Autoreactivity to proinsulin (PI) is essential for initiation of diabetogenesis in the non-obese diabetic (NOD) mouse and perhaps in humans. However, PI based clinical trials to achieve immune tolerance and prevent diabetes have failed to achieve therapeutic benefit in humans. Timing of antigen-specific therapy 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 allowing induction of tolerance to PI in a temporally controlled manner.
TIP mice were divided into 4 cohorts (C1-4). In C1 PI expression was induced from gestation. In C2 PI was not induced at all. In C3 PI was induced from 5 weeks of age, and in C4 PI was induced from gestation until 5 weeks of age. Pancreas histology was scored for immune infiltrate (insulitis) and diabetes onset was monitored in all 4 cohorts. Mice in C1 were protected from insulitis and diabetes as expected, whereas mice in C2 & C3 showed no protection from insulitis & developed diabetes. Significantly, mice in C4 with PI induced only in early life were also completely protected from insulitis and diabetes.
In humans evidence of preclinical diabetes often appears by 2 years of age. Our data suggest that early life is also crucial for development of autoimmune diabetes in NOD mice and that it does not occur de novo in later life. PI-based therapies may be more effective when used in the first few months of life in humans.