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Addition of rapamycin to anti-CD3 antibody improves long-term glycaemia control in diabetic NOD mice
Shira Perl1, Jordan Perlman, R P Weitzel
1Center for Human Immunology, NHLBI, NIH, Bethesda, Maryland, United States of America. perls@nhlbi.nih.gov
Aims/Hypothesis:
Non-Fc-binding Anti CD3 antibody has proven successful in reverting diabetes in the non-obese diabetes mouse model of type 1 diabetes and limited efficacy has been observed in human clinical trials. We hypothesized that addition of rapamycin, an mTOR inhibitor capable of inducing operational tolerance in allogeneic bone marrow transplantation, would result in improved diabetes reversal rates and overall glycemia.
Methods:
Seventy hyperglycemic non-obese diabetic mice were randomized to either a single injection of anti CD3 alone or a single injection of anti CD3 followed by 14 days of intra-peritoneal rapamycin. Mice were monitored for hyperglycemia and metabolic control.
Results:
Mice treated with the combination of anti CD3 and rapamycin had similar rates of diabetes reversal compared to anti CD3 alone (25/35 vs. 22/35). Mice treated with anti CD3 plus rapamycin had a significant improvement in glycemia control as exhibited by lower blood glucose levels in response to an intra-peritoneal glucose challenge; average peak blood glucose levels 30 min post intra-peritoneal injection of 2 gr/kg glucose were 6.9 mmol/L in the anti CD3 plus rapamycin group vs. 10 mmo/L in the anti CD3 alone (P<0.05).
Conclusions/Interpretation:
The addition of rapamycin to anti CD3 results in significant improvement in glycaemia control in diabetic NOD mice.
Insights
Adding rapamycin to anti CD3 therapy improved blood sugar control in diabetic mice. This combination therapy showed enhanced glycemic control in non-obese diabetic mice, offering potential for type 1 diabetes treatment.
Area of Science:
- Immunology
- Endocrinology
- Pharmacology
Background:
- Non-Fc-binding anti-CD3 antibody shows promise in type 1 diabetes models but has limited human efficacy.
- Rapamycin, an mTOR inhibitor, induces operational tolerance in transplantation.
Purpose of the Study:
- To investigate if rapamycin enhances the efficacy of anti-CD3 therapy in reverting diabetes.
- To assess the impact of combination therapy on diabetes reversal rates and glycemic control in non-obese diabetic (NOD) mice.
Main Methods:
- Seventy hyperglycemic NOD mice were randomized into two groups.
- One group received a single anti-CD3 injection; the other received anti-CD3 followed by 14 days of rapamycin.
- Mice were monitored for hyperglycemia and metabolic control.
Main Results:
- Diabetes reversal rates were similar between the anti-CD3 alone and combination therapy groups (25/35 vs. 22/35).
- The combination of anti-CD3 and rapamycin significantly improved glycemic control.
- Mice treated with combination therapy exhibited lower peak blood glucose levels during an intraperitoneal glucose challenge (6.9 mmol/L vs. 10 mmol/L).
Conclusions:
- The addition of rapamycin to anti-CD3 therapy significantly improves glycemic control in diabetic NOD mice.
- Combination therapy demonstrates potential for better metabolic management in type 1 diabetes.
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