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

With the conceptual advance some four decades ago that type 1 diabetes (T1D) represents an autoimmune disease, hope emerged that immune-based therapies would quickly evolve as a means to prevent and reverse the disorder. However, despite dozens of clinical trials seeking to achieve that purpose, the goal remains unfulfilled, at least in a pragmatic form. With the benefit of hindsight, multiple reasons are likely to account for this unfortunate situation, and several stand out: failure to appreciate disease heterogeneity; inappropriate utilization of and insight from rodent models of disease; inadequacies in addressing the immunologic and metabolic contributions to the disease; suboptimal trial designs; and lack of a clear understanding of the disorder’s pathogenesis. This review conveys 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 an immune-based means to prevent the loss of β-cells in T1D will emerge into clinical practice.