共 44 条
In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination
被引:100
作者:
Bayry, Jagadeesh
[1
,4
,5
,6
]
Tchilian, Elma Z.
[2
,3
]
Davies, Matthew N.
[1
]
Forbes, Emily K.
[2
,3
]
Draper, Simon J.
[2
,3
]
Kaveri, Srini V.
[4
,5
,6
]
Hill, Adrian V. S.
[1
,2
,3
,4
]
Kazatchkine, Michel D.
[5
,6
]
Beverley, Peter C. L.
[1
]
Flower, Darren R.
[1
]
Tough, David F.
[1
]
机构:
[1] Univ Oxford, Edward Jenner Inst Vaccine Res, Compton RG20 7NN, England
[2] Univ Oxford, Ctr Clin Vaccinol & Trop Med, Oxford OX3 7LJ, England
[3] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7LJ, England
[4] INSERM, U872, F-75006 Paris, France
[5] Univ Paris 06, Unite Mixte Rech Sante 872, Ctr Rech Cordeliers, F-75006 Paris, France
[6] Univ Paris 05, Unite Mixte Rech Sante 872, F-75006 Paris, France
来源:
基金:
英国医学研究理事会;
关键词:
CD4(+)CD25(+) regulatory T cells;
dendritic cells;
immune response;
vaccine;
D O I:
10.1073/pnas.0803453105
中图分类号:
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
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 (rHB-sAg) 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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页码:10221 / 10226
页数:6
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