Safe induction of autoantigen-specific long-term tolerance is the “holy grail” for the treatment of autoimmune diseases. In animal models of type 1 diabetes, oral or i.n. immunization with islet antigens induces Tregs that are capable of bystander suppression. However, such interventions are only effective early in the prediabetic phase. Here, we demonstrate that a novel combination treatment with anti-CD3ε–specific antibody and i.n. proinsulin peptide can reverse recent-onset diabetes in 2 murine diabetes models with much higher efficacy than with monotherapy with anti-CD3 or antigen alone. In vivo, expansion of CD25+Foxp3+ and insulin-specific Tregs producing IL-10, TGF-β, and IL-4 was strongly enhanced. These cells could transfer dominant tolerance to immunocompetent recent-onset diabetic recipients and suppressed heterologous autoaggressive CD8 responses. Thus, combining a systemic immune modulator with antigen-specific Treg induction is more efficacious in reverting diabetes. Since Tregs act site-specifically, this strategy should also be expected to reduce the potential for systemic side effects.
Damien Bresson, Lisa Togher, Evelyn Rodrigo, Yali Chen, Jeffrey A. Bluestone, Kevan C. Herold, Matthias von Herrath
Efficacy improvement of combination therapies compared with treatment with anti-CD3 alone in recent-onset diabetic NOD and RIP-LCMV mice