PREVENTION OF AUTOIMMUNE DIABETES IN NONOBESE DIABETIC MICE BY TREATMENT WITH A CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX BLOCKING PEPTIDE

The role of antigen presentation as a possible mechanism underlying ma jor histocompatibility complex (MHC) association of autoimmune disease has been studied in non-obese diabetic (NOD) mice. By screening for i nhibition of antigen presentation to NOD T cell hybridoma, we have sel ected a synthetic peptide, yTYTVHAAHAYTYt (small letters denote D amin o acids), that efficiently blocks antigen presentation by the NOD clas s II MHC molecule Aalpha(g7)Abeta(g7) (A(g7)) 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 present ation by the A(d) molecule. This peptide also inhibits the priming for A(g7)-restricted T cell responses in vivo, and prevents the spontaneo us development of diabetes in female NOD mice, when administered chron ically from 3 wk of age on. Chronic treatment with a control peptide, KMKMVHAAHAKMKM, that fails to bind to A(g7) has no effect on the disea se. These data indicate that antigen presentation by the A(g7) molecul e plays a pivotal role in the induction of autoimmune diabetes. Furthe rmore, the results demonstrate that interference with antigen presenta tion by a class II molecule can prevent the onset of spontaneous autoi mmune disease associated with the same molecule.