Protective DNA vaccination against organ-specific autoimmunity is highly specific and discriminates between single amino acid substitutions in the peptide autoantigen

DNA vaccines that encode encephalitogenic sequences in tandem can protect f rom subsequent experimental autoimmune encephalomyelitis induced with the c orresponding peptide. The mechanism for this protection and, in particular, if it is specific for the amino acid sequence encoding the vaccine are not known. We show here that a single amino acid exchange in position 79 from serine (nonself) to threonine (self) in myelin basic protein peptide MBP68- 85, which is a major encephalitogenic determinant for Lewis rats, dramatica lly alters the protection. Moreover, vaccines encoding the encephalitogenic sequence MBP68-85 do not protect against the second encephalitogenic seque nce MBP89-101 in Lewis rats and vice versa, Thus, protective immunity confe rred by DNA vaccination exquisitely discriminates between peptide target au toantigens. No bystander suppression was observed, The exact underlying mec hanisms remain elusive because no simple correlation between impact on ex v ivo responses and protection against disease were noted.