title: Treatment of autoimmune inflammation by a TLR7 ligand regulating the innate immune system.
abstract: The Toll-like receptors (TLR) have been advocated as attractive therapeutic targets because TLR signaling plays dual roles in initiating adaptive immune responses and perpetuating inflammation. Paradoxically, repeated stimulation of bone marrow mononuclear cells with a synthetic TLR7 ligand 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (called 1V136) leads to subsequent TLR hyporesponsiveness. Further studies on the mechanism of action of this pharmacologic agent demonstrated that the TLR7 ligand treatment depressed dendritic cell activation, but did not directly affect T cell function. To verify this mechanism, we utilized experimental allergic encephalitis (EAE) as an in vivo T cell dependent autoimmune model. Drug treated SJL/J mice immunized with proteolipid protein (PLP)(139-151) peptide had attenuated disease severity, reduced accumulation of mononuclear cells in the central nervous system (CNS), and limited demyelination, without any apparent systemic toxicity. Splenic T cells from treated mice produced less cytokines upon antigenic rechallenge. In the spinal cords of 1V136-treated EAE mice, the expression of chemoattractants was also reduced, suggesting innate immune cell hyposensitization in the CNS. Indeed, systemic 1V136 did penetrate the CNS. These experiments indicated that repeated doses of a TLR7 ligand may desensitize dendritic cells in lymphoid organs, leading to diminished T cell responses. This treatment strategy might be a new modality to treat T cell mediated autoimmune diseases.
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hayashi
authors.forename: Shiyin
authors.initials: S
authors.lastname: Yao
authors.forename: Brian
authors.initials: B
authors.lastname: Crain
authors.forename: Michael
authors.initials: M
authors.lastname: Chan
authors.forename: Rommel I
authors.initials: RI
authors.lastname: Tawatao
authors.forename: Christine
authors.initials: C
authors.lastname: Gray
authors.forename: Linda
authors.initials: L
authors.lastname: Vuong
authors.forename: Fitzgerald
authors.initials: F
authors.lastname: Lao
authors.forename: Howard B
authors.initials: HB
authors.lastname: Cottam
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carson
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D020556:Neutrophil Infiltration / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; C508876:SM360320; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D000225:Adenine