Background & Aim: Autoreactive T cells targeting proinsulin (PI) are required for initiation of anti-islet autoimmunity in the non-obese diabetic (NOD) mouse and perhaps in humans. Strategies inducing tolerance to PI from birth prevented diabetes in NOD mice. However, in human subjects with advanced pre-clinical diabetes provision of a self-antigen such as proinsulin with an aim to induce tolerance failed to achieve therapeutic benefit. Timing of antigen-specific intervention amongst other factors may be crucial to achieve clinical efficacy. To define a window for inducing lasting tolerance, we generated NOD mice with Tetracycline-regulated PI expression (TIP mice) in the antigen presenting cells (APC), allowing induction of tolerance to PI in a temporally controlled manner.
Results: PI was expressed in TIP mice over different time intervals, a) continually from gestation, b) from gestation until 5-7 weeks of age and c) from 5-7 weeks of age (after insulitis onset). Pancreata were harvested from TIP mice after 15 weeks of intervention to examine the autoimmune infiltrate in the islets (insulitis). TIP mice expressing PI continually from gestation were protected from insulitis similar to previous findings1, whereas TIP mice expressing PI from 5-7 weeks onwards showed partial protection from insulitis. Significantly, TIP mice expressing PI only from gestation until 5-7 weeks of age were also protected from insulitis. The effect of PI expression induced only during perinatal and/or neonatal period on diabetes is currently being investigated and will further define a window for inducing lasting tolerance to PI.
Conclusion: Our results from NOD mice with temporally controlled PI expression suggest that PI-based clinical interventions may prevent diabetes when used in first few years of life in genetically high-risk human subjects.
1: French MB et.al Diabetes 46 (1) 1997