Microencapsulated G3C hybridoma cell graft delays the onset of spontaneous diabetes in NOD mice by an expansion of Gitr+ Treg cells

As an alternative to lifelong insulin supplementation, potentiation of immune tolerance in type 1 diabetes patients could prevent the autoimmune destruction of pancreatic islet beta cells. This study was aimed to assess whether the G3c monoclonal antibody (mAb), which triggers the glucocorticoid-induced TNFR-related (Gitr) co-stimulatory receptor, promotes the expansion of regulatory T cells (Tregs) in SV129 (wild-type) and diabetic-prone NOD mice. The delivery of the G3c mAb via G3C hybridoma cells enveloped in alginate-based microcapsules (G3C/cps) for 3 weeks induced Foxp3+ Treg cell expansion in the spleen of wild-type mice but not in Gitr−/− mice. G3C/cps also induced the expansion of non-conventional Cd4+Cd25-/lowFoxp3lowGitrint/high (GITRsp) Tregs. Both Cd4+Cd25+GitrhighFoxp3+ and GITRsp Tregs (including also antigen-specific cells) were expanded in the spleen and pancreas of G3C/cps-treated NOD mice, and the number of intact islets was higher in G3C/cps-treated than in empty cps-treated and untreated animals. Consequently, all but two G3C/cps-treated mice did not develop diabetes and all but one survived till the end of the 24-week study. In conclusion, long-term Gitr triggering induces Treg expansion, thereby delaying/preventing diabetes development in NOD mice. This therapeutic approach may have promising clinical potential for the treatment of inflammatory and autoimmune diseases.