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Immune therapy in type 1 diabetes mellitus

Nature Reviews Endocrinology volume 9, pages 92–103 (2013)Cite this article

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Abstract

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder directed against the β cells of the pancreatic islets. The genetic risk of the disease is linked to HLA-DQ risk alleles and unknown environmental triggers. In most countries, only 10–15% of children or young adults newly diagnosed with T1DM have a first-degree relative with the disease. Autoantibodies against insulin, GAD65, IA-2 or the ZnT8 transporter mark islet autoimmunity. These islet autoantibodies may already have developed in children of 1–3 years of age. Immune therapy in T1DM is approached at three different stages. Primary prevention is treatment of individuals at increased genetic risk. For example, one trial is testing if hydrolyzed casein milk formula reduces T1DM incidence in genetically predisposed infants. Secondary prevention is targeted at individuals with persistent islet autoantibodies. Ongoing trials involve nonautoantigen-specific therapies, such as Bacillus Calmette–Guérin vaccine or anti-CD3 monoclonal antibodies, or autoantigen-specific therapies, including oral and nasal insulin or alum-formulated recombinant human GAD65. Trial interventions at onset of T1DM have also included nonautoantigen-specific approaches, and autoantigen-specific therapies, such as proinsulin peptides. Although long-term preservation of β-cell function has been difficult to achieve in many studies, considerable progress is being made through controlled clinical trials and animal investigations towards uncovering mechanisms of β-cell destruction. Novel therapies that prevent islet autoimmunity or halt progressive β-cell destruction are needed.

Key Points

  • As an autoimmune disease, type 1 diabetes mellitus (T1DM) is strongly associated with mutations in HLA-DQ risk alleles; non-HLA genes contributing to disease risk are related to the immune system

  • Autoantibodies to the β-cell autoantigens insulin, GAD65, IA-2 and the ZnT8 transporter are major markers of islet autoimmunity; the number of islet autoantibodies determines risk and time to T1DM clinical onset

  • Immune therapy for T1DM is approached at three stages: primary prevention, secondary prevention and intervention

  • Primary prevention requires identification of newborn babies at increased genetic risk of T1DM; induction of immunological tolerance to islet autoantigens is a goal, but is difficult to measure

  • Nonautoantigen-specific or autoantigen-specific interventions can be used at the secondary prevention stage in individuals who have developed persistent islet autoantibodies; combination therapies have yet to be carried out

  • Immune therapy interventions at onset of T1DM can involve both nonautoantigen-specific and autoantigen-specific therapies; the most common primary outcome in clinical studies and trials is the preservation of C-peptide levels

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Figure 1: Representation of type 1 diabetes mellitus aetiology and pathogenesis, which indicates the points at which primary prevention, secondary prevention or intervention can be attempted.
Figure 2: Survival distribution function in relation to the number of islet autoantibodies.
Figure 3: β-cell control of blood glucose varies markedly between children with at least two islet autoantibodies.
Figure 4: The figure depicts the immunological synapses involved in the processing of an antigen by an antigen-presenting cell.

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Acknowledgements

The studies in the authors laboratories were supported by the National Institutes of Health (NIH grant DK063861), Juvenile Diabetes Research Foundation (grant 17-2011-576), Swedish Research Council (grant K2011-54X-15312-07-6), Swedish Childhood Diabetes Fund (H. E. Larsson), Swedish Diabetes Foundation (Å. Lernmark), Skåne County Council for Research and Development, SUS Fund, and DIAPREPP (EU grant 202013).

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  1. Department of Clinical Sciences, Lund University, Jan Waldenströms gata 35, Skåne University Hospital SUS, Malmö, SE-20502, Sweden

    Åke Lernmark & Helena Elding Larsson

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Correspondence to Åke Lernmark.

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Å. Lernmark declares associations with the following companies: Diamyd Medical AB (consultant, grant/research support, patent holder/applicant), Probi AB (consultant) and Zealand Pharma (consultant). H. E. Larsson declares no competing interests.

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Lernmark, Å., Larsson, H. Immune therapy in type 1 diabetes mellitus. Nat Rev Endocrinol 9, 92–103 (2013). https://doi.org/10.1038/nrendo.2012.237

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