Prevention of autoimmune diabetes in non-obese diabetic mice by treatment with a class II major histocompatibility complex-blocking peptide.
The role of antigen presentation as a possible mechanism underlying major histocompatibility complex (MHC) association of autoimmune disease has been studied in non-obese diabetic (NOD) mice. By screening for inhibition of antigen presentation to NOD T cell hybridoma, we have selected a synthetic peptide, yTYTVHAAHAYTYt (small letters denote D amino acids), that efficiently blocks antigen presentation by the NOD class II MHC molecule A alpha g7A beta g7 (Ag7) in vitro. The inhibition is MHC selective, in that it does not affect antigen presentation by the E(d) and E(k) molecules, and has only a marginal effect on presentation by the A(d) molecule. This peptide also inhibits the priming for Ag7-restricted T cell responses in vivo, and prevents the spontaneous development of diabetes in female NOD mice, when administered chronically from 3 wk of age on. Chronic treatment with a control peptide, KMKMVHAAHAKMKM, that fails to bind to Ag7 has no effect on the disease. These data indicate that antigen presentation by the Ag7 molecule plays a pivotal role in the induction of autoimmune diabetes. Furthermore, the results demonstrate that interference with antigen presentation by a class II molecule can prevent the onset of spontaneous autoimmune disease associated with the same molecule.
Hurtenbach
U
U
Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
Lier
E
E
Adorini
L
L
Nagy
Z A
ZA
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects; D001324:Autoantigens / Q000378:metabolism; D001327:Autoimmune Diseases / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000187:drug effects*; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000627:therapeutic use*
D001324:Autoantigens; D000949:Histocompatibility Antigens Class II; D010455:Peptides