title: Synthetic imidazoquinolines potently and broadly activate the cellular immune response of patients with cutaneous T-cell lymphoma: synergy with interferon-gamma enhances production of interleukin-12.
abstract: Advanced cutaneous T-cell lymphoma (CTCL) is typically associated with a variety of profound defects of cellular immunity, including depressed dendritic cell numbers and function. Therefore, we investigated the ability of synthetic imidazoquinolines, which are agonists for Toll-like receptors (TLRs) 7 and 8, to enhance in vitro the cell-mediated immunity of patients with leukemic CTCL and Sézary syndrome. Patients' peripheral blood mononuclear cells (PBMCs) stimulated with the TLR7 agonist 3M-001 produced high levels of interferon (IFN)-alpha, and the TLR8 agonist 3M-002 potently induced predominantly interleukin (IL)-12 and IFN-gamma. Marked upregulation of CD69 and CD25 on natural killer (NK) cells and T cells from patients and an increase in NK cytolytic activity was also observed. We further demonstrate that priming of patients' PBMCs with IFN-gamma has the ability to synergistically enhance the production of IL-12 induced by a synthetic agonist for TLR8. The underlying mechanisms of increased IL-12 production in response to priming with IFN appears to involve an increase in IL-12 p35 and IL-12 p40 gene transcription and a decrease in IL-10 levels upon stimulation with the TLR8 agonist. Our data demonstrate the ability of imidazoquinolines to potently stimulate cellular immune responses of patients with CTCL and emphasizes the benefit of using a combination of biologic modifiers to further enhance their immune responses.
authors.affiliation: Department of Dermatology, University of Pennsylvania, PA 19104, USA. mwysocka@mail.med.upenn.edu
authors.forename: Maria
authors.initials: M
authors.lastname: Wysocka
authors.forename: Sarah
authors.initials: S
authors.lastname: Newton
authors.forename: Bernice M
authors.initials: BM
authors.lastname: Benoit
authors.forename: Camille
authors.initials: C
authors.lastname: Introcaso
authors.forename: Aidan S
authors.initials: AS
authors.lastname: Hancock
authors.forename: Jihed
authors.initials: J
authors.lastname: Chehimi
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Richardson
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gelfand
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
authors.forename: Alain H
authors.initials: AH
authors.lastname: Rook
mesh_terms: D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007111:Immunity, Cellular / Q000187:drug effects; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D016410:Lymphoma, T-Cell, Cutaneous / Q000276:immunology*; D011804:Quinolines / Q000494:pharmacology*; D012751:Sezary Syndrome / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051200:Toll-Like Receptor 8 / Q000819:agonists
chemical_list: C526116:3M 001; C526117:3M 002; D007093:Imidazoles; D011804:Quinolines; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D018664:Interleukin-12; D007371:Interferon-gamma