Immunomodulation of experimental autoimmune encephalomyelitis with ordered peptides based on MHC-TCR binding motifs.
T cell-mediated destruction of the myelin sheath causes inflammatory damage of the CNS in multiple sclerosis (MS). The major T and B cell responses in MS patients who are HLA-DR2 (about two-thirds of MS patients) react to a region between residues 84 and 103 of myelin basic protein (1 ). The crystal structure of HLA-DR2 complexed with myelin basic protein(84-102) confirmed that Lys(91) is the major TCR contact site, whereas Phe(90) is a major anchor to MHC and binds the hydrophobic P4 pocket (2 ). We have tested peptides containing repetitive 4-aa sequences designed to bind critical MHC pockets and to interfere with T cell activation. One such sequence, EYYKEYYKEYYK, ameliorates experimental autoimmune encephalomyelitis in Lewis rats, an animal model of MS.
Ruiz
P J
PJ
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. pedro@stanford.edu
DeVoss
J J
JJ
Nguyen
L V
LV
Fontoura
P P
PP
Hirschberg
D L
DL
Mitchell
D J
DJ
Garcia
K C
KC
Steinman
L
L
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D015802:HLA-DR2 Antigen / Q000378:metabolism; D006649:Histocompatibility Antigens / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D010455:Peptides / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000276:immunology
D000276:Adjuvants, Immunologic; D015802:HLA-DR2 Antigen; D006649:Histocompatibility Antigens; D000949:Histocompatibility Antigens Class II; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell