MHC class II allosteric site drugs: New immunotherapeutics for malignant, infections and autoimmune diseases

The discovery of che interactions of the 'Ii-Key' segment of the Ii protein with the major histocmpatibility complex (MHC) Class II allosteric site, w hich is adjacent to the antigenic peptide-binding site, creates therapeutic opportunities by regulating the antigenic peptide binding to MHC class II molecules. The binding of ii-Key to the MHC class II allosteric site loosen s the hold of the MHC Class II 'clamshell' on antigenic peptides and leads to highly efficient antigenic peptide charging to or releasing from the MHC class II antigenic peptide-binding groove. Ii-Key peptide-induced spilling of bound antigenic peptide, or replacement with inert blockers, leads to ' inert immunosuppression'. Highly efficient replacement of ambient with vacc ine peptides by Ii-Key permits 'active immunosuppression' for antigen-speci fic control of autoimmune diseases in the absence of cytokines or adjuvants . On the other hand, active immunization against cancer or infectious disea se can result from epitope replacement mediated by Ii-Key and accompanied b y cytokines or other adjuvants. Finally, linking the Ii-Key peptide through a simple polymethylene bridge to an antigenic sequence vastly increases th e potency of MHC Class II peptide vaccines. In summary, the discovery of th e MHC class II allosteric site allows one to increase the efficiency of MHC class II-related, antigenic epitope-specific therapy for malignant, infect ious, and autoimmune diseases. The focus of this review is on the mechanism and potential clinical use of such novel allosteric site-directed, Ii-key drugs.