title: Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7.
abstract: Activation of Toll-like receptors (TLR) contributes to the initiation and maintenance of chronic inflammation in autoimmune diseases, yet repeated exposure to a TLR agonist can induce hyporesponsiveness to subsequent TLR stimulation. Here, we used a synthetic TLR7 agonist, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320, 1V136) to study TLR7 induced attenuation of inflammatory responses and its application to autoimmune diseases. Repeated low dose administration of this TLR7 agonist induced hyporesponsiveness or tolerance to TLR2, -7, and -9 activators and limited the course of neural inflammation in an experimental allergic encephalomyelitis model. The hyporesponsiveness did not depend on T or B lymphocytes, but did require bone marrow derived cells. In addition, TLR7 tolerance reduced inflammation in a passive antibody mediated arthritis model. TLR7 tolerance did not cause global immunosuppression, because susceptibility to Listeria monocytogenes infection was not altered. The mechanism of TLR7 tolerance involved the up-regulation of 2 inhibitors of TLR signaling: Interleukin 1 Receptor Associated Kinase (IRAK) M, and Src homology 2 domain-containing inositol polyphosphate phosphatase (SHIP)-1. These findings suggest that induction of TLR7 tolerance might be a new therapeutic approach to subdue inflammation in autoimmune diseases.
authors.affiliation: Moores Cancer Center, and Department Medicine, University California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hayashi
authors.forename: Christine S
authors.initials: CS
authors.lastname: Gray
authors.forename: Michael
authors.initials: M
authors.lastname: Chan
authors.forename: Rommel I
authors.initials: RI
authors.lastname: Tawatao
authors.forename: Lisa
authors.initials: L
authors.lastname: Ronacher
authors.forename: Maureen A
authors.initials: MA
authors.lastname: McGargill
authors.forename: Sandip K
authors.initials: SK
authors.lastname: Datta
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; D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000276:immunology*
chemical_list: C508876:SM360320; D051199:Toll-Like Receptor 7; D000225:Adenine