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Treatment of multiple sclerosis with T–cell receptor peptides: Results of a double–blind pilot trial

Abstract

A T–cell receptor (TCR) peptide vaccine from the Vβ5.2 sequence expressed in multiple sclerosis (MS) plaques and on myelin basic protein (MBP)–specific T cells boosted peptide–reactive T cells in patients with progressive MS. Vaccine responders had a reduced MBP response and remained clinically stable without side effects during one year of therapy, whereas nonresponders had an increased MBP response and progressed clinically. Peptide–specific T helper 2 cells directly inhibited MBP–specific T helper 1 cells in vitro through the release of interleukin–10, implicating a bystander suppression mechanism that holds promise for treatment of MS and other autoimmune diseases.

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References

  1. Jerne, N.K. Idiotypic networks and other preconceived ideas. Immunol. Rev. 79, 5–24 (1984).

    CAS  Article  Google Scholar 

  2. Cohen, I.R. & Young, D.B. Autoimmunity, microbial immunity and the immunological homunculus. Immunol. Today 12, 105–110 (1991).

    CAS  Article  Google Scholar 

  3. Claverie, J.M., Prochnicka-Chalufour, A. & Bougueleret, A. Implications of a Fab-like structure for the T-cell receptor. Immunol. Today 10, 10–14 (1989).

    CAS  Article  Google Scholar 

  4. Davis, M.M. & Bjorkman, P.J. T-cell antigen receptor genes and T-cell recognition. Nature 334, 395–402 (1988).

    CAS  Article  Google Scholar 

  5. Williams, W.V., Weiner, D.B., Wadsworth, S. & Greene, M.I. The antigen-major histocompatibility complex-T-cell receptor interaction: A structural analysis. Immunol. Rev. 7, 339–344 (1988).

    CAS  Google Scholar 

  6. Vandenbark, A.A., Hashim, G.A. & Offner, H. T cell receptor peptides in treatment of autoimmune disease: Rationale and potential. J. Neurosci. Res. 43, 391–402 (1996).

    CAS  Article  Google Scholar 

  7. Heber-Katz, E. & Acha-Orbea, H. The V-region disease hypothesis: Evidence from autoimmune encephalomyelitis. Immunol. Today 10, 164–169 (1989).

    CAS  Article  Google Scholar 

  8. Lider, O., Reshef, T., Beraud, E., Ben-Nun, A. & Cohen, I.R. Anti-idiotypic network induced by T cell vaccination against experimental autoimmune encephalomyelitis. Science 239, 181–183 (1988).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  10. Offner, H., Hashim, G.A. & Vandenbark, A.A. T cell receptor peptide therapy triggers autoregulation of experimental encephalomyelitis. Science 251, 430–432 (1991).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  12. Stevens, D.B., Karpus, W.J., Gould, K.E. & Swanborg, R.H. Studies of Vβ8 T cell receptor peptide treatment in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 37, 123–129 (1991).

    Article  Google Scholar 

  13. Kumar, V. & Sercarz, E.E. The involvement of T cell receptor peptide-specific regulatory CD4+ T cells in recovery from antigen-induced autoimmune disease. J. Exp. Med. 178, 909–916 (1993).

    CAS  Article  Google Scholar 

  14. Gregorian, S.K., Lee, W.P., Doudikian, N. & Amento, E.P. Two distinct T cell receptor peptides independently regulate experimental autoimmune neuritis. Am. Assoc. Immunol. 150, 28A (1993).

    Google Scholar 

  15. Broeren, C.P.M. et al. CDR1 T-cell receptor β-chain peptide induces major histocompatibility complex class II-restricted T-T cell interactions. Proc. Natl. Acad. Set. USA 91, 5997–6001 (1994).

    CAS  Article  Google Scholar 

  16. Matsumoto, Y., Tsuchida, M., Hanawa, H. & Abo, T. T cell receptor peptide therapy for autoimmune encephalomyelitis: Stronger immunization is necessary for effective vaccination. Cell. Immunol. 153, 468–478 (1994).

    CAS  Article  Google Scholar 

  17. Kuhrober, A., Schirmbeck, R. & Reimann, J. Vaccination with T cell receptor peptides primes anti-receptor cytotoxic T lymphocytes (CTL) and anergizes T cells specifically recognized by these CTL. Eur. J. Immunol. 24, 1172–1180 (1994).

    CAS  Article  Google Scholar 

  18. Haqqui, T.M., Qu, X.-M., Ma, J. & Sy, M.S. Immunization with TCR Vβ region peptides completely prevents the induction of collagen induced arthritis. Ninth Int. Cong. Immunol. Abstr. 5014, 845 (1995).

    Google Scholar 

  19. Kotzin, B.L. et al. Preferential T cell receptor Vβ gene usage in myelin basic protein reactive T cell clones from patients with multiple sclerosis. Proc. Natl. Acad. Sci. U. S. A. 88, 9161–9165 (1991).

    CAS  Article  Google Scholar 

  20. Oksenberg, J.R. et al. Selection of T-cell receptor Vβ-Dβ-Jβ gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis. Nature 362, 68–70 (1993).

    CAS  Article  Google Scholar 

  21. Shimonkevitz, R., Murray, R. & Kotzin, B. Characterization of T-cell receptor Vβ usage in the brain of a subject with multiple sclerosis. Ann. N. Y. Acad. Sci. 756, 305–306 (1995).

    CAS  Article  Google Scholar 

  22. Bourdette, D.N. et al. Immunity to T cell receptor peptides in multiple sclerosis. I. Successful immunization of patients with synthetic Vβ5.2 and Vβ6.1 CDR2 peptides. J. Immunol. 152, 2510–2519 (1994).

    CAS  Google Scholar 

  23. Wucherpfennig, K.W. et al. Shared human T cell receptor Vβ usage to immunodominant regions of myelin basic protein. Science 248, 1016–1019 (1990).

    CAS  Article  Google Scholar 

  24. Ben-Nun, A. et al. Restricted T-cell receptor Vβ gene usage by myelin basic protein-specific T-cell clones in multiple sclerosis: Predominant genes vary in individuals. Proc. Natl. Acad. Sci. USA 88, 2466–2470 (1991).

    CAS  Article  Google Scholar 

  25. Vandenbark, A.A., Vainiene, M., Celnik, B., Hashim, G. & Offner, H. TCR peptide therapy decreases the frequency of encephalitogenic T cells in the periphery and the central nervous system. J. Neuroimmunol. 39, 251–260 (1992).

    CAS  Article  Google Scholar 

  26. Desquenne-Clark, L., Esch, T.R., Otvos, L. Jr. & Heber-Katz, E. T cell receptor peptide immunization leads to enhanced and chronic experimental allergic encephalomyelitis. Proc. Natl. Acad. Sci. USA 88, 7219–7223 (1991).

    CAS  Article  Google Scholar 

  27. Chou, Y.K. et al. MHC-restriction, cytokine profile, and immunoregulatory effects of human T cells specific for TCR Vβ CDR2 peptides: Comparison with myelin basic protein-specific T cells. J. Neurosci Res. (in the press).

  28. Falcioni, F. et al. Self tolerance to T cell receptor Vβ sequences. J. Exp. Med. 182, 249–254 (1995).

    CAS  Article  Google Scholar 

  29. Vandenbark, A.A. [Letter to the editor]. J. Immunol. 153, 910 (1994).

    Google Scholar 

  30. Sant'Angelo, D.B. et al. The specificity and orientation of a TCR to its peptide-MHC class II ligands. Immunity 4, 367–376 (1996).

    CAS  Article  Google Scholar 

  31. Voskuhl, R.R. et al. T helper 1 (Th1) functional phenotype of human myelin basic protein-specific T lymphocytes. Autoimmunity 15, 137–143 (1993).

    CAS  Article  Google Scholar 

  32. Chou, Y.K. et al. Immunity to T cell receptor peptides in multiple sclerosis. II. T cell recognition of Vβ5.2 and Vβ6.1 CDR2 peptides. J. Immunol. 152, 2520–2529 (1994).

    CAS  Google Scholar 

  33. Allegretta, M., Nicklas, J.A., Sriram, S. & Albertini, R.J. T cells responsive to myelin basic protein in patients with multiple sclerosis. Science 247, 718–721 (1990).

    CAS  Article  Google Scholar 

  34. Vandenbark, A.A. et al. Episodic changes in T cell frequencies to myelin basic protein in patients with multiple sclerosis. Neurology 43, 2416–2417 (1993).

    CAS  Article  Google Scholar 

  35. Zhang, J. et al. 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. 179, 973–984 (1994).

    CAS  Article  Google Scholar 

  36. Weiner, H.L. et al. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 259, 1321–1324 (1993).

    CAS  Article  Google Scholar 

  37. Zhang, J., Medaer, R., Stinissen, P., Hafler, D.A. & Raus, J.C.M. MHC-restricted depletion of human myelin basic protein-reactive T cells by T cell vaccination. Science 261, 1451–1454 (1993).

    CAS  Article  Google Scholar 

  38. Miller, A., Al-Sabagh, A., Santos, L.M.B., Prabhu-Das, M. & Weiner, H.L. Epitopes of myelin basic protein that trigger TGF-β release after oral tolerization are distinct from encephalitogenic epitopes and mediate epitope-driven bystander suppression. J. Immuno. 151, 7307–7315 (1993).

    CAS  Google Scholar 

  39. Karpus, W.J. & Swanborg, R.H. CD4+ suppressor cells inhibit the function of effector cells of EAE through a mechanism involving transforming growth factor-beta. J. Immunol. 146, 1163–1168 (1991).

    CAS  PubMed  Google Scholar 

  40. Swain, S.L. Regulation of the development of distinct subsets of CD4+ T cells. Res. Immunol. 142, 14–22 (1991).

    CAS  Article  Google Scholar 

  41. Racke, M.K. et al. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J. Exp. Med. 180, 1961–1966 (1994).

    CAS  Article  Google Scholar 

  42. Kennedy, M.K., Torrance, D.S., Picha, K.S. & Mohler, K.M. Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J. Immunol. 149, 2496–2505 (1992).

    CAS  PubMed  Google Scholar 

  43. Rott, O., Fleischer, B. & Cash, E. Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur. J. Immunol. 24, 1434–1440 (1994).

    CAS  Article  Google Scholar 

  44. Poser, C.M. et al. New Diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Ann. Neurol. 13, 227–236 (1983).

    CAS  Article  Google Scholar 

  45. Diebler, G.E., Boyd, L.F. & Kies, M.W. Enzymatic and nonenzymatic degradation of myelin basic protein. Neurochemistry 9, 1371–1385 (1984).

    Article  Google Scholar 

  46. Scharf, S.J., Griffith, R.L. & Erlich, H.A. Rapid typing of DNA sequence polymorphism at the HLA-DRB1 locus using the polymerase chain reaction and nonradioactive probes. Hum. Immunol. 30, 190–201 (1991).

    CAS  Article  Google Scholar 

  47. Taswell, C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J. Immunol. 26, 1614–1619 (1981).

    Google Scholar 

  48. Kurtzke, J.F. Further notes on disability evaluation in multiple sclerosis with scale modification. Neurology 15, 654–662 (1965).

    CAS  Article  Google Scholar 

  49. Hauser, S.L., Dawson, D.M. & Lehrich, J.C. Intensive immunosuppression in progressive multiple sclerosis: A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N. Engl. J. Med. 308, 173–180 (1983).

    CAS  Article  Google Scholar 

  50. Goodkin, D.E. et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann. Neurol. 37, 30–40 (1995).

    CAS  Article  Google Scholar 

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Vandenbark, A., Chou, Y., Whitham, R. et al. Treatment of multiple sclerosis with T–cell receptor peptides: Results of a double–blind pilot trial. Nat Med 2, 1109–1115 (1996). https://doi.org/10.1038/nm1096-1109

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