ArticleProceedings of the National Academy of Sciences of the United States of America2008
In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 121 citations in OpenAlex.
- Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study.BMC pharmacology & toxicology · 2013Trial
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- Early lymph node T follicular helper cell signalling hub drives influenza vaccine response in an ancestrally diverse cohort.EBioMedicine · 2025Article
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- Small Molecule CCR4 Antagonists Protect Mice fromBiomolecules · 2021Article
- Tumor resident regulatory T cells.Seminars in immunology · 2021Review
- The C-C Chemokine Receptor Type 4 Is an Immunomodulatory Target of Hydroxychloroquine.Frontiers in pharmacology · 2020Article
- Recent advances with Treg depleting fusion protein toxins for cancer immunotherapy.Immunotherapy · 2019Review
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- CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes.The Journal of experimental medicine · 2019Article
- The Contribution of the Immune System in Bone Metastasis Pathogenesis.International journal of molecular sciences · 2019Review
- Complex Stability and an Irrevertible Transition Reverted by Peptide and Fibroblasts in a Dynamic Model of Innate Immunity.Frontiers in immunology · 2019Article
- Dosing optimization of CCR4 immunotoxin for improved depletion of CCR4Molecular oncology · 2018Article
- Maximal Unbiased Benchmarking Data Sets for Human Chemokine Receptors and Comparative Analysis.Journal of chemical information and modeling · 2018Article
- Structural Analysis of Chemokine Receptor-Ligand Interactions.Journal of medicinal chemistry · 2017Review
- Cancer-FOXP3 directly activated CCL5 to recruit FOXP3Oncogene · 2017Article
- CCR4 is a determinant of melanoma brain metastasis.Oncotarget · 2017Article
- Inflammation: A Novel Therapeutic Target/Direction in Atherosclerosis.Current pharmaceutical design · 2017Review
- Towards the knowledge-based design of universal influenza epitope ensemble vaccines.Bioinformatics (Oxford, England) · 2016Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
Adjuvants are substances that enhance immune responses and thus improve the efficacy of vaccination. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants. We have therefore taken an approach to adjuvant discovery that uses in silico modeling and structure-based drug-design. As proof-of-principle we chose to target the interaction of the chemokines CCL22 and CCL17 with their receptor CCR4. CCR4 was posited as an adjuvant target based on its expression on CD4(+)CD25(+) regulatory T cells (Tregs), which negatively regulate immune responses induced by dendritic cells (DC), whereas CCL17 and CCL22 are chemotactic agents produced by DC, which are crucial in promoting contact between DC and CCR4(+) T cells. Molecules identified by virtual screening and molecular docking as CCR4 antagonists were able to block CCL22- and CCL17-mediated recruitment of human Tregs and Th2 cells. Furthermore, CCR4 antagonists enhanced DC-mediated human CD4(+) T cell proliferation in an in vitro immune response model and amplified cellular and humoral immune responses in vivo in experimental models when injected in combination with either Modified Vaccinia Ankara expressing Ag85A from Mycobacterium tuberculosis (MVA85A) or recombinant hepatitis B virus surface antigen (rHBsAg) vaccines. The significant adjuvant activity observed provides good evidence supporting our hypothesis that CCR4 is a viable target for rational adjuvant design.
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