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Therapeutic potential of Toll-like receptor 9 activation

Key Points

  • To detect and categorize infectious agents the innate immune system uses receptors that are specific for molecules present in broad classes of pathogens, but not in the host.

  • Perhaps the best understood of the receptor families that have evolved to detect pathogen-specific molecules are the Toll-like receptors (TLRs), of which 10 are known in humans.

  • TLRs that are specific for molecules representing extracellular pathogens, such as lipopolysaccharides or lipopeptides, are expressed at the cell surface, whereas TLRs that seem to function to detect intracellular pathogens are expressed within innate immune cells, and are specific for nucleic acids.

  • TLR9 detects unmethylated CpG motifs present in viral or bacterial DNA. Synthetic oligodeoxynucleotides containing CpG motifs ('CpG ODN') in a nuclease-resistant phosphorothioate backbone have been developed as TLR9 agonists.

  • In humans, TLR9 is constitutively expressed in only two immune cells, B cells and plasmacytoid dendritic cells (pDC). Because they only activate these two immune cell types, CpG ODN are not 'nonspecific immune activators', but rather are highly specific inducers of B cell and pDC immune responses.

  • TH1 immune activation by CpG ODN has been shown to have substantial therapeutic activity in mouse models of cancer, infectious disease and allergy/asthma.

  • Excessive doses of CpG ODN can induce a lethal systemic inflammatory response syndrome in rodents that is rodent-specific, apparently resulting from their broader distribution of TLR9 expression in more immune cell subsets compared to humans and other primates. CpG ODN have also been shown in animal models to induce or flare autoimmune disease, which has not been reported in humans or other primates.

  • More than 1,000 humans have been treated with CpG ODN in various clinical trials by several different companies, with encouraging evidence of efficacy with relatively little toxicity.

Abstract

In the decade since the discovery that mouse B cells respond to certain unmethylated CpG dinucleotides in bacterial DNA, a specific receptor for these 'CpG motifs' has been identified, Toll-like receptor 9 (TLR9), and a new approach to immunotherapy has moved into the clinic based on the use of synthetic oligodeoxynucleotides (ODN) as TLR9 agonists. This review highlights the current understanding of the mechanism of action of these CpG ODN, and provides an overview of the preclinical data and early human clinical trial results using these drugs to improve vaccines and treat cancer, infectious disease and allergy/asthma.

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Figure 1: Switching on antitumour immunity by in vivo dendritic cell activation through TLR9.

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Acknowledgements

I thank D. Arsemanlt for secretarial assistance.

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Competing interests

A.K. is an employee of Coley Pharmaceutical Group, inventor of patents on CpG ODN, and holds stock in Coley Pharmaceutical Group.

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Glossary

Pattern-recognition receptors

Receptors that bind to molecular patterns found in pathogens but not mammalian cells. Examples include the mannose receptor, which binds to terminally mannosylated and polymannosylated compounds, and Toll-like receptors, which are activated by various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA.

CpG motifs

DNA oligodeoxynucleotide sequences that include an unmethylated cytosine–guanosine sequence and certain flanking nucleotides, which have been found to induce innate immune responses through interaction with the Toll-like receptor 9.

Plasmacytoid dendritic cell

(pDC). A unique type of dendritic cell. These cells are also known as interferon (IFN)-producing cells because they are the main source of type I IFNs (such as, IFNα and IFNβ) during viral infections.

Co-stimulatory molecules

Soluble or membrane-bound molecules that signal to T cells (or other immune cells) and, having little or no effect alone, either enhance or modify the physiological effect of the primary signal, which is mediated by engagement of the T-cell receptor (or other receptors on other immune cells).

Plasma cells

Non-dividing, terminally differentiated immunoglobulin-secreting cells of the B-cell lineage.

Adoptive transfer

An experimental method in which lymphocytes from an antigen-primed donor mouse are introduced into an unprimed recipient mouse.

Adjuvant

An agent mixed with an antigen that enhances the immune response to that antigen upon immunization.

Seroconversion

Development of a detectable concentration of pathogen-specific antibodies in the serum as a result of infection or immunization.

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Krieg, A. Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 5, 471–484 (2006). https://doi.org/10.1038/nrd2059

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