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  • Review Article
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α-Galactosylceramide therapy for autoimmune diseases: prospects and obstacles

Nature Reviews Immunology volume 5, pages 31–42 (2005)Cite this article

Key Points

  • Invariant natural killer T (iNKT) cells are a subset of T cells that express a semi-invariant T-cell receptor (TCR) (composed of Vα14–Jα18 and Vβ8.2 in mice, and Vα24–Jα18 and Vβ11 in humans), together with markers of NK cells. These cells are specific for glycolipid antigens that are presented by the MHC-class-I-like molecule CD1d.

  • A distinguishing feature of iNKT cells, compared with conventional T cells and other T cells that are sometimes referred to as NKT cells, is their reactivity with the antitumor agent α-galactosylceramide (α-GalCer), a natural product isolated from a marine sponge.

  • In vivo activation of iNKT cells with α-GalCer results in a dynamic response that is characterized by rapid secretion of interleukin-4 and interferon-γ, transient downregulation of cell-surface TCR, clonal expansion and homeostatic contraction. Activation of iNKT cells in this manner also leads to the transactivation of various cells of the innate and adaptive immune systems and, in most mouse strains, to immune deviation to a T helper 2 (TH2) response.

  • The immunomodulatory activities of α-GalCer have been exploited for the treatment of various diseases, including autoimmune diseases. Specifically, α-GalCer and related glycolipids prevent disease in experimental models of type 1 diabetes, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and Graves' thyroiditis. However, treatment efficacy was influenced by various parameters, including the dose, route, timing and frequency of injections, and the particular mouse strain that was used, which in some cases paradoxically resulted in disease exacerbation.

  • Available evidence indicates that α-GalCer prevents autoimmunity by promoting TH2 responses. However, recruitment of tolerogenic dendritic cells and induction of regulatory T cells might also have a role.

  • Although preclinical studies have raised considerable enthusiasm for developing α-GalCer as an immunotherapy for autoimmune diseases, there are several concerns about using α-GalCer therapy for humans. In particular, in some preclinical studies, α-GalCer exacerbated rather than prevented disease, indicating that treatment with α-GalCer might accelerate disease in some individuals. Furthermore, treatment with α-GalCer has several adverse side-effects in mice, including liver toxicity and exacerbation of atherosclerosis, raising additional safety concerns.

  • Some of the obstacles associated with human α-GalCer therapy might be overcome by using structural analogues of α-GalCer (such as the compound known as OCH) by co-administration of reagents that modulate iNKT-cell responses or by co-administration with other therapeutics for autoimmune diseases.

  • Translation of the preclinical studies of α-GalCer to the treatment of human autoimmunity also requires a better understanding of the immunological properties of human iNKT cells and their responses to stimulation with glycolipids.

Abstract

Autoimmune responses are normally kept in check by immune-tolerance mechanisms, which include regulatory T cells. In recent years, research has focused on the role of a subset of natural killer T (NKT) cells — invariant NKT (iNKT) cells, which are a population of glycolipid-reactive regulatory T cells — in controlling autoimmune responses. Because iNKT cells strongly react with a marine-sponge-derived glycolipid, α-galactosylceramide (α-GalCer), it has been possible to specifically target and track these cells. As I discuss here, although preclinical studies have shown considerable promise for the development of treatment with α-GalCer as a therapeutic modality for autoimmune diseases, several obstacles need to be overcome before moving α-GalCer therapy from the bench to the bedside.

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Figure 1: Schematic view of the ligand-specificity of iNKT cells compared with conventional T cells.
Figure 2: Structure of α-GalCer and related glycolipids.
Figure 3: The in vivo response of iNKT cells to stimulation with α-GalCer.
Figure 4: Capacity of α-GalCer-activated iNKT cells to modulate innate and adaptive immunity.
Figure 5: Proposed mechanism for the capacity of α-GalCer to modulate TH1-dominant autoimmunity.

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Acknowledgements

I apologize to those whose work I failed to cite. I thank the members of my laboratory and many colleagues and collaborators, in particular S. Joyce, R. Singh, C.-R. Wang, D. Unutmaz and A. Major for helpful discussions and sharing unpublished data, and S. Joyce for critical reading of the manuscript. My laboratory is supported by the National Institutes of Health (United States).

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  1. Department of Microbiology and Immunology, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, 37232, Tennessee, USA

    Luc Van Kaer

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DATABASES

Entrez Gene

CD1d

CD95

granulocyte/macrophage colony-stimulating factor

IFN-γ

IL-2

IL-4

IL-10

IL-12

IL-13

NK1.1

TGF-β

tumour-necrosis factor

FURTHER INFORMATION

Luc Van Kaer's laboratory

Glossary

T HELPER 1

(TH1). Antigen-activated, conventional CD4+ T cells can differentiate into TH1 cells, which produce interleukin-2 (IL-2), interferon-γ and tumour-necrosis factor, or TH2 cells, which produce IL-4, IL-5, IL-6, IL-10 and IL-13.

OESTRADIOL

A member of the oestrogen family of steroid hormones. It is the most potent female hormone that occurs naturally. It is produced by the ovaries and is responsible for the growth of the breast, the development of secondary sexual characteristics and the maturation of long bones. Oestradiol also impacts on immune responses, including the profile of cytokines produced by invariant natural killer T cells.

'DANGER' SIGNALS

Agents that alert the immune system to danger and thereby promote the generation of adaptive immune responses. Danger signals can be associated with microbial invaders (exogenous danger signals) or produced by damaged cells (endogenous danger signals).

NON-OBESE DIABETIC MICE

(NOD mice). Mice of the NOD strain spontaneously develop a form of autoimmunity that closely resembles human type 1 diabetes. Prevalence of disease is higher in female than male animals and can be accelerated by treatment with cyclophosphamide, which is thought to deplete regulatory T cells.

OSTEOPONTIN

An extracellular-matrix protein that supports adhesion and migration of inflammatory cells. It has recently been recognized as an immunoregulatory T-helper-1-type cytokine.

ACTIVATION-INDUCED CELL DEATH

(AICD). A form of regulated cell death, which is induced during lymphocyte activation. During a normal immune response, most antigen-specific lymphocytes undergo AICD.

α-GALCER–CD1d TETRAMERS

Tetrameric forms of CD1d molecules bound to α-galactosylceramide (α-GalCer), which have sufficient affinity for the T-cell receptor of invariant natural killer T cells to allow the detection of these cells by flow cytometry.

INSULITIS

An infiltration of lymphocytes into pancreatic islets during the progression of type 1 diabetes. Insulitis can be innocuous or destructive.

EXPERIMENTAL ALLERGIC (AUTOIMMUNE) ENCEPHALOMYELITIS

(EAE). An experimental model of human multiple sclerosis that is induced in susceptible animals by immunization with central-nervous-system antigens. EAE can be induced in various mammalian species, including mice. Several different mouse models have been established that develop either self-limiting (monophasic) or recurring (relapsing–remitting) disease.

COLLAGEN-INDUCED ARTHRITIS

(CIA). An experimental model of rheumatoid arthritis. Arthritis is induced by immunization of susceptible animals with collagen type II.

SYSTEMIC LUPUS ERYTHEMATOSUS

(SLE). A systemic autoimmune disease that is characterized by multi-organ failure and autoantibodies specific for nuclear antigens. Both hereditary and induced mouse models of SLE are available.

COLITIS

An inflammatory disease of the colon. In humans, colitis is most commonly classified as ulcerative colitis or Crohn's disease, two inflammatory bowel diseases that have unknown aetiology. Various hereditary and induced mouse models of human colitis have been developed.

GRAVES' THYROIDITIS

Graves' disease, the most common form of hyperthyroidism in humans results from activating antibodies specific for the thyroid-stimulating-hormone receptor (TSHR). In mouse models of Graves' thyroiditis, disease is induced by immunization with the TSHR.

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Kaer, L. α-Galactosylceramide therapy for autoimmune diseases: prospects and obstacles. Nat Rev Immunol 5, 31–42 (2005). https://doi.org/10.1038/nri1531

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