Cholera toxin B subunit fusion to autoantigen vaccines such as proinsulin (CTB-INS) down regulates dendritic cell (DC) activation and induces the synthesis of DC immunosuppressive cytokines. Recent studies of CTB-INS induction of immune tolerance in human DCs indicate that increased IDO1 biosynthesis may play an important role in CTB-INS vaccine inhibition of DC activation. Previous studies suggest transforming growth factor beta (TGF-β) may play a role in the stimulation of IDO1 biosynthesis for induction of immunological tolerance in murine DCs. To elucidate the mechanisms by which CTB-INS may stimulate IDO1 biosynthesis and mediate tolerance in human DCs, we investigated the contribution of TGF-β superfamily ligand proteins to CTB-INS induction of IDO biosynthesis in human monocyte-derived DCs (moDCs). Our previous studies demonstrated that CTB-INS activates the non-canonical NF-κB pathway to induce IDO1 biosynthesis in human DCs. However, experiments presented in this dissertation demonstrate that the CTB-INS fusion protein also stimulates biosynthesis of the immunoregulatory molecules TGF-β1, activin-A and integrin αvβ8 a molecule known to activate TGF-β1. In addition, CTB-INS stimulates increased levels of Smad2/3 phosphorylation in the vaccinated DCs. Further, we confirmed that CTB-INS upregulation of the TGF-β superfamily is unrelated to IDO1 biosynthesis in human moDCs. In conclusion, our experimental findings identified novel immunoregulatory functions of CTB-INS fusion protein and suggest the fusion protein may utilize previously unidentified mechanisms for the regulation of human DC activation to mediate tolerance, a significant finding for development of clinical applications in the therapy of tissue specific autoimmunity.
","abstract_html":"<p>Cholera toxin B subunit fusion to autoantigen vaccines such as proinsulin (CTB-INS) down regulates dendritic cell (DC) activation and induces the synthesis of DC immunosuppressive cytokines. Recent studies of CTB-INS induction of immune tolerance in human DCs indicate that increased IDO1 biosynthesis may play an important role in CTB-INS vaccine inhibition of DC activation. Previous studies suggest transforming growth factor beta (TGF-β) may play a role in the stimulation of IDO1 biosynthesis for induction of immunological tolerance in murine DCs. To elucidate the mechanisms by which CTB-INS may stimulate IDO1 biosynthesis and mediate tolerance in human DCs, we investigated the contribution of TGF-β superfamily ligand proteins to CTB-INS induction of IDO biosynthesis in human monocyte-derived DCs (moDCs). Our previous studies demonstrated that CTB-INS activates the non-canonical NF-κB pathway to induce IDO1 biosynthesis in human DCs. However, experiments presented in this dissertation demonstrate that the CTB-INS fusion protein also stimulates biosynthesis of the immunoregulatory molecules TGF-β1, activin-A and integrin αvβ8 a molecule known to activate TGF-β1. In addition, CTB-INS stimulates increased levels of Smad2/3 phosphorylation in the vaccinated DCs. Further, we confirmed that CTB-INS upregulation of the TGF-β superfamily is unrelated to IDO1 biosynthesis in human moDCs. In conclusion, our experimental findings identified novel immunoregulatory functions of CTB-INS fusion protein and suggest the fusion protein may utilize previously unidentified mechanisms for the regulation of human DC activation to mediate tolerance, a significant finding for development of clinical applications in the therapy of tissue specific autoimmunity.</p>","abstract_has_math":false,"creators":["Esebanmen, Grace Edosewe"],"institution":null,"degree_name":"Doctor of Philosophy (Medical Science)","degree_level":"Dissertation","degree_discipline":"Earth and Biological Sciences","degree_department":null,"school":null,"contributors":["Langridge, William H. R.","Brand, Leonard R.","Firek, Anthony","Khan, Salma","Nick, Kevin E.","Phillips, Suzanne","Soto, Ubaldo"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2017,"date_issued":"2017-06-01T07:00:00Z","date_published":"2017-06-01T07:00:00Z","updated_at":"2026-07-24T02:52:38Z","subjects":["Biological Phenomena, Cell Phenomena, and Immunity","Medical Cell Biology","Medical Sciences","Medicine and Health Sciences","Transforming Growth Factor beta; Receptors; Transforming Growth Factor beta; Dendritic Cells -- immunology; Cholera Toxin -- Immunology; Proinsulin -- Immunology; Recombinant Fusion Proteins -- Immunology","Immunosuppressive Cytokines; Biosynthesis; Immunological Tolerance;"],"languages":["English"],"rights":["This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://scholarsrepository.llu.edu/etd/361","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Langridge, William H. 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The author retains all other copyrights."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://scholarsrepository.llu.edu/etd/361"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Cholera toxin B subunit fusion to autoantigen vaccines such as proinsulin (CTB-INS) down regulates dendritic cell (DC) activation and induces the synthesis of DC immunosuppressive cytokines. Recent studies of CTB-INS induction of immune tolerance in human DCs indicate that increased IDO1 biosynthesis may play an important role in CTB-INS vaccine inhibition of DC activation. Previous studies suggest transforming growth factor beta (TGF-β) may play a role in the stimulation of IDO1 biosynthesis for induction of immunological tolerance in murine DCs. To elucidate the mechanisms by which CTB-INS may stimulate IDO1 biosynthesis and mediate tolerance in human DCs, we investigated the contribution of TGF-β superfamily ligand proteins to CTB-INS induction of IDO biosynthesis in human monocyte-derived DCs (moDCs). Our previous studies demonstrated that CTB-INS activates the non-canonical NF-κB pathway to induce IDO1 biosynthesis in human DCs. However, experiments presented in this dissertation demonstrate that the CTB-INS fusion protein also stimulates biosynthesis of the immunoregulatory molecules TGF-β1, activin-A and integrin αvβ8 a molecule known to activate TGF-β1. In addition, CTB-INS stimulates increased levels of Smad2/3 phosphorylation in the vaccinated DCs. Further, we confirmed that CTB-INS upregulation of the TGF-β superfamily is unrelated to IDO1 biosynthesis in human moDCs. In conclusion, our experimental findings identified novel immunoregulatory functions of CTB-INS fusion protein and suggest the fusion protein may utilize previously unidentified mechanisms for the regulation of human DC activation to mediate tolerance, a significant finding for development of clinical applications in the therapy of tissue specific autoimmunity.
"]},{"key":"dc:title","label":"Title","values":["The Role of TGF-β in CTB-Insulin Regulated Human Dendritic Cell Tolerance"]}]}],"canonical_facts":{"dc:contributor":["Langridge, William H. R.","Brand, Leonard R.","Firek, Anthony","Khan, Salma","Nick, Kevin E.","Phillips, Suzanne","Soto, Ubaldo"],"dc:creator":["Esebanmen, Grace Edosewe"],"dc:description.abstract":["Cholera toxin B subunit fusion to autoantigen vaccines such as proinsulin (CTB-INS) down regulates dendritic cell (DC) activation and induces the synthesis of DC immunosuppressive cytokines. Recent studies of CTB-INS induction of immune tolerance in human DCs indicate that increased IDO1 biosynthesis may play an important role in CTB-INS vaccine inhibition of DC activation. Previous studies suggest transforming growth factor beta (TGF-β) may play a role in the stimulation of IDO1 biosynthesis for induction of immunological tolerance in murine DCs. To elucidate the mechanisms by which CTB-INS may stimulate IDO1 biosynthesis and mediate tolerance in human DCs, we investigated the contribution of TGF-β superfamily ligand proteins to CTB-INS induction of IDO biosynthesis in human monocyte-derived DCs (moDCs). Our previous studies demonstrated that CTB-INS activates the non-canonical NF-κB pathway to induce IDO1 biosynthesis in human DCs. However, experiments presented in this dissertation demonstrate that the CTB-INS fusion protein also stimulates biosynthesis of the immunoregulatory molecules TGF-β1, activin-A and integrin αvβ8 a molecule known to activate TGF-β1. In addition, CTB-INS stimulates increased levels of Smad2/3 phosphorylation in the vaccinated DCs. Further, we confirmed that CTB-INS upregulation of the TGF-β superfamily is unrelated to IDO1 biosynthesis in human moDCs. In conclusion, our experimental findings identified novel immunoregulatory functions of CTB-INS fusion protein and suggest the fusion protein may utilize previously unidentified mechanisms for the regulation of human DC activation to mediate tolerance, a significant finding for development of clinical applications in the therapy of tissue specific autoimmunity.
"],"dc:identifier":["https://scholarsrepository.llu.edu/etd/361"],"dc:language":["English"],"dc:rights":["This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights."],"dc:subject":["Biological Phenomena, Cell Phenomena, and Immunity","Medical Cell Biology","Medical Sciences","Medicine and Health Sciences","Transforming Growth Factor beta; Receptors; Transforming Growth Factor beta; Dendritic Cells -- immunology; Cholera Toxin -- Immunology; Proinsulin -- Immunology; Recombinant Fusion Proteins -- Immunology","Immunosuppressive Cytokines; Biosynthesis; Immunological Tolerance;"],"dc:title":["The Role of TGF-β in CTB-Insulin Regulated Human Dendritic Cell Tolerance"],"thesis:degree_discipline":["Earth and Biological Sciences"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (Medical Science)"]},"updated_at":"2026-07-24T02:52:38Z"}