Toll-like receptor 4 agonistic monoclonal antibody reverses new onset type 1 diabetes (BA12P.106)

Viral, parasitic or bacterial infections can prevent T1D in NOD mice. The “hygiene hypothesis” proposes that the incidence of autoimmunity is increasing due to decreased immune stimulation in childhood, offering a rationale for stimulation of innate immunity as a treatment for T1D. We demonstrate that a TLR4/MD-2 specific agonistic monoclonal antibody, UT18, can not only prevent T1D, but also reverse new onset T1D (diagnosed by polyuria, weight loss, and elevated blood glucose). UT15, a control TLR4/MD-2 non-agonistic monoclonal antibody, neither prevented nor reversed T1D. In the prevention studies, UT18 treatment resulted in decreased insulitis vs. UT15 treatment. UT18 treatment permanently reversed new onset T1D in 9/13 mice, while UT15 treated mice rapidly progressed to end-stage diabetes (>600 mg/dl). Mice successfully treated with UT18 had less severe islet infiltration and increased insulin positive beta-cell area compared to UT15 controls. Transfer of CD4+ and CD8+ T-cells (from mice successfully treated with UT18) did not cause diabetes for up to 75 days post transfer, whereas cells transferred from UT15 and non-diabetic NOD mice rapidly caused disease. The lack of T cell mediated diabetes transfer suggests that T cell tolerance was restored in new onset diabetic mice treated with UT18. Restoration of T cell tolerance via TLR-4/MD-2 mediated innate immune stimulation is a promising new pathway for treatment of T1D and other T cell mediated autoimmune diseases.