Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplantation

OBJECTIVE—In type 1 diabetes, allogeneic pancreatic islet
transplant 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 transplant remains to be determined.
Among the different subsets of CD4 Tregs, the T
inducible regulatory type 1 (Tr1) cells can be generated from
naive T-cells in the presence of interleukin-10 (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 transplant.
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 transplant. The two models
differed in their therapeutic stringency, based on the mean
rejection time of untreated mice that underwent a transplant.
RESULTS—Transfer of polyclonal Tr1 cells engendered graft
tolerance only in the nonstringent mouse model. Conversely, cell
therapy with Ag-specific Tr1 cells induced an IL-10–dependent
tolerance in the stringent mouse model of islet transplant. 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 transplant and that its
therapeutic efficacy is highly dependent on the antigen specificity
of these cells.