{"id":{"repo_id":"strathclyde","oai_identifier":"oai:strathclyde:m900nt49x"},"canonical_url":"https://search.dev.ndltd.org/etd/strathclyde/oai:strathclyde:m900nt49x","repository":{"repo_id":"strathclyde","name":"University of Strathclyde","base_url":"https://stax.strath.ac.uk/catalog/oai"},"display":{"title":"The effect of small molecule analogues of the immunomodulatory helminth product ES-62 on denritic cell responses","abstract":"ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, targets immune system cells including dendritic cells (DCs), to subvert inflammatory responses. The post-translational addition of phosphorylcholine (PC) is responsible for many of the immunomodulatory properties of this molecule and as ES-62 is potentially immunogenic, and therefore unsuitable as a drug, a library of small molecule analogues (SMAs) of ES-62 based on its PC moiety has been synthesised. The aim of this project was to investigate the effects of these SMAs on DCs. From a library of 79 compounds, 6 SMAs (11a, 12b, 11e, 11h, 11i and 11k) were selected as they significantly down-regulated LPS-induced cytokine production in vitro. ES-62 requires TLR4 and MyD88 to mediate many of its anti-inflammatory effects. However, cytokine inhibition mediated by SMAs 11a, 12b, 11e and 11i is generally intact in TLR4 knock-out (KO) and MyD88 KO bmDCs. Cytokine inhibition was found to be mediated through inhibition of LPS-induced cytokine gene expression and to be associated with reduction in LPS-induced activation of NF-κBp65, and MAPKs p38 and ERK. The SMAs also suppress LPS-induced up-regulation of CD40 and CD86; priming a DC phenotype that inhibits the production of IFN-γ by naïve T cells in vitro. Pre-exposure of DCs to 11a or 11i prior to LPS stimulation in vitro primes the cells to suppress the expansion of Ag-specific T cells in vivo, and this is associated with significantly inhibited numbers of IL-17A+CD4+ cells. Furthermore, mice subjected to collagen-induced arthritis pre-treated with 11a/12b-DCs had significantly reduced disease compared to mice inoculated with untreated DCs, and this was accompanied by a significant inhibition of IL-17+ cells in the draining lymph nodes. Thus overall this study has found that SMAs based on the PC moiety of ES-62 can modulate DCs such that they prime reduced TH17 responses in vivo.","abstract_html":"ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, targets immune system cells including dendritic cells (DCs), to subvert inflammatory responses. The post-translational addition of phosphorylcholine (PC) is responsible for many of the immunomodulatory properties of this molecule and as ES-62 is potentially immunogenic, and therefore unsuitable as a drug, a library of small molecule analogues (SMAs) of ES-62 based on its PC moiety has been synthesised. The aim of this project was to investigate the effects of these SMAs on DCs. From a library of 79 compounds, 6 SMAs (11a, 12b, 11e, 11h, 11i and 11k) were selected as they significantly down-regulated LPS-induced cytokine production in vitro. ES-62 requires TLR4 and MyD88 to mediate many of its anti-inflammatory effects. However, cytokine inhibition mediated by SMAs 11a, 12b, 11e and 11i is generally intact in TLR4 knock-out (KO) and MyD88 KO bmDCs. Cytokine inhibition was found to be mediated through inhibition of LPS-induced cytokine gene expression and to be associated with reduction in LPS-induced activation of NF-κBp65, and MAPKs p38 and ERK. The SMAs also suppress LPS-induced up-regulation of CD40 and CD86; priming a DC phenotype that inhibits the production of IFN-γ by naïve T cells in vitro. Pre-exposure of DCs to 11a or 11i prior to LPS stimulation in vitro primes the cells to suppress the expansion of Ag-specific T cells in vivo, and this is associated with significantly inhibited numbers of IL-17A+CD4+ cells. Furthermore, mice subjected to collagen-induced arthritis pre-treated with 11a/12b-DCs had significantly reduced disease compared to mice inoculated with untreated DCs, and this was accompanied by a significant inhibition of IL-17+ cells in the draining lymph nodes. Thus overall this study has found that SMAs based on the PC moiety of ES-62 can modulate DCs such that they prime reduced TH17 responses in vivo.","abstract_has_math":false,"creators":["Lumb,Felicity Elspeth"],"institution":"University of Strathclyde","degree_name":"phd","degree_level":"doctoral-pg","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2016,"date_issued":"2016","date_published":"2016","updated_at":"2026-07-24T04:52:04Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.48730/fvzr-s132"],"render_values":[{"text":"10.48730/fvzr-s132","href":"https://doi.org/10.48730/fvzr-s132","code":true}]},{"key":"dc:identifier","label":"Identifier","values":["T14221"],"render_values":[{"text":"T14221","href":null,"code":true}]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["201179752"],"render_values":[{"text":"201179752","href":null,"code":true}]}]},"links":{"outbound_url":"https://stax.strath.ac.uk/concern/theses/m900nt49x","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Lumb,Felicity Elspeth"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["201179752"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2016"]},{"key":"dc:date.issued","label":"Date","values":["2016"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Strathclyde Institute of Pharmacy and Biomedical Sciences"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Strathclyde"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["doctoral-pg"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["phd"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["T14221"]},{"key":"dc:identifier.doi","label":"DOI","values":["10.48730/fvzr-s132"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://stax.strath.ac.uk/concern/theses/m900nt49x"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, targets immune system cells including dendritic cells (DCs), to subvert inflammatory responses. The post-translational addition of phosphorylcholine (PC) is responsible for many of the immunomodulatory properties of this molecule and as ES-62 is potentially immunogenic, and therefore unsuitable as a drug, a library of small molecule analogues (SMAs) of ES-62 based on its PC moiety has been synthesised. The aim of this project was to investigate the effects of these SMAs on DCs. From a library of 79 compounds, 6 SMAs (11a, 12b, 11e, 11h, 11i and 11k) were selected as they significantly down-regulated LPS-induced cytokine production in vitro. ES-62 requires TLR4 and MyD88 to mediate many of its anti-inflammatory effects. However, cytokine inhibition mediated by SMAs 11a, 12b, 11e and 11i is generally intact in TLR4 knock-out (KO) and MyD88 KO bmDCs. Cytokine inhibition was found to be mediated through inhibition of LPS-induced cytokine gene expression and to be associated with reduction in LPS-induced activation of NF-κBp65, and MAPKs p38 and ERK. The SMAs also suppress LPS-induced up-regulation of CD40 and CD86; priming a DC phenotype that inhibits the production of IFN-γ by naïve T cells in vitro. Pre-exposure of DCs to 11a or 11i prior to LPS stimulation in vitro primes the cells to suppress the expansion of Ag-specific T cells in vivo, and this is associated with significantly inhibited numbers of IL-17A+CD4+ cells. Furthermore, mice subjected to collagen-induced arthritis pre-treated with 11a/12b-DCs had significantly reduced disease compared to mice inoculated with untreated DCs, and this was accompanied by a significant inhibition of IL-17+ cells in the draining lymph nodes. Thus overall this study has found that SMAs based on the PC moiety of ES-62 can modulate DCs such that they prime reduced TH17 responses in vivo."]},{"key":"dc:description.abstract","label":"Abstract","values":["ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, targets immune system cells including dendritic cells (DCs), to subvert inflammatory responses. The post-translational addition of phosphorylcholine (PC) is responsible for many of the immunomodulatory properties of this molecule and as ES-62 is potentially immunogenic, and therefore unsuitable as a drug, a library of small molecule analogues (SMAs) of ES-62 based on its PC moiety has been synthesised. The aim of this project was to investigate the effects of these SMAs on DCs. From a library of 79 compounds, 6 SMAs (11a, 12b, 11e, 11h, 11i and 11k) were selected as they significantly down-regulated LPS-induced cytokine production in vitro. ES-62 requires TLR4 and MyD88 to mediate many of its anti-inflammatory effects. However, cytokine inhibition mediated by SMAs 11a, 12b, 11e and 11i is generally intact in TLR4 knock-out (KO) and MyD88 KO bmDCs. Cytokine inhibition was found to be mediated through inhibition of LPS-induced cytokine gene expression and to be associated with reduction in LPS-induced activation of NF-κBp65, and MAPKs p38 and ERK. The SMAs also suppress LPS-induced up-regulation of CD40 and CD86; priming a DC phenotype that inhibits the production of IFN-γ by naïve T cells in vitro. Pre-exposure of DCs to 11a or 11i prior to LPS stimulation in vitro primes the cells to suppress the expansion of Ag-specific T cells in vivo, and this is associated with significantly inhibited numbers of IL-17A+CD4+ cells. Furthermore, mice subjected to collagen-induced arthritis pre-treated with 11a/12b-DCs had significantly reduced disease compared to mice inoculated with untreated DCs, and this was accompanied by a significant inhibition of IL-17+ cells in the draining lymph nodes. Thus overall this study has found that SMAs based on the PC moiety of ES-62 can modulate DCs such that they prime reduced TH17 responses in vivo."]},{"key":"dc:title","label":"Title","values":["The effect of small molecule analogues of the immunomodulatory helminth product ES-62 on denritic cell responses"]}]}],"canonical_facts":{"dc:creator":["Lumb,Felicity Elspeth"],"dc:creator.authoridentifier":["201179752"],"dc:date":["2016"],"dc:date.issued":["2016"],"dc:description":["ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, targets immune system cells including dendritic cells (DCs), to subvert inflammatory responses. The post-translational addition of phosphorylcholine (PC) is responsible for many of the immunomodulatory properties of this molecule and as ES-62 is potentially immunogenic, and therefore unsuitable as a drug, a library of small molecule analogues (SMAs) of ES-62 based on its PC moiety has been synthesised. The aim of this project was to investigate the effects of these SMAs on DCs. From a library of 79 compounds, 6 SMAs (11a, 12b, 11e, 11h, 11i and 11k) were selected as they significantly down-regulated LPS-induced cytokine production in vitro. ES-62 requires TLR4 and MyD88 to mediate many of its anti-inflammatory effects. However, cytokine inhibition mediated by SMAs 11a, 12b, 11e and 11i is generally intact in TLR4 knock-out (KO) and MyD88 KO bmDCs. Cytokine inhibition was found to be mediated through inhibition of LPS-induced cytokine gene expression and to be associated with reduction in LPS-induced activation of NF-κBp65, and MAPKs p38 and ERK. The SMAs also suppress LPS-induced up-regulation of CD40 and CD86; priming a DC phenotype that inhibits the production of IFN-γ by naïve T cells in vitro. Pre-exposure of DCs to 11a or 11i prior to LPS stimulation in vitro primes the cells to suppress the expansion of Ag-specific T cells in vivo, and this is associated with significantly inhibited numbers of IL-17A+CD4+ cells. Furthermore, mice subjected to collagen-induced arthritis pre-treated with 11a/12b-DCs had significantly reduced disease compared to mice inoculated with untreated DCs, and this was accompanied by a significant inhibition of IL-17+ cells in the draining lymph nodes. Thus overall this study has found that SMAs based on the PC moiety of ES-62 can modulate DCs such that they prime reduced TH17 responses in vivo."],"dc:description.abstract":["ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, targets immune system cells including dendritic cells (DCs), to subvert inflammatory responses. The post-translational addition of phosphorylcholine (PC) is responsible for many of the immunomodulatory properties of this molecule and as ES-62 is potentially immunogenic, and therefore unsuitable as a drug, a library of small molecule analogues (SMAs) of ES-62 based on its PC moiety has been synthesised. The aim of this project was to investigate the effects of these SMAs on DCs. From a library of 79 compounds, 6 SMAs (11a, 12b, 11e, 11h, 11i and 11k) were selected as they significantly down-regulated LPS-induced cytokine production in vitro. ES-62 requires TLR4 and MyD88 to mediate many of its anti-inflammatory effects. However, cytokine inhibition mediated by SMAs 11a, 12b, 11e and 11i is generally intact in TLR4 knock-out (KO) and MyD88 KO bmDCs. Cytokine inhibition was found to be mediated through inhibition of LPS-induced cytokine gene expression and to be associated with reduction in LPS-induced activation of NF-κBp65, and MAPKs p38 and ERK. The SMAs also suppress LPS-induced up-regulation of CD40 and CD86; priming a DC phenotype that inhibits the production of IFN-γ by naïve T cells in vitro. Pre-exposure of DCs to 11a or 11i prior to LPS stimulation in vitro primes the cells to suppress the expansion of Ag-specific T cells in vivo, and this is associated with significantly inhibited numbers of IL-17A+CD4+ cells. Furthermore, mice subjected to collagen-induced arthritis pre-treated with 11a/12b-DCs had significantly reduced disease compared to mice inoculated with untreated DCs, and this was accompanied by a significant inhibition of IL-17+ cells in the draining lymph nodes. Thus overall this study has found that SMAs based on the PC moiety of ES-62 can modulate DCs such that they prime reduced TH17 responses in vivo."],"dc:identifier":["T14221"],"dc:identifier.doi":["10.48730/fvzr-s132"],"dc:identifier.uri":["https://stax.strath.ac.uk/concern/theses/m900nt49x"],"dc:publisher.department":["Strathclyde Institute of Pharmacy and Biomedical Sciences"],"dc:publisher.institution":["University of Strathclyde"],"dc:title":["The effect of small molecule analogues of the immunomodulatory helminth product ES-62 on denritic cell responses"],"dc:type.qualificationlevel":["doctoral-pg"],"dc:type.qualificationname":["phd"]},"updated_at":"2026-07-24T04:52:04Z"}