title: Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates.
abstract: TLR ligands (TLR-Ls) represent novel vaccine adjuvants, but their immunologic effects in humans remain poorly defined in vivo. In the present study, we analyzed the innate responses stimulated by different TLR-Ls in rhesus macaques. MPL (TLR4-L), R-848 (TLR7/8-L), or cytosine-phosphate-guanine oligodeoxynucleotide (TLR9-L) induced a rapid and robust expansion of blood neutrophils, with a concomitant reduction in PBMCs. Furthermore, all TLR-Ls induced rapid (3-8 hours) expansion of CD14(+) monocytes, but only TLR7/8-L and TLR9-L mobilized the CD14(+)CD16(+) and CD14(dim)CD16(++) monocytes, and only TLR7/8-L and TLR9-L induced activation of myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs), production of IP-10 and type-I IFN, and expression of type-I IFN-related and chemokine genes in the blood. In the draining lymph nodes (LNs), consistent with the effects in blood, all TLR-Ls induced expansion of CD14(+) monocytes, but only TLR7/8-L and TLR9-L expanded the activated CD14(+)CD16(+) cells. TLR4-L and TLR9-L differentially induced the expansion of mDCs and pDCs (1-3 days), but did not activate DCs. In contrast, TLR7/8-L did not induce DC expansion, but did activate mDCs. Finally, both TLR9-L and TLR7/8-L induced the expression of genes related to chemokines and type-I IFNs in LNs. Thus different TLR-Ls mediate distinct signatures of early innate responses both locally and systemically.
authors.affiliation: Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kwissa
authors.forename: Helder I
authors.initials: HI
authors.lastname: Nakaya
authors.forename: Herold
authors.initials: H
authors.lastname: Oluoch
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D007271:Injections, Intradermal; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008253:Macaca mulatta / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000819:agonists*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D007093:Imidazoles; D018836:Inflammation Mediators; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors; C402365:resiquimod