Rapamycin prevents and breaks the anti-CD3-induced tolerance in NOD mice.
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. 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 well-known for its immunomodulatory activity in mice and humans, could increase the therapeutic effectiveness of anti-CD3 treatment in type 1 diabetes.


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.
Valle
Andrea
A
San Raffaele Diabetes Research Institute, Milan, Italy.
Jofra
Tatiana
T
Stabilini
Angela
A
Atkinson
Mark
M
Roncarolo
Maria-Grazia
MG
Battaglia
Manuela
M
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use
D000906:Antibodies; D001786:Blood Glucose; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D020123:Sirolimus