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OBJECTIVE- Non-Fc-binding anti-CD3-speciflc antibodies represent a promising therapy for preserving C-peptide production in subjects with recent-onset type 1 diabetes. 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 with regard to its ability to impart metabolic preservation without additional actions designed to maintain immunological tolerance. We used the NOD mouse model to test whether rapamycin, a compound wellknown for its immunomodulatory activity in mice and humans, could increase the therapeutic effectiveness of anti-CD3 treatment in type 1 diabetes.
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 type 1 diabetes and maintain a state of long-term tolerance was monitored and compared with 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 - Our findings indicate that, when combined with anti-CD3, rapamycin exerts a detrimental effect on the disease outcome in NOD mice for as long as it is administered. These results suggest strong caution with regard to combining these treatments in type 1 diabetic patients. Diabetes 58: 875-881, 2009
The NOD mouse is widely used as a model of human type 1 diabetes (1). Whereas a large number of therapeutic approaches have shown success in preventing type 1 diabetes in NOD mice, agents demonstrating the clear ability to reverse established disease and restore self-tolerance in this ani- mal model have been far more difficult to identify (2). Among the limited number of treatments demonstrated to revert established disease in diabetic NOD mice is the non-Fc-binding anti-CD3ε antibody (anti-CD3) (3). Indeed, a short-term treatment with anti-CD3 at the time of diabetes onset is sufficient to reverse the disease, induce long-term remission, and prevent recurrent immune responses, including those against transplanted syngeneic pancreatic islets (4). The exact mechanism of action by which anti-CD3 provides this beneficial effect is still not fully known, but it is clear that its tolerogenic capacity develops...