A conformationally-constrained MHC class III-A(g7)-derived peptide protects NOD mice from the development of diabetes

Allele-specific peptide vaccination against disease-associated MHC class II molecules is a promising new strategy for modulating self-antigen presenta tion to autoreactive T cells in autoimmune diseases. To evaluate the potent ial of this approach for treatment of insulin-dependent diabetes mellitus ( IDDM), we have designed a cyclic peptide vaccine, DiavaX, from the third hy pervariable region of the beta-chain of the NOD mouse MHC class II I-A(g7). NOD mice were treated at 5 and 9 weeks of age with 100 mu g DiavaX emulsif ied in alum, a control peptide in alum, or alum alone. At the end of the st udy, 87% of alum treated mice had developed diabetes, compared with only 28 % of DiavaX-treated mice. None of the control peptides, including a linear I-A(g7), a scrambled cyclic I-A(g7), or an analogous cyclic I-A(s) peptide, reduced the incidence of diabetes, demonstrating that the protective effec t of DiavaX is conformationally dependent and both allele- and sequence-spe cific. DiavaX treatment did not cause any general immune suppression, but d id induce peptide-specific antibodies and memory T cells. DiavaX-induced pr otection from diabetes was associated with the maintenance of anon-destruct ive islet-associated autoimmune response. These data indicate that a confor mationally constrained peptide from the disease-associated MHC represents a potential vaccine candidate for the prevention of clinical IDDM. (C) 1999 Academic Press.