Rapamycin Prevents and Breaks the Anti-CD3–Induced Tolerance in NOD Mice

Abstract

Objective Non-Fc-binding anti-CD3 specific antibodies represent a promising therapy for preserving C-peptide production in subjects with recent onset type 1 diabetes (T1D). However, the mechanisms by which anti-CD3 exerts its beneficial effect are still poorly understood and it is questionable whether this therapeutic approach will prove durable in its ability to impart metabolic preservation without additional actions designed to maintain immunological tolerance. We took advantage of the NOD mouse model to test whether rapamycin - a compound well known for its immunomodulatory activity in mice and humans - could increase the therapeutic effectiveness of anti-CD3 treatment in T1D.

Research Design and Methods Rapamycin was administered to diabetic NOD mice simultaneously with anti-CD3, or to NOD mice cured by anti-CD3 therapy. The ability of this combined therapy to revert T1D and maintain a state of long-term tolerance was monitored and compared to that of anti-CD3 therapy alone.

Results Rapamycin inhibited the ability of anti-CD3 to revert disease without affecting the frequency/phenotype of T cells. Rapamycin also reinstated diabetes in mice whose disease was previously reversed by anti-CD3. Withdrawal of rapamycin in these latter animals promptly restored a normoglycemic state.

Conclusions These findings indicate that, when combined with anti-CD3, rapamycin exerts a detrimental effect on the disease outcome in NOD mice as long as it is administered. These results suggest strong caution at combining these treatments in T1D patients.