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  • Review Article
  • Published:

Immunotherapeutic uses of CpG oligodeoxynucleotides

Nature Reviews Immunology volume 4, pages 249–259 (2004)Cite this article

Key Points

  • Single-stranded DNA containing CpG motifs triggers an innate immune response that is characterized by the production of polyreactive immunoglobulin and the production of T helper 1 (TH1)-type and pro-inflammatory cytokines, and chemokines.

  • CpG DNA interacts with Toll-like receptor 9 (TLR9) in the endosomal vesicles of human B cells and plasmacytoid dendritic cells, initiating a signalling cascade that proceeds through myeloid differentiation primary response gene 88 (MYD88) and culminates in the translocation of nuclear factor-κB (NF-κB) from the cytoplasm to the nucleus. The subsequent cytokine response indirectly activates various other cell types, including natural killer cells, T cells and macrophages.

  • Human immune cells are stimulated by three structurally distinct classes of CpG oligodeoxynucleotide (ODN). Different types of immune response are triggered by each class of ODN.

  • The innate immune response that is triggered by CpG ODNs improves host resistance to a wide range of pathogenic bacteria, viruses and parasites.

  • By facilitating the production of TH1-type and pro-inflammatory cytokines, and promoting the functional maturation of professional antigen-presenting cells, CpG ODNs accelerate and boost the generation of antigen-specific immunity when co-administered with vaccines.

  • By promoting TH1-biased immunity, CpG ODNs dampen the development of TH2-cell-mediated allergic responses. Reduced allergen-specific IgE production and improved lung function accompany the administration of CpG ODNs with allergen.

  • CpG DNA has the potential to worsen organ-specific autoimmune disease and cause other pathological changes when administered repeatedly at a high dose. However, the regimens that are required to achieve the therapeutic effects described above have not caused adverse events in normal animals or humans.

  • CpG ODNs have been administered safely to more than 500 individuals. Preclinical and clinical results indicate that these agents will be of therapeutic value in the treatment of allergic disorders and for improving host immunity against infectious pathogens.

Abstract

Synthetic oligodeoxynucleotides (ODNs) that contain immunostimulatory CpG motifs trigger an immunomodulatory cascade that involves B and T cells, natural killer cells and professional antigen-presenting cells. The response to CpG ODNs skews the host's immune milieu in favour of T helper 1 (TH1)-cell responses and pro-inflammatory cytokine production — an effect that underlies their use as immunoprotective agents, vaccine adjuvants and anti-allergens. Preclinical studies provide evidence that CpG ODNs are effective for each of these uses. Ongoing clinical studies indicate that CpG ODN use is safe in humans, and that they modulate the immune response to co-administered allergens and vaccines.

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Figure 1: Potential therapeutic uses of CpG oligodeoxynucleotides (ODNs).
Figure 2: CpG-DNA–TLR9-mediated cell signalling.
Figure 3: Mechanism by which CpG ODNs facilitate innate and adaptive immune responses.
Figure 4: Potential safety concerns associated with the use of CpG oligodeoxynucleotides (ODNs).

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I hold a patent position on the discovery of CpG oligodeoxynucleotides.

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DATABASES

LocusLink

CD4

CEBP

CREB

IFN-α

IFN-γ

IL-1

IL-4

IL-5

IL-6

IL-12

IL-18

IRAK

MYD88

NF-κB

TLR9

TNF

TRAF6

Glossary

PATHOGEN-ASSOCIATED MOLECULAR PATTERNS

(PAMPs). The innate immune system is stimulated by interaction with a highly conserved, but limited, set of molecular structures that are expressed by infectious microorganisms but absent (or rarely expressed) by the host. These PAMPs are recognized by a set of germline-encoded receptors, of which the family of Toll-like receptors is the best described.

TH1/TH2 CELLS

Two functionally distinct subsets of CD4+ T cells. T helper 1 (TH1) cells produce type 1 cytokines (including interleukin-2, IL-2, and interferon-γ) that support macrophage activation, the generation of cytotoxic T cells and the production of opsonizing antibodies. TH2 cells produce type 2 cytokines (including IL-4, IL-5 and/or IL-13) that support B-cell activation, the production of non-opsonizing antibodies, allergic reactions and the expulsion of extracellular parasites.

PLASMACYTOID DENDRITIC CELLS

(pDCs). A subset of DCs that were first described in humans and termed 'plasmacytoid' because of their microscopic appearance, which is similar to plasmablasts. In humans, these DCs can be derived from lineage-negative stem cells in peripheral blood and are the main producers of type I interferons (IFNs) in response to viral infections. Recent studies have identified a subset of type I IFN-producing DCs in mice, which are characterized by expression of B220 and Ly6C/G.

TOXIC SHOCK

A state of circulatory collapse and end-organ failure that is associated with the release of tumour-necrosis factor by host mononuclear cells in response to an infectious challenge.

LUPUS

(Also known as systemic lupus erythematosus, SLE). Lupus is an autoimmune disease that affects many tissues and cell types. Disease is characterized by the production of pathogenic autoantibodies that form immune complexes that can damage the kidneys and lungs. Multiple immune abnormalities, particularly associated with the increased activation of B and T cells, typify active disease.

EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

(EAE). An animal model of multiple sclerosis — a chronic demyelinating disease in humans. In animals, EAE is induced by injecting antigens derived from the myelin sheath of nerve cells, including myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein, together with a potent adjuvant.

MOLECULAR MIMICRY

A mechanism for the induction of autoimmunity in which the host mounts an immune response against a protein or peptide expressed by a pathogen that resembles a determinant also present on self-tissue. The induction of a pathogen-specific immune response therefore results in a crossreactive response to the self-tissue that causes pathology.

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Klinman, D. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 4, 249–259 (2004). https://doi.org/10.1038/nri1329

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