Immunotherapy of type 1 diabetes: where are we and where should we be going?

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by destruction of insulin-producing pancreatic beta cells. Many broad-based immunosuppressive and antigen-specific immunoregulatory therapies have been and are currently being evaluated for their utility in the prevention and treatment of T1D. Looking forward, this review discusses the potential therapeutic use of antigen-specific tolerance strategies, including tolerance induced by "tolerogenic" antigen-presenting cells pulsed with diabetogenic antigens and transfer of induced or expanded regulatory T cells, which have demonstrated efficacy in nonobese diabetic (NOD) mice. Depending on the time of therapeutic intervention in the T1D disease process, antigen-specific immunoregulatory strategies may be employed as monotherapies, or in combination with short-term tolerance-promoting immunoregulatory drugs and/or drugs promoting differentiation of insulin-producing beta cells from endogenous progenitors.

Figure 1. Model of Epitope Spreading and Tolerance Therapy in the Pathogenesis of Type 1 Diabetes in the NOD Mouse

Progression of T1D in the NOD mouse involves the sequential activation of autoreactive T cells to multiple diabetogenic epitopes via epitope spreading which accumulate until clinical diagnosis when sufficient autoreactive effector cells are present to cause destruction of the majority of the β cell mass. The insulin B chain epitope 9–23 (InsB_9–23) (A - red effector cells) appears to be the initiating or very early pathogenic diabetogenic epitope in the NOD mouse based on the ability of tolerance induced by ECDI-fixed splenocytes coupled with either intact insulin or InsB_9–23 in 4–6 week old mice to inhibit development of clinical diabetes (1). As β cell destruction continues responses to additional islet antigens, e.g. InsB_15–23 and/or IRGP (B - blue effector cells) and eventually epitopes on the insulin A or B chains (C - green effector cells) are activated. Epitopes on the InsA or Ins B chain (outside of B_9–23) epitopes on chain appear to be dominant at the stage of transition to overt disease (loss of approximately 75% of islet mass) based on the ability tolerance induced by insulin-coupled, but not InsB_9–23-coupled, splenocytes to ameliorate disease progression in 18–20 week old NOD mice (2). Recovery from (i.e., reversal) chronic T1D when all of the β cells have been destroyed would be expected to require a combination of tolerance to the autoantigens which were responsible for initial β cell destruction and a β cell regeneration and/or replacement strategy which may require allo- or xenoantigen tolerance in therapies involving islet cell transplantation (3). A similar pattern of epitope spreading is postulated to occur in human T1D.