MHC class II isotype- and allele-specific attenuation of experimental autoimmune encephalomyelitis.
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.D(n) allelic product of the RT1(n) haplotype that is presenting autoantigen in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in LEW.1N rats. Peptide p17 (Ac-FWFLDNAPL-NH(2)) 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.
Experimental Neuroimmunology Laboratory, Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.
Katrien L
KL
de Graaf
Silvia
S
Barth
Martin M
MM
Herrmann
Maria K
MK
Storch
Christoph
C
Otto
Tomas
T
Olsson
Arthur
A
Melms
Günther
G
Jung
Karl-Heinz
KH
Wiesmüller
Robert
R
Weissert
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D019151:Peptide Library; D010455:Peptides / Q000276:immunology*; D020033:Protein Isoforms / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001324:Autoantigens; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D019151:Peptide Library; D010455:Peptides; D020033:Protein Isoforms