Two clinical trials testing an altered peptide ligand (APL) in multiple sclerosis report seemingly contradictory results. Immunologic analysis shows that the biological effects of APLs extend far beyond what was initially envisioned, raising important issues for the development of this type of therapy (pages 1167–1175 & 1176–1182).
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References
Zamvil, S.S. & Steinman, L. The T-lymphocyte in experimental allergic encephalomyelitis. Ann. Rev. Immunol. 8, 579–621 (1990).
Wraith, D., McDevitt, H., Steinman, L. & Acha-Orbea, H. T cell recognition as the target for immune intervention in autoimmune disease . Cell 57, 709–715 (1989).
Nicholson, L. & Kuchroo, V. T cell recognition of self and altered self antigens. Crit. Rev. Immunol. 17, 449–462 (1997).
Kappos, L., et al. Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. Nature Med. 6 1176–1182 ( 2000).
Bielekova, B., et al. Encephalitogenic potential of myelin basic protein peptide (amino acid 83-99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand. Nature Med. 6 1167–1175 (2000).
Zinkernagel, R.M. & Doherty, P.C. The discovery of MHC restriction. Immunol. Today 18, 14 –17 (1997).
Townsend, A., et al. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell 44, 959–968 ( 1986).
Sloan-Lancaster, J. & Allen, P. Altered peptide ligand-induced partial T cell activation: molecular mechanisms and role in T cell biology. Annu. Rev. Immunol. 14, 1–27 (1996).
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).
Steinman, L. A few autoreactive cells in an autoimmune infiltrate control a vast population of nonspecific cells: a tale of smart bombs and the infantry. Proc. Natl. Acad. Sci. USA 93, 2253– 2256 (1996).
Nicholson, L., Murtaza, A., Hafler, B., Sette, A. & Kuchroo, V. A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens. Proc. Natl. Acad. Sci. USA 94, 9279–9284 (1997).
Martin, R., McFarland, H.F. & McFarlin, D.E. Immunological aspects of demyelinating diseases. Ann. Rev. Immunol. 10, 153–187 (1992).
Luchinetti, C., Bruck, W., Rodriguez, M. & Lassmann, H. Distinct patterns of multiple sclerosis pathology indicates heterogeneity in pathogenesis. Brain Pathol. 6, 259– 274 (1996).
Genain, C., Cannella, B., Hauser, S. & Raine, C. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nature Med. 5, 170– 175 (1999).
Genain, C.P., et al. Late complications of immune deviation therapy in a non human primate. Science 274, 2054– 2057 (1996).
Wucherpfennig, K.W. & Strominger, J.L. Molecular mimicry in T cell mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995).
Gran, B., Hemmer, B., Vergelli, M., McFarland, H. & Martin, R. Molecular mimicry and multiple sclerosis: degenerate T-cell recognition and the induction of autoimmunity . Ann. Neurol. 45, 559– 567 (1999).
Madrenas, J. & Germain, R. Variant TCR ligands: new insights into the molecular basis of antigen-dependent signal transduction and T cell activation. Semin. Immunol. 8, 83–106 (1996).
Ausubel, L., Kwan, C., Sette, A., Kuchroo, V. & Hafler, D. Complementary mutations in an antigenic peptide allow for crossreactivity of autoreactive T-cell clones. Proc. Natl. Acad. Sci. USA 93, 15317– 15322 (1996).
Tuohy, V., et al. The epitope spreading cascade during progression of experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol. Rev. 164 93–100 ( 1998).
Aharoni, R., Teitelbaum, D., Arnon, R. & Sela, M. Copolymer 1 acts against the immunodominant epitope 82–100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. Proc. Natl. Acad. Sci. USA 96, 634–639 (1999).
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Genain, C., Zamvil, S. Specific immunotherapy: One size does not fit all. Nat Med 6, 1098–1100 (2000). https://doi.org/10.1038/80424
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DOI: https://doi.org/10.1038/80424
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