Abstract
Aims/HypothesisNon-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.MethodsSeventy 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.ResultsMice 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/InterpretationThe addition of rapamycin to anti CD3 results in significant improvement in glycaemia control in diabetic NOD mice.
Highlights
Multiple medications have shown efficacy in preventing diabetes in the NOD mouse model of T1D, yet fewer have shown efficacy in reversing the disease after onset of overt hyperglycemia [1].Among the immunomodulatory drugs that revert diabetes in the NOD mouse, anti CD3 has been studied extensively and has shown limited efficacy in clinical trials [2,3,4]
We have previously demonstrated that rapamycin, an immunomodulatory agent, can induce operational tolerance in patients with sickle cell disease following non myloablative bone marrow transplant resulting in stable mixed chimerism, even in the absence of long-term immunosuppression
Percent reversal of hyperglycemia was higher in the anti CD3+rapamycin N = 25 out of 35 mice than the anti CD3 alone 22 out 35 mice reverted (P = NS, Fig. 1a)
Summary
Among the immunomodulatory drugs that revert diabetes in the NOD mouse, anti CD3 has been studied extensively and has shown limited efficacy in clinical trials [2,3,4]. While NOD mice become insulin independent for long periods of time post treatment with anti CD3, humans have shown only temporary incomplete improvement in beta cell function. Possible explanations for the incomplete response observed in humans include a smaller residual beta cell mass, limited regenerative capacity of beta cells, or incomplete halt of the autoimmune attack. If the latter is the dominant cause of the incomplete responses observed to date, additional strategies aimed at tolerance inductionwarrant exploration. The long-term efficacy of islet transplantation has been limited by recurrent/persistent autoimmunity, and this barrier will prove limiting with any new strategy involving the differentiation of pluripotent stem cells to a beta cell phonotype for transplantation
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