Immunoprofiling toll-like receptor ligands: Comparison of immunostimulatory and proinflammatory profiles in ex vivo human blood models
| Autor: | Sunil A. David, Xinkun Wang, Hemamali J. Warshakoon, Subbalakshmi S. Malladi, Nikunj M. Shukla, Matthew R. Kimbrell, Jennifer D. Hood |
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| Rok vydání: | 2010 |
| Předmět: |
Toll-like receptor
Innate immune system Gene Expression Profiling Toll-Like Receptors Immunology Monophosphoryl Lipid A TLR7 In Vitro Techniques Biology Ligands Cell biology Proinflammatory cytokine Imidazoquinoline TLR2 chemistry.chemical_compound Blood Immune system Adjuvants Immunologic chemistry Humans General Pharmacology Toxicology and Pharmaceutics Cells Cultured Protein Binding |
| Zdroj: | Human Vaccines. 6:322-335 |
| ISSN: | 1554-8619 1554-8600 |
| DOI: | 10.4161/hv.6.4.10866 |
| Popis: | There is a pressing need for the development of novel, safe and effective adjuvants. The recent discovery and characterization of pathogen-associated molecular pattern (PAMP)-recognizing elements such as the Toll-like, NOD-like and RIG-like receptors, has brought into sharp focus the role of PAMPs in bridging the innate and adaptive immune responses, and a detailed understanding of the immunostimulatory vis-à-vis proinflammatory activities could lead to the development of effective adjuvants, monophosphoryl lipid A being an excellent example. We describe in this paper a series of hierarchical assays that were employed to characterize TLR agonists in vitro including primary TLR-reporter assays, secondary indices of immune activation, and tertiary screens characterizing transcriptomal activation patterns to identify optimal immunostimulatory chemotypes. The evaluation of representative members of known human TLR agonists demonstrate that TLR2, -4, -5 and -7 agonists were immunostimulatory. TLR7 agonists were extremely immunostimulatory, stimulating nearly all subsets of lymphocytes without inducing proinflammatory cytokine responses. The TLR5 agonist, flagellin, while immunostimulatory, was also highly proinflammatory. These results suggest that TLR agonists other than lipid A-like chemotypes could be developed into potential adjuvants, and that this series of hierarchical assays could be adapted to rapidly identify in large libraries, compounds with adjuvantic potential that lack proinflammatory responses. |
| Databáze: | OpenAIRE |
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