Treatment of Autoimmune Inflammation by a TLR7 Ligand Regulating the Innate Immune System
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{"title"=>"Treatment of Autoimmune Inflammation by a TLR7 Ligand Regulating the Innate Immune System", "type"=>"journal", "authors"=>[{"first_name"=>"Tomoko", "last_name"=>"Hayashi", "scopus_author_id"=>"7406386416"}, {"first_name"=>"Shiyin", "last_name"=>"Yao", "scopus_author_id"=>"8378237800"}, {"first_name"=>"Brian", "last_name"=>"Crain", "scopus_author_id"=>"7006450528"}, {"first_name"=>"Michael", "last_name"=>"Chan", "scopus_author_id"=>"35309655200"}, {"first_name"=>"Rommel I.", "last_name"=>"Tawatao", "scopus_author_id"=>"8944876600"}, {"first_name"=>"Christine", "last_name"=>"Gray", "scopus_author_id"=>"26325553900"}, {"first_name"=>"Linda", "last_name"=>"Vuong", "scopus_author_id"=>"55634809200"}, {"first_name"=>"Fitzgerald", "last_name"=>"Lao", "scopus_author_id"=>"44361198100"}, {"first_name"=>"Howard B.", "last_name"=>"Cottam", "scopus_author_id"=>"7003781390"}, {"first_name"=>"Dennis A.", "last_name"=>"Carson", "scopus_author_id"=>"7201743527"}, {"first_name"=>"Maripat", "last_name"=>"Corr", "scopus_author_id"=>"7003585737"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"23029281", "sgr"=>"84867628506", "doi"=>"10.1371/journal.pone.0045860", "scopus"=>"2-s2.0-84867628506", "pui"=>"365879992", "issn"=>"19326203"}, "id"=>"c684fc9e-fff7-318c-8edb-88166fe43f6d", "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.", "link"=>"http://www.mendeley.com/research/treatment-autoimmune-inflammation-tlr7-ligand-regulating-innate-immune-system", "reader_count"=>22, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>4, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>7, "Other"=>2, "Student > Master"=>2, "Student > Bachelor"=>4, "Unspecified"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>4, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>7, "Other"=>2, "Student > Master"=>2, "Student > Bachelor"=>4, "Unspecified"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Medicine and Dentistry"=>7, "Agricultural and Biological Sciences"=>8, "Immunology and Microbiology"=>5, "Unspecified"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>8}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/566622"], "description"=>"<p>(A) SJL/J mice were i.p. immunized with PLP<sub>139–151</sub> in CFA with Ptx. Mice (n = 26/group) received 150 nmol/animal 1V136 or vehicle s.c. daily from day 6 onward. The mice were scored for disease and the data were pooled from four independent experiments. Bar indicates <i>p</i><0.05 by two-way ANOVA with Bonferroni <i>post hoc</i> tests. (B) SJL mice were immunized as above (n = 14/group) and treated from day 5 to 18 with 150 nmol/animal 1V136 or vehicle s.c. and disease was monitored up to 60 days. Data are pooled from 2 independent experiments and the bar indicates <i>p</i><0.05 by two-way ANOVA with Bonferroni <i>post hoc</i> tests. (C, D) Splenocytes obtained from vehicle- (n = 5) and 1V136-treated (n = 5) SJL/J EAE mice at 19 days were restimulated <i>in vitro</i> with PLP<sub>139–151</sub> peptide for 3 days. Levels of IFN-γ (C), and IL-17 (D) in the supernatants were determined by ELISA. Data shown are means ± SEM and are representative of three independent experiments that showed similar trends. p<0.05 compared vehicle-treated group by Student t test.</p>", "links"=>[], "tags"=>["ligand", "reduced", "responses", "eae"], "article_id"=>237109, "categories"=>["Neuroscience", "Microbiology", "Immunology"], "users"=>["Tomoko Hayashi", "Shiyin Yao", "Brian Crain", "Michael Chan", "Rommel I. Tawatao", "Christine Gray", "Linda Vuong", "Fitzgerald Lao", "Howard B. Cottam", "Dennis A. Carson", "Maripat Corr"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045860.g003", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TLR7_ligand_treatment_reduced_clinical_severity_and_T_cell_responses_of_EAE_mice_/237109", "title"=>"TLR7 ligand treatment reduced clinical severity, and T cell responses of EAE mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-28 01:58:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/3074540", "https://ndownloader.figshare.com/files/300237", "https://ndownloader.figshare.com/files/300272", "https://ndownloader.figshare.com/files/300345", "https://ndownloader.figshare.com/files/300400", "https://ndownloader.figshare.com/files/300445"], "description"=>"<div><p>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 <em>in vivo</em> T cell dependent autoimmune model. Drug treated SJL/J mice immunized with proteolipid protein (PLP)<sub>139–151</sub> 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.</p> </div>", "links"=>[], "tags"=>["autoimmune", "inflammation", "tlr7", "ligand", "regulating", "innate"], "article_id"=>119188, "categories"=>["Neuroscience", "Microbiology", "Immunology"], "users"=>["Tomoko Hayashi", "Shiyin Yao", "Brian Crain", "Michael Chan", "Rommel I. Tawatao", "Christine Gray", "Linda Vuong", "Fitzgerald Lao", "Howard B. Cottam", "Dennis A. Carson", "Maripat Corr"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0045860.s001", "https://dx.doi.org/10.1371/journal.pone.0045860.s002", "https://dx.doi.org/10.1371/journal.pone.0045860.s003", "https://dx.doi.org/10.1371/journal.pone.0045860.s004", "https://dx.doi.org/10.1371/journal.pone.0045860.s005", "https://dx.doi.org/10.1371/journal.pone.0045860.s006"], "stats"=>{"downloads"=>9, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Treatment_of_Autoimmune_Inflammation_by_a_TLR7_Ligand_Regulating_the_Innate_Immune_System/119188", "title"=>"Treatment of Autoimmune Inflammation by a TLR7 Ligand Regulating the Innate Immune System", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-09-28 02:33:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/566383"], "description"=>"<p>C57BL/6 mice (n = 5/group) were intradermally immunized with OVA (50 µg) mixed with (A) ISS-ODN (50 µg) or (B) alum (0.5 mg) on days 0 and 7. Immunized mice were treated daily with 1V136 (150 nmol/mouse) (black bar) or vehicle (white bar) s.c. from day 7 onward. On day 21 mice were sacrificed and splenocytes were harvested. Splenocytes were cultured with OVA (100 µg/ml) <i>ex vivo</i> for 5 days, and IFN-γ (A) or IL-5 (B) in the culture supernatant was measured by ELISA. p<0.05 by Student t test compared to vehicle treated. (C) On the day of harvest the splenocytes were also nonspecifically stimulated with PMA and ionomycin, and CD4<sup>+</sup> T cells were analyzed by flow cytometry for intracellular IFN-γ. Data shown are representative of three independent experiments that exhibited similar results. (D) C57BL/6 mice (n = 5/group) were intradermally immunized with OVA (50 µg) mixed with ISS-ODN (50 µg) on days 0 and 7. Immunized mice were treated daily with 1V136 (150 nmol/mouse) (black bar) or vehicle (white bar) s.c. from day 5 onward. On day 21 mice were sacrificed and splenocytes were harvested and enriched for CD4<sup>+</sup> cells by magnetic beads. The enriched CD4<sup>+</sup> T cells were cultured with OVA (100 µg/ml) and BMDCs for 3 days and IFN-γ in the culture supernatant was measured by ELISA. p<0.05 by Student t test compared to vehicle treated. (E) An aliquot of the enriched CD4<sup>+</sup> T cells above were CFSE labeled, and cultured for 3 days with BMDC and OVA. The proliferation was assessed by flow cytometry. (F) BMDCs were treated with 1V136 (1 µM) or vehicle for 18 h, washed and restimulated with 1V136 (1 µM). The expression of MHC class II, CD40, CD80, CD86, or OX40L in the gated CD11c population were evaluated by flow cytometry. The data shown are representative of three independent experiments. (G) Representative histogram plots of MHC class II and CD86 in the CD11c<sup>+</sup> gated populations are shown. Light gray areas are isotype controls.</p>", "links"=>[], "tags"=>["ligand", "reduced", "antigen", "responses", "dendritic"], "article_id"=>236866, "categories"=>["Neuroscience", "Microbiology", "Immunology"], "users"=>["Tomoko Hayashi", "Shiyin Yao", "Brian Crain", "Michael Chan", "Rommel I. Tawatao", "Christine Gray", "Linda Vuong", "Fitzgerald Lao", "Howard B. Cottam", "Dennis A. Carson", "Maripat Corr"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045860.g001", "stats"=>{"downloads"=>3, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TLR7_ligand_treatment_reduced_antigen_specific_T_cell_responses_and_dendritic_cell_activation_/236866", "title"=>"TLR7 ligand treatment reduced antigen specific T cell responses and dendritic cell activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-28 01:54:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/566977"], "description"=>"<p>(A) Mixed glial cells were cultured from the brains neonatal mice and tested for enrichment after 6 weeks by flow cytometry using anti-CD11b antibodies. (B) These primary microglial cultures were treated with vehicle (white bar) or 1 µM 1V136 (black bar) overnight. The cells were then re-stimulated with vehicle (Veh), 1V136 or LPS for 18 h and supernatants were collected. A panel of cytokines and chemokines was analyzed by Luminex microbead assay for IL-1β, KC, MIP-1α, and MCP-1. Data shown are mean ± SEM of triplicates and are representative of three independent experiments. p<0.05 by Student t test compared to vehicle pretreated cells.</p>", "links"=>[], "tags"=>["ligand", "induced", "hyporesponsiveness", "cns", "cd11b-enriched"], "article_id"=>237454, "categories"=>["Neuroscience", "Microbiology", "Immunology"], "users"=>["Tomoko Hayashi", "Shiyin Yao", "Brian Crain", "Michael Chan", "Rommel I. Tawatao", "Christine Gray", "Linda Vuong", "Fitzgerald Lao", "Howard B. Cottam", "Dennis A. Carson", "Maripat Corr"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045860.g005", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TLR7_ligand_treatment_induced_hyporesponsiveness_in_primary_CNS_CD11b_enriched_cultures_/237454", "title"=>"TLR7 ligand treatment induced hyporesponsiveness in primary CNS CD11b-enriched cultures.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-28 02:04:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/566482"], "description"=>"<p>(A) CFSE-labeled CD4<sup>+</sup> T cells were prepared from WT or <i>Tlr7<sup>−/−</sup></i> mice immunized with OVA/CFA. WT or <i>Tlr7<sup>−/−</sup></i> BMDCs were incubated with these primed CD4<sup>+</sup> T cells with OVA (100 µg/mL) in the presence or the absence of 1V136 (1 µM) for five days. T cell proliferation was monitored by flow cytometry. Representative plots are shown from three experiments. (B) The culture supernatants were assessed for IFN-γ levels by ELISA. The data shown are representative of two independent experiments. p<0.05 by Student <i>t</i> test compared to vehicle control.</p>", "links"=>[], "tags"=>["ligand", "selectively", "impaired", "dendritic"], "article_id"=>236970, "categories"=>["Neuroscience", "Microbiology", "Immunology"], "users"=>["Tomoko Hayashi", "Shiyin Yao", "Brian Crain", "Michael Chan", "Rommel I. Tawatao", "Christine Gray", "Linda Vuong", "Fitzgerald Lao", "Howard B. Cottam", "Dennis A. Carson", "Maripat Corr"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045860.g002", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TLR7_ligand_treatment_selectively_impaired_dendritic_cell_and_not_T_cell_function_/236970", "title"=>"TLR7 ligand treatment selectively impaired dendritic cell and not T cell function.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-28 01:56:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/566855"], "description"=>"<p>(A) Representative sagittal sections of lumbar spinal cords from vehicle-treated or 1V136-treated EAE mice. H&E stained sections are shown in the left panels (×40 original magnification) and the insets are shown at higher magnification (middle panels, ×200 original magnification). Areas of demyelination are indicated by the arrows in the LFB stained sections (right panels). Scale bars:100 µm. (B) The total number of infiltrating cells isolated from pooled spinal cords from vehicle-treated (Veh) or 1V136-treated (1V136) EAE mice (n = 5/group). The data shown are averages of three independent experiments ± SEM. <i>p</i><0.05 by Student t test. (C) 1V136 treatment reduced chemokine expression in the spinal cords in the EAE mice. Chemokine expression levels in the spinals cords were reduced in 1V136-treated EAE mice. RNA was extracted from pooled spinal cord samples collected from 1V136-treated (n = 4) or vehicle-treated (n = 4) mice. mRNA levels of IL-1β, KC, MCP-1 or MIP-1α were analyzed by qPCR methods. The data were normalized to 18S ribosomal RNA gene and are presented as arbitrary units. <i>p</i><0.05 by Student t test. Data shown are representative of two independent experiments that exhibited similar results. (D) The levels of CD80 and CD86 mRNA transcripts were also reduced in the spinal cords of 1V136 treated mice. Data are presented as arbitrary units as normalized to GAPDH. <i>p</i><0.05 by Student <i>t</i> test.</p>", "links"=>[], "tags"=>["ligand", "reduced", "spinal", "cellular", "chemokines", "cytokines", "eae"], "article_id"=>237336, "categories"=>["Neuroscience", "Microbiology", "Immunology"], "users"=>["Tomoko Hayashi", "Shiyin Yao", "Brian Crain", "Michael Chan", "Rommel I. Tawatao", "Christine Gray", "Linda Vuong", "Fitzgerald Lao", "Howard B. Cottam", "Dennis A. Carson", "Maripat Corr"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045860.g004", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TLR7_ligand_treatment_reduced_spinal_cellular_infiltration_and_spinal_chemokines_and_cytokines_of_EAE_mice_/237336", "title"=>"TLR7 ligand treatment reduced spinal cellular infiltration, and spinal chemokines and cytokines of EAE mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-28 02:02:16"}

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