Reversal of T1D and Rapid Reduction of β-Cell Stress by IL-10-Dependent MDSCs Induced by TLR4-Ab.

Therapy with IgG3 Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD2) agonistic antibody (TLR4-Ab) is a novel approach to type 1 diabetes (T1D) immunotherapy that targets the innate immune system by inducing immunoregulatory myeloid-derived suppressor cells (MDSCs). We sought to define the mechanisms by which TLR4-Ab induces MDSCs and how they reverse T1D. TLR4-Ab induction of MDSCs requires interleukin 10 signaling in the bone marrow, and MDSCs mediate suppression via inducible nitric oxide synthase. Induction of immunoregulatory MDSCs results in profound downregulation of β-cell endoplasmic reticulum stress and unfolded protein response associated with acute T1D. Establishing mechanisms by which TLR4-Ab reverses acute T1D defines new therapeutic pathways for human T1D that target innate immunity to restore immune tolerance.