Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity.
This study explores antigen administration via mucosal surfaces as a potential means of inducing antigen-specific non-responsiveness in experimental autoimmune encephalomyelitis (EAE). In the H-2u mouse model of EAE, the acetylated N-terminal peptide of myelin basic protein represents a dominant T cell epitope which on its own is sufficient to induce disease. Oral administration of the encephalitogenic peptide over a wide range of doses failed to induce oral tolerance to EAE. In marked contrast, a single intranasal dose of this peptide (Ac1-9 or Ac1-11) profoundly inhibited EAE when administered prior to disease induction. We investigated this phenomenon further by using two analogues of Ac1-11 with alanine or tyrosine at position 4 which display higher affinity binding to the I-Au molecule than the original peptide with lysine at this position. There was a positive correlation between the degree of protection from EAE and the affinity of individual peptides for class II MHC. Peptide inhalation inhibited not only EAE induced by subcutaneous injection of the encephalitogenic peptide but also disease induced by a complex mixture of potential auto-antigens such as spinal cord homogenate. Thus, in contrast to oral tolerance, nonresponsiveness by peptide inhalation is inducible with the encephalitogenic peptide in the absence of additional regulatory epitopes. The finding that a single epitope may protect against EAE induced with whole spinal cord homogenate implies, however, that regulatory mechanisms affecting additional potential self-epitopes may play a significant role.
Metzler
B
B
Cambridge University Department of Pathology, UK.
Wraith
D C
DC
D000280:Administration, Inhalation; D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007108:Immune Tolerance; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000008:administration & dosage* / Q000737:chemistry; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology
D001324:Autoantigens; D000949:Histocompatibility Antigens Class II; D004676:Myelin Basic Protein; D009842:Oligopeptides