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Short Peptide-Based Tolerogens Without Self-Antigenic or Pathogenic Activity Reverse Autoimmune Disease¹

Nathan Karin^§,||, Ofer Binah^§,¶, Nir Grabie^||, Dennis J. Mitchell^*, Bella Felzen^¶, Matthew D. Solomon^*, Paul Conlon, Amitabh Gaur, Nicholas Ling and Lawrence Steinman^2,*,

^* Department of Neurology and Neurological Sciences, Beckman Center for Molecular and Genetic Medicine-B002, Stanford University School of Medicine, Stanford, CA 94305; Department of Immunology, The Weizmann Institute for Science, Rehovot, Israel; Neurocrine Biosciences, Inc., La Jolla, CA 92121; ^§ Rappaport Family Institute for Research in the Medical Sciences, ^¶ The Bernard Katz Center for Cell Biophysics, and ^|| Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

An immunodominant epitope of myelin basic protein (MBP), VHFFKNIVTPRTP (p87–99), is a major target of T cells in brain lesions of multiple sclerosis (MS), and this peptide can trigger experimental autoimmune encephalomyelitis (EAE). We designed truncated peptides based on this pathogenic 13-mer that are not antigenic. These short peptides reduced production of IFN- and TNF- in vivo. Moreover, paraplegic rats given the 7-mer FKNIVTP in soluble form showed total reversal of paralysis in 24 h. Truncated peptides that are too small to stimulate antigenic responses to pathogenic regions of myelin basic protein are nevertheless effective tolerogens and are able to anergize autoreactive T cells. Short peptide-based tolerogens, devoid of immunogenic and pathogenic potential, may be attractive for therapy of autoimmune diseases.

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