Tolerance Induction with Agonist Peptides Recognized by Autoaggressive Lymphocytes is Transient: Therapeutic Potential for Type 1 Diabetes is Limited and 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 (T1D) or multiple sclerosis (MS) to prevent disease. Depending on the timing of immunization, use of adjuvant and route of administration either elimination of autoaggressive T cells or induction of regulation reflected by cytokine shifts were described. Since it was also reported that such agonist peptides could enhance autoimmunity by activating aggressive lymphocytes, our goal was to re-evaluate their efficacy in an antigen-specific model of virally-induced T1D that allowed us to precisely track the autoaggressive response. We find that rather than the route of administration (oral versus sc) the precise timing is important for inducing tolerance to self-antigens. Tolerance is transient and only immunization during a susceptible phase 10 to 20 days prior to the induction of disease but not in prediabetic mice resulted in protection. Further, use of a stronger adjuvant (CFA) compared to IFA enhanced the protective effect. Mechanistically, a transient loss of autoaggressive 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 might only find a limited use in treating autoimmune disorders, because tolerance induction is transient and treatment has to be given very early, ideally prior to activation of the aggressive response.