Adoptive Infusion of Tolerogenic Dendritic Cells Prolongs the Survival of Pancreatic Islet Allografts: A Systematic Review of 13 Mouse and Rat Studies

Objective: The first Phase I study of autologous tolerogenic dendritic cells (Tol-DCs) in Type 1 diabetes (T1D) patients was recently completed. Pancreatic islet transplantation is an effective therapy for T1D, and infusion of Tol-DCs can control diabetes development while promoting graft survival. In this study, we aim to systematically review islet allograft survival following infusion of Tol-DCs induced by different methods, to better understand the mechanisms that mediate this process. Methods: We searched PubMed and Embase (from inception to February 29th, 2012) for relevant publications. Data were extracted and quality was assessed by two independent reviewers. We semiquantitatively analyzed the effects of Tol-DCs on islet allograft survival using mixed leukocyte reaction, Th1/Th2 differentiation, Treg induction, and cytotoxic T lymphocyte activity as mechanisms related-outcomes. We discussed the results with respect to possible mechanisms that promote survival. Results: Thirteen articles were included. The effects of Tol-DCs induced by five methods on allograft survival were different. Survival by each method was prolonged as follows: allopeptide-pulsed Tol-DCs (42.14 +/- 44 days), drug intervention (39 days), mesenchymal stem cell induction (23 days), genetic modification (8.99 +/- 4.75 days), and other derivation (2.61 +/- 6.98 days). The results indicate that Tol-DC dose and injection influenced graft survival. Single-dose injections of 10(4) Tol-DCs were the most effective for allograft survival, and multiple injections were not superior. Tol-DCs were also synergistic with immunosuppressive drugs or costimulation inhibitors. Possible mechanisms include donor specific T cell hyporesponsiveness, Th2 differentiation, Treg induction, cytotoxicity against allograft reduction, and chimerism induction. Conclusions: Tol-DCs induced by five methods prolong MHC mismatched islet allograft survival to different degrees, but allopeptide-pulsed host DCs perform the best. Immunosuppressive or costimulatory blockade are synergistic with Tol-DC on graft survival. Multiple injections are not superior to single injection. Yet more rigorously designed studies with larger sample sizes are still needed in future.