Tolerance induction with agonist peptides recognized by autoaggressive lymphocytes is transient: Therapeutic potential for type 1 diabetes is limitedand depends on time-point of administration, choice of epitope and adjuvant

Immunization with agonist peptides recognized by autoaggressive lymphocytes has been used successfully in several animal models for type 1 diabetes (T 1D) or multiple sclerosis (MS) to prevent disease. Depending on the timing of immunization, use of adjuvant and route of administration either elimina tion of autoaggressive T cells or induction of regulation reflected by cyto kine shifts were described. Since it was also reported that such agonist pe ptides could enhance autoimmunity by activating aggressive lymphocytes, our goal was to re-evaluate their efficacy in an antigen-specific model of vir ally-induced T1D that allowed us to precisely track the autoaggressive resp onse. We find that rather than the route of administration (oral versus sc) the precise timing is important for inducing tolerance to self-antigens. T olerance is transient and only immunization during a susceptible phase 10 t o 20 days prior to the induction of disease but not in prediabetic mice res ulted in protection. Further, use of a stronger adjuvant (CFA) compared to IFA enhanced the protective effect. Mechanistically, a transient loss of au toaggressive T cells was responsible for preventing disease, the effect was quantitative and no regulatory lymphocytes or cytokine shifts were induced by any of our treatments. Thus, MHC class I-restricted agonist peptides mi ght only find a limited use in treating autoimmune disorders, because toler ance induction is transient and treatment has to be given very early, ideal ly prior to activation of the aggressive response. (C) 2001 Academic Press.