Therapies to Suppress β Cell Autoimmunity in Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that is generally considered to be T cell-driven. Accordingly, most strategies of immunotherapy for T1D prevention and treatment in the clinic have targeted the T cell compartment. To date, however, immunotherapy has had only limited clinical success. Although certain immunotherapies have promoted a protective effect, efficacy is often short-term and acquired immunity may be impacted. This has led to the consideration of combining different approaches with the goal of achieving a synergistic therapeutic response. In this review, we will discuss the status of various T1D therapeutic strategies tested in the clinic, as well as possible combinatorial approaches to restore β cell tolerance.

Keywords: autoimmunity; diabetes; immunoregulation; immunotherapy.

Figure 1

The progression and treatment of β cell autoimmunity. Top panel: In general, overt diabetes results from the gradual loss of functional insulin-producing β cells due to the inflammatory environment driven by infiltrating self-reactive T cells and antigen-presenting cells (APC). Although β cell-specific T cell clones are detected in both healthy and type 1 diabetes (T1D) susceptible individuals, a number of factors promote T1D development in the latter population. Decreased efficiency of negative selection in the thymus allows for the increased escape of β cell-specific T cell clones into the periphery. In the periphery, β cell-specific T cells are stimulated in the pancreatic lymph nodes (PLN) by APC derived from the islets, leading to effector T cells (Teff) differentiation due to suboptimal Foxp3⁺Treg suppression. These pathogenic Teff then infiltrate the islets and drive inflammation leading to reduced β cell function and/or survival. Bottom panel: Several distinct therapeutic interventions have been tested for the prevention or treatment of T1D. The major approaches have included: administration of β cell autoantigens, expansion of Foxp3⁺Treg, Ab therapies that alter T cell responses, therapeutic reagents that tolerize APC function, neutralization of proinflammatory molecules, or treatments that expand or enhance β cell function and/or survival. Some of these approaches have had clinical, albeit limited, success. Future therapeutic interventions should look toward refinement in the specificity of these treatments, and the development of combinatorial therapies targeting multiple arms of the immune system, as T1D is a multi-pronged autoimmune disease.