Abstract

Objective- In type 1 diabetes (T1D), allogeneic pancreatic islet transplantation restores insulin production, but life-threatening immunosuppression is required to avoid graft rejection. Induction of antigen (Ag)-specific tolerance by cell therapy with regulatory T cells (Tregs) represents an attractive alternative approach but its therapeutic efficacy in islet transplantation remains to be determined. Among the different subsets of CD4⁺ Tregs, the T inducible regulatory type 1 (Tr1) cells can be generated from naïve T cells in the presence of IL-10 and represent one promising therapeutic choice. This study was designed to define the efficacy of Tr1-cell therapy in preclinical models of islet transplantation.

Research Design And Methods- Non Ag-specific polyclonal Tr1 cells and donor Ag-specific Tr1 cells were transferred, in the absence of any pharmacological treatment, in two distinct mouse models of islet transplantation. The two models differed in their therapeutic stringency, based on the mean rejection time of transplanted untreated mice.

Results- Transfer of polyclonal Tr1 cells engendered graft tolerance only in the non-stringent mouse model. Conversely, cell therapy with Ag-specific Tr1 cells induced an IL-10--dependent tolerance in the stringent mouse model of islet transplantation. The therapeutic advantage of Ag-specific Tr1 cells over polyclonal Tr1 cells was due to their donor Ag-specificity.

Conclusions- These results demonstrate that Tr1-cell therapy leads to tolerance in settings of islet transplantation and that its therapeutic efficacy is highly dependent on the antigen specificity of these cells.