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MHC Class II Isotype- and Allele-Specific Attenuation of Experimental Autoimmune Encephalomyelitis¹

Katrien L. de Graaf^*, Silvia Barth^*, Martin M. Herrmann^*, Maria K. Storch, Christoph Otto, Tomas Olsson^¶, Arthur Melms^*, Günther Jung^,||, Karl-Heinz Wiesmüller^,|| and Robert Weissert^2,*

^* Experimental Neuroimmunology Laboratory, Department of General Neurology, Hertie Institute for Clinical Brain Research, and Department of Organic Chemistry, University of Tübingen, Tübingen, Germany; Department of Neurology, University of Graz, Graz, Austria; Experimental Transplantation Immunology, Department of Surgery, University of Würzburg, Würzburg, Germany; ^¶ Neuroimmunology Unit, Center for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden; and ^|| EMC Microcollections, Tübingen, Germany

Most autoimmune diseases are associated with certain MHC class II haplotypes. Autoantigen-based specific immune therapy can lead either to beneficial or, in the context of inflammatory conditions, detrimental outcomes. Therefore, we designed a platform of peptides by combinatorial chemistry selected in a nonbiased Ag-independent approach for strong binding to the rat MHC class II isotype RT1.Dⁿ allelic product of the RT1ⁿ haplotype that is presenting autoantigen in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in LEW.1N rats. Peptide p17 (Ac-FWFLDNAPL-NH₂) was capable of suppressing the induction of and also ameliorated established experimental autoimmune encephalomyelitis. MHC class II isotype and allele specificity of the therapeutic principle were demonstrated in myelin basic protein-induced experimental autoimmune encephalomyelitis in LEW rats bearing the RT1^l haplotype. A general immunosuppressive effect of the treatment was excluded by allogeneic heart transplantation studies. In vitro studies demonstrated the blocking effect of p17 on autoantigenic T cell responses. We thus demonstrate a rational design of strong MHC class II-binding peptides with absolute isotype and allele specificity able to compete for autoantigenic sequences presented on disease-associated MHC class II molecules.

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