title: Comparison of rat and human responses to toll-like receptor 7 activation.
abstract: Toll-like receptors recognize invading microorganisms and activate innate immune responses. Their discovery has opened up a range of therapeutic possibilities, in particular for infectious diseases. Responses to TLR agonists have been largely studied in mice and little information exists in other species. Given that rats are commonly used for pharmacokinetic and toxicology studies in drug development, we compared TLR7 responses in rat and human. Stimulation of rat and human peripheral blood mononuclear cells with the TLR7 agonist SM360320 showed that in rat cells, the interferon-induced gene, 2', 5' oligoadenylate synthase and tumor necrosis factor alpha were induced at lower concentrations and to a greater degree compared with human cells. Both human and rat cells demonstrated tolerance and could not be restimulated following initial treatment with high concentrations of SM360320. Reducing the concentration of the initial treatment allowed cells to be restimulated following a period of recovery. The initial treatment concentration had to be reduced to a greater extent to enable restimulation of rat cells compared with human cells. Dosing whole rats repeatedly with different concentrations of SM360320 confirmed the in vitro results. Treatment of human cells with high concentrations of interferon alpha did not induce tolerance to subsequent treatment with SM360320 indicating that tolerance occurs in the TLR7 signaling pathway, rather than the interferon signaling pathway. We conclude that rat and human cells respond differently to TLR7 activation and that these differences should be considered when using rat as a model to study TLR7 agonists.
authors.affiliation: Drug Safety Research & Development, Pfi zer Global Research and Development, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Clarke
authors.forename: Carl
authors.initials: C
authors.lastname: Laxton
authors.forename: Nigel
authors.initials: N
authors.lastname: Horscroft
authors.forename: Virgile
authors.initials: V
authors.lastname: Richard
authors.forename: Amy
authors.initials: A
authors.lastname: Thomas
authors.forename: Tanya
authors.initials: T
authors.lastname: Parkinson
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000187:drug effects / Q000378:metabolism; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000378:metabolism*
chemical_list: D016898:Interferon-alpha; C508876:SM360320; D051199:Toll-Like Receptor 7; D014409:Tumor Necrosis Factor-alpha; D015088:2',5'-Oligoadenylate Synthetase; D000225:Adenine