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Drug Insight: new immunomodulatory therapies in type 1 diabetes

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 89–98 (2006)Cite this article

Abstract

Animal models and human studies have provided strong evidence that the immune response that causes type 1A diabetes is initiated against a limited array of antigens but acquires breadth and depth until β-cell mass has been critically compromised. Two recent trials confirmed the ability to identify relatives at risk for development of diabetes, but were unsuccessful in preventing disease. Treatment of at-risk individuals with oral insulin, which is postulated to be an antigen in the disease, did however show efficacy in a subgroup of these subjects, suggesting that antigen-specific prevention approaches might be successful in the right group of subjects at the right time. Earlier trials showed that the natural progression of disease can be altered with conventional immune suppression but these approaches have been supplanted by tolerance-induction strategies. Anti-CD3 monoclonal antibodies have shown efficacy in preventing the loss of insulin production over the first 2 years of disease without chronic immune suppression. The mechanisms are novel, and appear to involve induction of immune regulation by the monoclonal antibody. Ultimately, preservation and even improvement in β-cell mass is the goal of therapy. The means needed to achieve this will depend on the timing and mechanisms of the immune intervention and might require combinations of agents.

Key Points

  • Type 1A diabetes mellitus results form the progressive and specific autoimmune destruction of insulin-secreting pancreatic β cells; the disease develops over a period of years and continues after initial clinical presentation

  • The ultimate goal of therapeutic interventions is preservation (and even increase) of β-cell mass; the level of endogenous β-cell function is related to the ease and stability of metabolic control

  • Identification of suitable candidates for therapy, appropriate timing and specificity of intervention are critical for successful intervention; high-risk relatives of patients with type 1 diabetes can be identified using a combination of metabolic and immunologic measurements

  • New approaches for immune therapy such as anti-CD3 antibodies have shown success in modulating the natural history of the disease without the need for chronic immune suppression; in the future, to cause lasting remission of disease, it is likely that combinatorial approaches will be needed

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Figure 1: Expansion and diversification of the autoimmune response precedes clinical type 1 diabetes mellitus

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Acknowledgements

Supported by National Institutes of Health grants DK57846, AI98-010, DK063608, RR00645, and DK063608.

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  1. KC Herold is an Associate Professor of Medicine, and S Cernea is a Postdoctoral Research Fellow

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  1. Columbia University, New York, USA

    Simona Cernea & Kevan C Herold

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Correspondence to Kevan C Herold.

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Cernea, S., Herold, K. Drug Insight: new immunomodulatory therapies in type 1 diabetes. Nat Rev Endocrinol 2, 89–98 (2006). https://doi.org/10.1038/ncpendmet0082

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