Molecular and Cellular Response Profiles Induced by the TLR4 Agonist-Based Adjuvant Glucopyranosyl Lipid A

Autor: Jennifer Woo, Chin-Fen Yang, Zheng Liu, Rosemary Sweetwood, Hong Jin, Stacie L. Lambert, Jackie Zhao, Lily Cheng
Rok vydání: 2012
Předmět:
Mouse
Microarrays
T-Lymphocytes
medicine.medical_treatment
lcsh:Medicine
Aluminum Hydroxide
Pharmacology
Lipid A
Mice
lcsh:Science
Receptor
Cells
Cultured
Oligonucleotide Array Sequence Analysis
Mice
Inbred BALB C
Multidisciplinary
Reverse Transcriptase Polymerase Chain Reaction
Muscles
Vaccination
Animal Models
Flow Cytometry
Innate Immunity
Cytokines
Medicine
lipids (amino acids
peptides
and proteins)
Emulsions
Female
Adjuvant
hormones
hormone substitutes
and hormone antagonists
Research Article
Agonist
medicine.drug_class
Immunology
Biology
Real-Time Polymerase Chain Reaction
Major histocompatibility complex
Model Organisms
Immune system
Adjuvants
Immunologic
In vivo
Vaccine Development
medicine
Animals
cardiovascular diseases
RNA
Messenger
Gene Expression Profiling
lcsh:R
Immunity
nutritional and metabolic diseases
Computational Biology
Water
Dendritic Cells
Toll-Like Receptor 4
Gene Expression Regulation
Immune System
Leukocytes
Mononuclear
TLR4
biology.protein
lcsh:Q
Clinical Immunology
Oils
Biomarkers
Zdroj: PLoS ONE
PLoS ONE, Vol 7, Iss 12, p e51618 (2012)
ISSN: 1932-6203
Popis: BACKGROUND: Toll-like receptor (TLR)4 agonists are known potent immunostimulatory compounds. These compounds can be formulated as part of novel adjuvants to enhance vaccine medicated immune responses. However, the contribution of the formulation to the innate in vivo activity of TLR4 agonist compounds is not well understood. METHODOLOGY AND PRINCIPAL FINDINGS: We evaluated synthetic TLR4 agonist Glucopyranosyl Lipid A (GLA) for its effects on molecular and cellular innate immune responses in the murine model. Microarray techniques were used to compare the responses to GLA in an aqueous formulation or in an oil-in-water Stable Emulsion formulation (GLA-SE) versus either SE alone or the mineral salt aluminum hydroxide (alum) at the muscle injection site over multiple timepoints. In contrast to the minimal gene upregulation induced by SE and alum, both GLA and GLA-SE triggered MyD88- and TRIF-dependent gene expression. Genes for chemokines, cytokine receptors, signaling molecules, complement, and antigen presentation were also strongly upregulated by GLA and GLA-SE. These included chemokines for T(H)1-type T cells (CXCL9 and CXCL10) and mononuclear leukocytes (CCL2, CCL3) among others. GLA-SE induced stronger and more sustained gene upregulation than GLA in the muscle; GLA-SE induced genes were also detected in local draining lymph nodes and at lower levels in peripheral blood. Both GLA and GLA-SE resulted in increased cellular trafficking to the draining lymph nodes and upregulated MHC molecules and ICAM1 on local dendritic cells. GLA and GLA-SE transiently upregulated circulating MCP-1, TNFα, IFNγ and IP-10 in blood. CONCLUSIONS/SIGNIFICANCE: While GLA and GLA-SE activate a large number of shared innate genes and proteins, GLA-SE induces a quantitatively and qualitatively stronger response than GLA, SE or alum. The genes and proteins upregulated could be used to facilitate selection of appropriate adjuvant doses in vaccine formulations.
Databáze: OpenAIRE
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