{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T23:41:59Z","timestamp":1791157319791,"version":"4.1.0"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"29","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,7,22]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>in silico<\/jats:italic>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    CD25\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    T cell proliferation in an\n                    <jats:italic>in vitro<\/jats:italic>\n                    immune response model and amplified cellular and humoral immune responses\n                    <jats:italic>in vivo<\/jats:italic>\n                    in experimental models when injected in combination with either Modified Vaccinia Ankara expressing Ag85A from\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0803453105","type":"journal-article","created":{"date-parts":[[2008,7,11]],"date-time":"2008-07-11T21:35:05Z","timestamp":1215812105000},"page":"10221-10226","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":115,"title":["<i>In silico<\/i>\n                    identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination"],"prefix":"10.1073","volume":"105","author":[{"given":"Jagadeesh","family":"Bayry","sequence":"first","affiliation":[{"name":"*The Edward Jenner Institute for Vaccine Research, University of Oxford, Compton RG20 7NN, United Kingdom;"},{"name":"Unit\u00e9 872, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, F-75006 Paris, France;"},{"name":"Centre de Recherche des Cordeliers, Unit\u00e9 Mixte de Recherche-Sant\u00e9 872, Universite Pierre et Marie Curie-Paris 6, F-75006 Paris, France; and"},{"name":"Unit\u00e9 Mixte de Recherche-Sant\u00e9 872, Universit\u00e9 Paris Descartes, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elma Z.","family":"Tchilian","sequence":"additional","affiliation":[{"name":"**Centre for Clinical Vaccinology and Tropical Medicine, and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7LJ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew N.","family":"Davies","sequence":"additional","affiliation":[{"name":"*The Edward Jenner Institute for Vaccine Research, University of Oxford, Compton RG20 7NN, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily K.","family":"Forbes","sequence":"additional","affiliation":[{"name":"**Centre for Clinical Vaccinology and Tropical Medicine, and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7LJ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon J.","family":"Draper","sequence":"additional","affiliation":[{"name":"**Centre for Clinical Vaccinology and Tropical Medicine, and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7LJ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srini V.","family":"Kaveri","sequence":"additional","affiliation":[{"name":"Unit\u00e9 872, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, F-75006 Paris, France;"},{"name":"Centre de Recherche des Cordeliers, Unit\u00e9 Mixte de Recherche-Sant\u00e9 872, Universite Pierre et Marie Curie-Paris 6, F-75006 Paris, France; and"},{"name":"Unit\u00e9 Mixte de Recherche-Sant\u00e9 872, Universit\u00e9 Paris Descartes, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian V. S.","family":"Hill","sequence":"additional","affiliation":[{"name":"*The Edward Jenner Institute for Vaccine Research, University of Oxford, Compton RG20 7NN, United Kingdom;"},{"name":"**Centre for Clinical Vaccinology and Tropical Medicine, and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7LJ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel D.","family":"Kazatchkine","sequence":"additional","affiliation":[{"name":"Unit\u00e9 872, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, F-75006 Paris, France;"},{"name":"Centre de Recherche des Cordeliers, Unit\u00e9 Mixte de Recherche-Sant\u00e9 872, Universite Pierre et Marie Curie-Paris 6, F-75006 Paris, France; and"},{"name":"Unit\u00e9 Mixte de Recherche-Sant\u00e9 872, Universit\u00e9 Paris Descartes, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C. L.","family":"Beverley","sequence":"additional","affiliation":[{"name":"*The Edward Jenner Institute for Vaccine Research, University of Oxford, Compton RG20 7NN, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren R.","family":"Flower","sequence":"additional","affiliation":[{"name":"*The Edward Jenner Institute for Vaccine Research, University of Oxford, Compton RG20 7NN, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David F.","family":"Tough","sequence":"additional","affiliation":[{"name":"*The Edward Jenner Institute for Vaccine Research, University of Oxford, Compton RG20 7NN, United 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