The challenge of modulating β-cell autoimmunity in type 1 diabetes

Abstract

With the conceptual advance about four decades ago that type 1 diabetes represents an autoimmune disease, hope arose that immune-based therapies would soon emerge to prevent and reverse the disorder. However, despite dozens of clinical trials seeking to achieve these goals, the promise remains unfulfilled, at least in a pragmatic form. With the benefit of hindsight, several important reasons are likely to account for this disappointing outcome, including failure to appreciate disease heterogeneity, inappropriate use of rodent models of disease, inadequacies in addressing the immunological and metabolic contributions to the disease, suboptimal trial designs, and lack of a clear understanding of the pathogenesis of type 1 diabetes. In this Series paper, we convey how recent knowledge gains in these areas, combined with efforts related to disease staging and emerging mechanistic data from clinical trials, provide cautious optimism that immune-based approaches to prevent the loss of β cells in type 1 diabetes will emerge into clinical practice.

Figure 1.. Shifts in T1D clinical research emphasis over the past 10 years.

Therapeutic agents and target mechanisms/objectives are noted for T1D clinical trials over the past decade, organized by their year of first publication. Current ongoing studies are noted with their expected year of completion.

Figure 2.. Considerations to improve T1D immune therapy trials.

Implementing these eight notions may accelerate identification of effective immune therapies for T1D and application in clinical settings.