The Imidazoquinoline Toll-Like Receptor-7/8 Agonist Hybrid-2 Potently Induces Cytokine Production by Human Newborn and Adult Leukocytes
| Autor: | Umeharu Ohto, Sunil A. David, Simon D. van Haren, David J. Dowling, Toshiyuki Shimizu, Rajalakshmi Balakrishna, H. Tanji, Lakshmi Ganapathi, Ilana Bergelson, Ofer Levy, Subbalakshmi S. Malladi, Nikunj M. Shukla |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Agonist
Adult medicine.drug_class medicine.medical_treatment Recombinant Fusion Proteins lcsh:Medicine Pharmacology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system Pregnancy medicine Leukocytes Humans lcsh:Science 030304 developmental biology 0303 health sciences Toll-like receptor Multidisciplinary business.industry lcsh:R Imidazoles Infant Newborn TLR7 Dendritic Cells TLR8 Fetal Blood 3. Good health Up-Regulation Imidazoquinoline Cytokine HEK293 Cells chemistry Toll-Like Receptor 7 Toll-Like Receptor 8 Immunology Quinolines Cytokines Female lcsh:Q Resiquimod business Immunosuppressive Agents 030215 immunology Research Article |
| Zdroj: | PLoS ONE, Vol 10, Iss 8, p e0134640 (2015) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Background Newborns and young infants are at higher risk for infections than adults, and manifest suboptimal 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-κB 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-α, and IL-1β. Consistent with its relatively high in vitro activity, crystallographic studies suggest that absence in Hybrid-2 of an ether oxygen of the C2-ethoxymethyl 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. |
| Databáze: | OpenAIRE |
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