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Type 1 diabetes: translating mechanistic observations into effective clinical outcomes

Nature Reviews Immunology volume 13, pages 243–256 (2013)Cite this article

Subjects

Key Points

  • For more than 25 years, type 1 diabetes (T1D) has been recognized as an autoimmune disease. The mechanisms involve innate and adaptive immune responses that appear to be triggered by environmental factors on the appropriate genetic background.

  • Genetic studies have suggested that immunological pathways may contribute to disease development. These pathways involve genes that are involved in the acquisition and maintenance of immune tolerance.

  • Immune mechanisms that may contribute to the pathogenesis of T1D include failures in central tolerance, dysregulation of tolerance in the periphery as well as active immune responses against pathogens.

  • Preclinical studies in rodent models have shed light on pathological immunological mechanisms and have begun to address environmental factors that may modify the disease. These models have also been useful for identifying the autoantigens that are recognized by T cells in patients with T1D.

  • Some clinical studies have successfully modified the chronic loss of C peptide that is characteristic of T1D. Not all therapeutic approaches have worked, and the duration of the efficacy is limited. These findings suggest that future trials should explore other options, including combinations of therapeutic agents and earlier intervention at the pre-diabetic period.

  • Not all of the findings in preclinical studies have been successfully translated into the clinic. Some investigators have criticized the validity of the preclinical models, but a careful analysis of the preclinical studies suggests that their ability to predict outcomes is strong. Details concerning a broad number of variables, including dosage and timing of agents, may not have been fully considered in the design of clinical trials.

Abstract

Type 1 diabetes (T1D) remains an important health problem, particularly in western countries, where the incidence has been increasing in younger children. In 1986, Eisenbarth described T1D as a chronic autoimmune disease. Work over the past three-and-a-half decades has identified many of the genetic, immunological and environmental factors that are involved in the disease and have led to hypotheses concerning its pathogenesis. Clinical trials have been conducted to test these hypotheses but have had mixed results. Here, we discuss the findings that have led to our current concepts of the disease mechanisms involved in T1D and the clinical studies promoted by these studies. The findings from preclinical and clinical studies support the original proposed model for how T1D develops but have also suggested that this disease is more complex than was originally thought and will require broader treatment approaches.

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Figure 1: Revision of the Eisenbarth model of type 1 diabetes.
Figure 2: Results of immunotherapy trials in type 1 diabetes.
Figure 3: Regulatory T cells that have lost FOXP3 expression may contribute to autoimmune disease.

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Acknowledgements

K.C.H. is supported by the US National Institutes of Health (U19 AI082713, DK045735, DK057846 and UL1RR024139) and the JDRF (2011-248, 2007–1059). D.A.A.V. is supported by the National Institutes of Health (DK089125, AI039480, AI091977, AI052199), the St. Jude National Cancer Institute Comprehensive Cancer Center (CA21765) and the American Lebanese Syrian Associated Charities (ALSAC). J.A.B is supported by the National Institutes of Health (AI50834, AI046643, JDRF 4-2011-248, U19 AI056388). A.C. is supported by the UK Medical Research Council, the Wellcome Trust and the European Union.

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Authors and Affiliations

  1. Department of Immunobiology, Yale University, New Haven, 06520, Connecticut, USA

    Kevan C. Herold

  2. Department of Immunology, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Dario A. A. Vignali

  3. Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK

    Anne Cooke

  4. Diabetes Center and Department of Medicine, University of California San Francisco, San Francisco, 94143, California, USA

    Jeffrey A. Bluestone

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Competing interests

Jeffrey A. Bluestone has a patent for teplizumab. Kevan C. Herold has received a grant from MacroGenic, Inc., and Islet Sciences, Inc. He has a patent pending for analysis of β-cell death and is on the Advisory Board for Islet Sciences, Inc. Dario A. A. Vignali and Anne Cooke declare no competing financial interests.

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Glossary

Anti-thymocyte globulin

Polyclonal antibodies against human T cells that are produced by immunizing rabbits or horses.

Cyclosporin A

An immunosuppressive drug that inhibits calcineurin, a Ca2+-dependent serine/threonine phosphatase that is necessary for the nuclear translocation of the transcription factor nuclear factor of activated T cells (NFAT).

C peptide

The connecting peptide that joins the A chain and B chain of insulin in the proinsulin molecule.

Hygiene hypothesis

The theory that the lack of early childhood exposure to infectious agents, symbiotic microorganisms (for example, changes in gut microflora) and parasites increases susceptibility to allergic and autoimmune diseases by modulating immune system development.

Insulitis

Inflammation of the islets of Langerhans in the pancreas that comprises a complex cellular infiltrate that invades and destroys the islets of Langerhans. The cellular composition includes CD4+ T cells, CD8+ T cells, regulatory T cells, B cells, dendritic cells, natural killer cells and macrophages.

Gut microbiome

This is the collective community of bacteria in the small and large intestines.

Forkhead box P3

(FOXP3). A forkhead/winged helix family transcription factor that is a crucial master regulator of regulatory T cell development and function.

Regulatory T cells

(TReg cells). A rare subpopulation of CD4+ T cells that are endowed with potent suppressive capacity. They typically express the transcription factor FOXP3+. Both naturally occurring TReg cells (which develop in the thymus) and adaptive TReg cells (which acquire their regulatory activity in the periphery) have been described.

Invariant natural killer T cells

(iNKT cells). Cells that share properties of T cells and natural killer (NK) cells and recognize the non-polymorphic CD1d molecule, which is an antigen-presenting molecule that binds self lipids and foreign lipids and glycolipids. They recognize α-galactosylceramide presented on CD1d molecules and have restricted T cell receptor (TCR) usage.

T helper 17 cells

(TH17 cells). A subset of CD4+ T cells that is characterized by its expression of the transcription factors RORγ, RORα and signal transducer and activator of transcription 3 (STAT3). They are involved in inflammatory responses and normally have an important protective role at epithelial and mucosal surfaces. Their development involves a combination of TGFβ, interleukin 21 (IL-21), IL-23 and IL-1β, and they secrete IL-17, IL-22, IL-22 and in some circumstances granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or interferon-γ (IFNγ).

Specific-pathogen-free conditions

(SPF conditions). Mice raised under SPF conditions are guaranteed to be free of a defined list of mouse pathogens.

Germ-free mice

Also known as gnotobiotic mice, these are mice that do not harbour any bacteria, viruses or parasites.

'Type B' T cells

A term that has been used to describe CD4+ T cells that recognize and respond to unstable peptide–MHC complexes, which arise when peptides are loaded onto MHC class II molecules in the absence of H2-DM-mediated editing.

HEp-2

A human epithelial cell line that is commonly used as a target for immunofluorescent detection of a wide range of nuclear and cytoplasmic staining antibodies. Distinct staining patterns are associated with particular antibody specificities. For example, a homogeneous nuclear staining pattern is indicative of antibodies that react with double-stranded DNA or chromatin, whereas a speckled nuclear-staining pattern is indicative of antibodies that react with small nuclear ribonucleoproteins.

CD28–B7 co-stimulation

A crucial receptor–ligand interaction that is required for maximal T cell activation and survival.

Rapamycin

An immunosuppressive drug that, in contrast to calcineurin inhibitors (such as cyclosporin A and FK506), does not prevent T cell activation but blocks interleukin-2-mediated clonal expansion by blocking mammalian target of rapamycin (mTOR). It does not interfere with the function and expansion of naturally occurring regulatory T cells.

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Herold, K., Vignali, D., Cooke, A. et al. Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol 13, 243–256 (2013). https://doi.org/10.1038/nri3422

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