Addition of rapamycin to anti-CD3 antibody improves long-term glycaemia control in diabetic NOD mice

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 toleran...

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Bibliographic Details
Published in:PloS one 2013-06, Vol.8 (6), p.e67189-e67189
Main Authors: Perl, Shira, Perlman, Jordan, Weitzel, R P, Phang, Oswald, Hsieh, Matthew M, Tisdale, John
Format: Article
Language:English
Subjects:
Analysis
Animals
Antibodies
Antibodies - therapeutic use
Biology
Blood
Blood glucose
Blood sugar
Bone marrow
Bone marrow transplantation
CD3 antigen
CD3 Complex - immunology
Clinical trials
Diabetes
Diabetes mellitus
Diabetes Mellitus, Experimental - complications
Diabetes Mellitus, Experimental - drug therapy
Drug dosages
Female
Glucose
Hematology
Humans
Hyperglycemia
Hyperglycemia - complications
Hyperglycemia - drug therapy
Immunological tolerance
Immunology
Injection
Lymphocytes
Medical research
Medicine
Mice
Mice, Inbred NOD
Obesity
Peptides
Peritoneum
Rapamycin
Rodents
Sickle cell disease
Sirolimus - pharmacology
Sirolimus - therapeutic use
TOR protein
Transplantation
Transplants & implants
Type 1 diabetes
Viral antibodies
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Summary: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. 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. 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
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0067189