Peptide dose, MHC affinity, and target self-antigen expression are critical for effective immunotherapy of nonobese diabetic mouse prediabetes

Cross-reactive T cells that recognize both Tep69 (dominant nonobese diabeti c (NOD) T cell epitope in ICA69 (islet cell autoantigen of 69 kDa)) and ABB OS (dominant NOD T cell epitope in BSA) are routinely generated during huma n and NOD mouse prediabetes, Here we analyzed how systemic administration o f these mimicry peptides affects progressive autoimmunity in adoptively tra nsferred and cyclophosphamide-accelerated NOD mouse diabetes. These models were chosen to approximate mid to late stage prediabetes, the typical statu s of probands in human intervention trials. Unexpectedly, high dose (100 mu g) i.v. ABBOS prevented, while Tep69 exacerbated, disease in both study mo dels. Peptide effects required cognate recognition of endogenous self-Ag, b ecause both treatments were ineffective in ICA69(null) NOD congenic mice ad optively transferred with wild-type, diabetic splenocytes. The affinity of ABBOS for NOD I-A(g7) was orders of magnitude higher than that of Tep69, Th is explained 1) the expansion of the mimicry T cell pool following i.v. Tep 69, 2) the long-term unresponsiveness of these cells after i.v. ABBOS, and 3) precipitation of the disease after low dose i.v. ABBOS. Disease precipit ation and prevention in mid to late stage prediabetes are thus governed by affinity profiles and doses of therapeutic peptides, ABBOS or ABBOS analogu es with even higher MHC affinity may be candidates for experimental interve ntion strategies in human prediabetes, but the dose translation from NOD mi ce to humans requires caution.