共 45 条
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
论文数: 0 引用数: 0
h-index: 0
机构:
Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA
Harvard Univ, Sch Med, Boston, MA USA Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

Van Haren, Simon
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h-index: 0
机构:
Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA
Harvard Univ, Sch Med, Boston, MA USA Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

Dowling, David J.
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h-index: 0
机构:
Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA
Harvard Univ, Sch Med, Boston, MA USA Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

Bergelson, Ilana
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h-index: 0
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Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

Shukla, Nikunj M.
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h-index: 0
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Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

Malladi, Subbalakshmi S.
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h-index: 0
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Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

Balakrishna, Rajalakshmi
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h-index: 0
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Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

Tanji, Hiromi
论文数: 0 引用数: 0
h-index: 0
机构:
Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

Ohto, Umeharu
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h-index: 0
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Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

Shimizu, Toshiyuki
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h-index: 0
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Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

David, Sunil A.
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h-index: 0
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Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

Levy, Ofer
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h-index: 0
机构:
Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA
Harvard Univ, Sch Med, Boston, MA USA Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA
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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