Targeted immune interventions for type 1 diabetes: not as easy as it looks!

Abstract

Purpose of review: Although insulin is lifesaving and sustaining for those with type 1 diabetes (T1D), curing the disease will be much more complex than simple replacement of this hormone. T1D is an autoimmune disease orchestrated by T cells, and includes many arms of the immune response. Tremendous effort has gone into understanding its underlying immune, genetic, and environmental causes, and this progress has led to immunologically based clinical trials in T1D. This review will focus primarily on the clinical trials of the past decade that have attempted to translate these fundamental findings.

Recent findings: It is known that powerful, nonspecific immune suppressants can temporarily slow the course of newly diagnosed T1D, yet are too toxic for long-term use, especially in children. Recent clinical trials to reverse T1D have used newly developed therapies that target specific components of the immune process believed to be involved with T1D. Although well justified and designed, no recent approach has resulted in clinical remission and few have had any effect on disease course.

Summary: Advances in our fundamental understanding of how the human diabetes immune response is activated and regulated coupled with lessons that have been learnt from the most recent era of completed trials are guiding us toward the development of more effective, multipronged therapies to ablate diabetes autoimmunity, restore immune tolerance, preserve β cells, and, ultimately, improve the lives of patients with T1D.

Figure 1

Balancing effector and regulatory T cells in health, T1D, and with therapies. (A) Individuals free from diabetes may have no circulating beta-cell specific effector T cells (Teff; left) or have sufficient, functional peripheral regulatory T cells (Tregs) to counterbalance Teffs (right) and keep beta cells free from autoimmune damage. (B) In subjects who develop T1D, Teffs may become resistant to Tregs (left), Treg numbers may diminish (center), or, despite sufficient numbers, Tregs may become dysfunctional (right) resulting in T cell-mediated destruction of beta cells. (C) Therapies which temporarily suppress Teffs (left) or bolster Treg number or function (center) may be able to temporarily slow beta cell decline, but it may take therapies that both target Teffs and increase beta-cell-specific Tregs (right) to have a substantive and long-lasting effect.