The Imidazoquinoline Toll-Like Receptor-7/8 Agonist Hybrid-2 Potently Induces Cytokine Production by Human Newborn and Adult Leukocytes

被引:38
作者
Ganapathi, Lakshmi [1 ,2 ]
Van Haren, Simon [1 ,2 ]
Dowling, David J. [1 ,2 ]
Bergelson, Ilana [1 ]
Shukla, Nikunj M. [3 ]
Malladi, Subbalakshmi S. [3 ]
Balakrishna, Rajalakshmi [3 ]
Tanji, Hiromi [4 ]
Ohto, Umeharu [4 ]
Shimizu, Toshiyuki [4 ]
David, Sunil A. [3 ]
Levy, Ofer [1 ,2 ]
机构
[1] Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Boston, MA USA
[3] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA
[4] Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan
来源
PLOS ONE | 2015年 / 10卷 / 08期
基金
美国国家卫生研究院; 比尔及梅琳达.盖茨基金会;
关键词
INNATE IMMUNITY; VACCINE ADJUVANTS; EARLY-LIFE; RESPONSES; IMMUNIZATION; MECHANISMS; CHALLENGES; SURVIVAL; DISTINCT; CELLS;
D O I
10.1371/journal.pone.0134640
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
Background Newborns and young infants are at higher risk for infections than adults, and manifest sub-optimal vaccine responses, motivating a search for novel immunomodulators and/or vaccine adjuvants effective in early life. In contrast to most TLR agonists (TLRA), TLR8 agonists such as imidazoquinolines (IMQs) induce adult-level Th1-polarizing cytokine production from human neonatal cord blood monocytes and are candidate early life adjuvants. We assessed whether TLR8-activating IMQ congeners may differ in potency and efficacy in inducing neonatal cytokine production in vitro, comparing the novel TLR7/8-activating IMQ analogues Hybrid-2, Meta-amine, and Para-amine to the benchmark IMQ resiquimod (R848). Methods TLRA-induced NF-kappa B activation was measured in TLR-transfected HEK cells. Cytokine production in human newborn cord and adult peripheral blood and in monocyte-derived dendritic cell cultures were measured by ELISA and multiplex assays. X-ray crystallography characterized the interaction of human TLR8 with Hybrid-2. Results Hybrid-2 selectively activated both TLR7 and 8 and was more potent than R848 in inducing adult-like levels of TNF-alpha, and IL-1 beta. Consistent with its relatively high in vitro activity, crystallographic studies suggest that absence in Hybrid-2 of an ether oxygen of the C2-ethoxy-methyl substituent, which can engage in unfavorable electrostatic and/or dipolar interactions with the carbonyl oxygen of Gly572 in human TLR8, may confer greater efficacy and potency compared to R848. Conclusions Hybrid-2 is a selective and potent TLR7/8 agonist that is a candidate adjuvant for early life immunization.
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页数:12
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