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Rapamycin prevents and breaks the anti-CD3-induced tolerance in NOD mice
Andrea Valle1, Tatiana Jofra, Angela Stabilini
1San Raffaele Diabetes Research Institute, Milan, Italy.
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.
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.
Insights
Combining rapamycin with anti-CD3 antibody therapy worsened type 1 diabetes outcomes in mice. Rapamycin hindered anti-CD3
Area of Science:
- Immunology
- Endocrinology
- Pharmacology
Background:
- Non-Fc-binding anti-CD3 antibodies show promise for preserving C-peptide in recent-onset type 1 diabetes.
- Mechanisms of anti-CD3 efficacy and long-term tolerance are not fully understood.
- Investigating combination therapies to enhance anti-CD3 effectiveness is crucial.
Purpose of the Study:
- To evaluate if rapamycin enhances the therapeutic effectiveness of anti-CD3 treatment in type 1 diabetes.
- To assess the impact of combining rapamycin with anti-CD3 on disease reversion and tolerance in NOD mice.
Main Methods:
- Diabetic NOD mice received simultaneous anti-CD3 and rapamycin, or rapamycin after anti-CD3-induced cure.
- Monitored disease reversion, long-term tolerance, and T-cell frequency/phenotype.
- Compared outcomes with anti-CD3 therapy alone.
Main Results:
- Rapamycin inhibited anti-CD3's ability to reverse type 1 diabetes in NOD mice.
- Rapamycin did not alter T-cell frequency or phenotype.
- Rapamycin reinstated diabetes in previously cured mice; withdrawal restored normoglycemia.
Conclusions:
- Combined anti-CD3 and rapamycin treatment had a detrimental effect on type 1 diabetes in NOD mice.
- Rapamycin's negative impact persisted as long as it was administered.
- Caution is advised when considering this combination therapy for human type 1 diabetes patients.
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