RESUMO
Recognition of microbial molecules by mammalian host receptors is essential to mount an immune response. Hexaacylated LPS is the prototypic example of a bacterial molecule recognized by the receptor complex TLR4/MD-2 with its lipid A moiety, whereas bacterial lipopeptides are recognized by TLR2. Here we show that a series of synthetic triacylated lipid A-like molecules are weak Toll-like receptor (TLR) agonists (mainly TLR2 agonists) but very potent TLR4/MD-2 antagonists (submicromolar range). Not only do they block human cell responses to LPS but also to whole gram-negative bacteria, and they inhibit the phagocytosis of gram-negative bacteria. These compounds may represent promising immunomodulatory agents.
Assuntos
Fatores Imunológicos/farmacologia , Lipídeo A/farmacologia , Antígeno 96 de Linfócito/metabolismo , Receptor 4 Toll-Like/agonistas , Bactérias Gram-Negativas/imunologia , Bactérias Gram-Negativas/metabolismo , Células HEK293 , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/imunologia , Lipídeo A/síntese química , Lipídeo A/imunologia , Antígeno 96 de Linfócito/imunologia , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/imunologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismoRESUMO
Ndelta-L-Homoserinyl-D-ornithinol pseudodipeptides N-acylated with typical Escherichia coli lipid A fatty acid residues and mono-O- or bis-O-phosphorylated have been prepared and their properties investigated. The derivatives carrying two phosphate groups were found to be inducers of NO production. In addition, while they were unable to induce significantly the production of interleukin-6 (IL-6) by human PBMC cells, these compounds behaved also as potent antagonists of LPS-induced IL-6 production in the same human cells system. In conclusion, the molecules described here are the first members of an original class of immunobiologically active lipid A mimics based on an acyclic pseudodipeptide backbone carrying only the essential functionalities of the parent lipid A structure (OM-174). As the products exhibit very low endotoxicity and pyrogenicity, this class of lipid A mimics therefore opens a new generation of immunoadjuvants that possibly could reach clinical applications.
Assuntos
Adjuvantes Imunológicos/síntese química , Dipeptídeos/química , Ácidos Graxos/química , Homosserina/análogos & derivados , Homosserina/síntese química , Lipídeo A/química , Organofosfatos/síntese química , Adjuvantes Imunológicos/farmacologia , Animais , Células Cultivadas , Escherichia coli , Homosserina/farmacologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mimetismo Molecular , Óxido Nítrico/biossíntese , Organofosfatos/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In this study, we tested two triacylated pseudo-dipeptidic molecules, OM-197-MP-AC and OM-294-BA-MP as candidate adjuvants for allergy vaccines. Both molecules induce human dendritic cell (h-DC) maturation and polarize naïve T cells toward the Th1 type with IFNgamma production. Only OM-294-BA-MP induces IL10 gene expression both in monocyte-derived DCs and CD4+ naïve T cells. Sublingual administration of OM-294-BA-MP plus the antigen enhances tolerance induction in BALB/c mice with established asthma to ovalbumin with an impact on both airways hyperresponsiveness and lung inflammation. Given its Th1/Treg polarizing properties, OM-294-BA-MP is a valid candidate for sublingual allergy vaccines.