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Therapeutics targeting the innate immune system

Nature Reviews Immunology volume 4, pages 512–520 (2004)Cite this article

Key Points

  • The recent advances in our knowledge of the proteins and the signalling pathways that are involved in innate immunity, together with the identification of cognate ligands for protein receptors of the innate immune system, provide new targets for drug development, which might be useful for combating various human diseases.

  • The key receptors in the innate immune system are the Toll-like receptors (TLRs), of which there are ten in humans, and the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, which are intracellular sensors of bacterial products.

  • The leucine-rich repeats present in both TLRs and NOD1/2, and the Toll/interleukin-1 receptor (TIR) domains of TLRs, could be exploited as drug targets.

  • Agonists or antagonists that target the ligand-binding sites of these receptors might also yield new drugs. Small-molecule agonists that target the TLRs have already been developed.

  • The heteromeric nature of the signalling complexes that contain TLRs in association with other molecules might also provide targets for the development of therapeutic drugs.

  • Although further developments could be hampered by limitations on our ability to express proteins for high-throughput screens and by the problems associated with blocking protein–protein interactions, it should be possible to build on the initial success of imidazole quinoline molecules that target TLR7 and TLR8, and the modified CpG-containing compounds that target TLR9.

Abstract

Proteins that recognize the components and products of microorganisms have an important role in innate immunity. Here, I focus on recent advances in our understanding of the function of several such protein families. In particular, I consider how members of the TLR (Toll-like receptor), NOD (nucleotide-binding oligomerization domain)-protein and MyD88 (myeloid differentiation primary-response protein 88) families are providing emerging opportunities for the development of new therapeutics that modify innate immune responses in ways which benefit the host.

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Figure 1: Innate immunity at the crossroads.
Figure 2: TLRs as targets for therapy.
Figure 3: NOD1 and NOD2 as targets for therapy.

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Acknowledgements

I thank J. C. Mathison for comments and editorial support and P. Rutledge for administrative support. This work was supported by the National Institutes of Health, The Charles Dana Foundation and The Novartis Foundation.

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Authors and Affiliations

  1. Department of Immunology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Richard J. Ulevitch

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  1. Richard J. Ulevitch
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Competing interests

Richard J. Ulevitch is a consultant for the Corixa Corporation (Seattle, United States), which has developed monophosphoryl-lipid-A-based adjuvants, the Ribi adjuvant system and the synthetic adjuvant RC-529. His laboratory also has a grant that is part of a National Institutes of Health (United States) Program Project in which Corixa workers are the Principal Investigators.

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DATABASES

Entrez Gene

CD14

IKK-α

IKK-β

IL-1R1

IRAK1

IRAK4

IRF3

MD2

MyD88

NOD1

NOD2

RICK

SARM

TIRAP

TLR1

TLR2

TLR3

TLR4

TLR5

TLR6

TLR7

TLR8

TLR9

TLR11

TRAF6

TRAM

TRIF

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Ulevitch, R. Therapeutics targeting the innate immune system. Nat Rev Immunol 4, 512–520 (2004). https://doi.org/10.1038/nri1396

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