The induction of antigen (Ag)-specific tolerance and replacement of islet β-cells are major
ongoing goals for the treatment of Type 1 Diabetes (T1D). Our group previously
showed that a hybrid insulin peptide (2.5HIP) is a critical autoantigen for diabetogenic CD4<sup>+</sup>
T cells in the non-obese diabetic (NOD) mouse model. In this study, we
investigated whether induction of Ag-specific tolerance using 2.5HIP-coupled
tolerogenic nanoparticles (NPs) could protect diabetic NOD mice from disease
recurrence upon syngeneic islet transplantation. Islet graft survival was
significantly prolonged in mice treated with 2.5HIP NPs, but not NPs containing
the insulin B chain peptide 9-23. Protection in 2.5HIP
NP-treated mice was attributed
both to the simultaneous induction of anergy in 2.5HIP-specific effector T
cells and to the expansion of Foxp3+ regulatory T cells specific for the same
antigen. Notably, our results indicate that effector
function of graft-infiltrating CD4<sup>+</sup> and CD8<sup>+</sup> T cells
specific for other β-cell epitopes was significantly
impaired, suggesting a novel mechanism of therapeutically induced linked
suppression. This work establishes that
tolerance induction with a hybrid insulin peptide can delay recurrent autoimmunity
in NOD mice, which could inform the development of an Ag-specific therapy for
T1D.
Long-Term Islet Graft Survival in NOD Mice by Abrogation of Recurrent Autoimmunity