Kies, M.W. Large scale preparation of myelin basic protein from central nervous system tissue of several mammalian species. Prep. Biochem. 2, 139–165 ( 1972).

    CAS  PubMed  Google Scholar 

  53. Ling, N. et al. Isolation, primary structure, and synthesis of human hypothalamic somatocrinin: growth hormone-releasing factor. Proc. Natl. Acad. Sci. USA 81, 4302–4306 ( 1984).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Houghten, R.A. General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids. Proc. Natl. Acad. Sci. USA 82, 5131 –5135 (1985).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Lefkovits, I. & Waldmann, H. Limiting dilution analysis of the cells of immune system. The clonal basis of the immune response. Immunol. Today 5, 265–277 (1984).

    CAS  Article  PubMed  Google Scholar 

  56. Zhang, J. et al. Increased frequency of interleukin-2-responsive T cells specific for myelin basic protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J. Exp. Med. 179, 973–984 (1994).

    CAS  Article  PubMed  Google Scholar 

  57. Muraro, P.A., Pette, M., Bielekova, B., McFarland, H.F. & Martin, R. Human autoreactive CD4+ T cells from naive CD45RA+ and memory CD45RO+ subsets differ with respect to epitope specificity and functional antigen avidity. J. Immunol. 164, 5474– 5481 (2000).

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank T. Staehelin (Novartis, Basel, Switzerland) and P. Conlon (Neurocrine Biosciences, San Diego, California, California) for comments, W.E. Biddison, C.S. Stuerzebecher (Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health) and M. Connors (National Institute of Allergy and Infectious Diseases, National Institutes of Health) for critical reading of the manuscript, L. Tranquill and S. Yun (Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health) for technical assistance, H. Griffith and J. McCartin R.N. for nursing assistance, and J. Black and R. Hill for assistance in MRI collection. The phase II clinical trial of CGP 77116 is supported by Neurocrine, Biosciences (San Diego, California) and Novartis (Basel, Switzerland).

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bielekova, B., Goodwin, B., Richert, N. et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand. Nat Med 6, 1167–1175 (2000). https://doi.org/10.1038/80516

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/80516

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing