Have we pushed the needle for treatment of Type 1 diabetes?

Abstract

Studies with immunologics have shown that the natural history of Type 1 diabetes can be modified. These studies have targeted key mediators of the disease and recent analyses, together with studies in preclinical models have identified mechanisms that may be involved in the clinical effects. Several issues remain including specificity of the interventions, adverse effects of the treatments, and duration of their effects. Future studies are likely to include more specific approaches with agents such as cell therapies with selected immune regulatory subsets, antigen specific therapies, and combinations of agents with complementary mechanisms of activity.

Figure 1

Type 1 diabetes pathogenesis and β cell protective factors. CD8+ effector T cells are considered the mediators of β cell killing, with the final common pathway involving a multitude of cells including autoreactive CD4+, CD8+, and B cells, failures of Tregs, and β cells that have changed susceptibly to killing and apoptosis. The pathogenesis is thought to begin with the release of β cell antigens, which antigen presenting cells (APCs) uptake and present to CD4+ and CD8+ T cells by Class II and Class I major histocompatibility molecules (MHC II and MHC I). This activates several pathways that ultimately lead to the immune destruction of β cells, via FasL-mediated apoptosis, release of chemokines and cytokines, and direct cytolytic killing. Recent studies have focused on new therapeutic targets that may help protect β cells from immune attack (highlighted in blue). These include therapies that target immune dysregulation, such as IL-2 and Treg infusions. There is also interest in understanding how intrinsic factors in β cells affect their response to immune attack and immune therapies. Endoplasmic reticulum stress may contribute to β cell death, and the tyrosine kinase inhibitor imatinib may inhibit this pathway. There is also some evidence that β cell dedifferentiation contributes to the pathology of T1D, with a subpopulation that is able to resist immune killing, which has increased expression of immune inhibitory proteins like PD-L1. Therapies that target these protective factors, used in combination with other immune therapies, could be beneficial for the treatment of T1D.