Type 1 diabetes mellitus is a chronic inflammatory disease in which insulin producing β-cells of the pancreatic islets are killed by autoreactive cells of the immune system in response to a loss of tolerance. Dendritic cells (DC) interact predominantly with naïve T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this dissertation, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic β-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1) shown to be directly linked to CTB-INS-induced DC activation and maturation. Treatment of vaccinated DCs with the pharmacological NF-κB inhibitors ACHP or DHMEQ inhibited IDO1 biosynthesis, suggesting a role for NF-κB signaling in CTB-INS vaccine up-regulation of dendritic cell IDO1. Further, blocking the NF-κB-inducing kinase (NIK) phosphorylation of IKK-α dimers and translocation of p52/RelB complexes to the nucleus with anti-NIK siRNA, significantly inhibited IDO1 expression in human DCs. Chromatin immunoprecipitation (ChIP) analysis, showed that RelB-p52 dimers bound dendritic cell NF-κB consensus sequences in the IDO1 promoter region, demonstrating vaccine stimulation of NF-κB non-canonical pathway activation of IDO1 expression in human DCs in vivo. Addition of the Tumor Necrosis Factor Associated Factors (TRAF) TRAF6 and TRAF 2, 3 blocking peptides to vaccinated DCs dramatically reduced the level of IDO1 biosynthesis and stimulated DC suggesting the vaccine may function in the same signaling pathway as TNFR super-family for the up-regulation of IDO1 biosynthesis in vaccinated dendritic cells. Together, these data confirm CTB-INS vaccine activation of the non-canonical NF-κB signaling pathway TNFR receptor family up-regulation of dendritic cell IDO1 biosynthesis permitting vaccine inhibition of DC maturation leading to the suppression of type 1 diabetes development.
","abstract_html":"<p>Type 1 diabetes mellitus is a chronic inflammatory disease in which insulin producing β-cells of the pancreatic islets are killed by autoreactive cells of the immune system in response to a loss of tolerance. Dendritic cells (DC) interact predominantly with naïve T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this dissertation, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic β-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1) shown to be directly linked to CTB-INS-induced DC activation and maturation. Treatment of vaccinated DCs with the pharmacological NF-κB inhibitors ACHP or DHMEQ inhibited IDO1 biosynthesis, suggesting a role for NF-κB signaling in CTB-INS vaccine up-regulation of dendritic cell IDO1. Further, blocking the NF-κB-inducing kinase (NIK) phosphorylation of IKK-α dimers and translocation of p52/RelB complexes to the nucleus with anti-NIK siRNA, significantly inhibited IDO1 expression in human DCs. Chromatin immunoprecipitation (ChIP) analysis, showed that RelB-p52 dimers bound dendritic cell NF-κB consensus sequences in the IDO1 promoter region, demonstrating vaccine stimulation of NF-κB non-canonical pathway activation of IDO1 expression in human DCs in vivo. Addition of the Tumor Necrosis Factor Associated Factors (TRAF) TRAF6 and TRAF 2, 3 blocking peptides to vaccinated DCs dramatically reduced the level of IDO1 biosynthesis and stimulated DC suggesting the vaccine may function in the same signaling pathway as TNFR super-family for the up-regulation of IDO1 biosynthesis in vaccinated dendritic cells. Together, these data confirm CTB-INS vaccine activation of the non-canonical NF-κB signaling pathway TNFR receptor family up-regulation of dendritic cell IDO1 biosynthesis permitting vaccine inhibition of DC maturation leading to the suppression of type 1 diabetes development.</p>","abstract_has_math":false,"creators":["Mbongue, Jacques Christian"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Basic Sciences","degree_department":null,"school":null,"contributors":["Langridge, William H. R.","De Leon, Marino","Figueroa, Johnny","Firek, Anthony","Khan, Salma","Tang, Jiping"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2016,"date_issued":"2016-06-01T07:00:00Z","date_published":"2016-06-01T07:00:00Z","updated_at":"2026-07-24T02:52:38Z","subjects":["Cellular and Molecular Physiology","Medical Biochemistry","Medical Cell Biology","Medical Immunology","Medical Physiology","Physiology","Dendritic Cells; Immunity; Cellular; Cell Differentiation; Diabetes Mellitus; Type 1;","Immunological Homeostasis; Chimeric Fusion Protein Vaccine; Vaccine inhibitation;"],"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/348","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/348"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Type 1 diabetes mellitus is a chronic inflammatory disease in which insulin producing β-cells of the pancreatic islets are killed by autoreactive cells of the immune system in response to a loss of tolerance. Dendritic cells (DC) interact predominantly with naïve T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this dissertation, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic β-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1) shown to be directly linked to CTB-INS-induced DC activation and maturation. Treatment of vaccinated DCs with the pharmacological NF-κB inhibitors ACHP or DHMEQ inhibited IDO1 biosynthesis, suggesting a role for NF-κB signaling in CTB-INS vaccine up-regulation of dendritic cell IDO1. Further, blocking the NF-κB-inducing kinase (NIK) phosphorylation of IKK-α dimers and translocation of p52/RelB complexes to the nucleus with anti-NIK siRNA, significantly inhibited IDO1 expression in human DCs. Chromatin immunoprecipitation (ChIP) analysis, showed that RelB-p52 dimers bound dendritic cell NF-κB consensus sequences in the IDO1 promoter region, demonstrating vaccine stimulation of NF-κB non-canonical pathway activation of IDO1 expression in human DCs in vivo. Addition of the Tumor Necrosis Factor Associated Factors (TRAF) TRAF6 and TRAF 2, 3 blocking peptides to vaccinated DCs dramatically reduced the level of IDO1 biosynthesis and stimulated DC suggesting the vaccine may function in the same signaling pathway as TNFR super-family for the up-regulation of IDO1 biosynthesis in vaccinated dendritic cells. Together, these data confirm CTB-INS vaccine activation of the non-canonical NF-κB signaling pathway TNFR receptor family up-regulation of dendritic cell IDO1 biosynthesis permitting vaccine inhibition of DC maturation leading to the suppression of type 1 diabetes development.
"]},{"key":"dc:title","label":"Title","values":["Mechanism of Chimeric Vaccine Mediated Immune Suppression of Human Dendritic Cells"]}]}],"canonical_facts":{"dc:contributor":["Langridge, William H. R.","De Leon, Marino","Figueroa, Johnny","Firek, Anthony","Khan, Salma","Tang, Jiping"],"dc:creator":["Mbongue, Jacques Christian"],"dc:description.abstract":["Type 1 diabetes mellitus is a chronic inflammatory disease in which insulin producing β-cells of the pancreatic islets are killed by autoreactive cells of the immune system in response to a loss of tolerance. Dendritic cells (DC) interact predominantly with naïve T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this dissertation, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic β-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1) shown to be directly linked to CTB-INS-induced DC activation and maturation. Treatment of vaccinated DCs with the pharmacological NF-κB inhibitors ACHP or DHMEQ inhibited IDO1 biosynthesis, suggesting a role for NF-κB signaling in CTB-INS vaccine up-regulation of dendritic cell IDO1. Further, blocking the NF-κB-inducing kinase (NIK) phosphorylation of IKK-α dimers and translocation of p52/RelB complexes to the nucleus with anti-NIK siRNA, significantly inhibited IDO1 expression in human DCs. Chromatin immunoprecipitation (ChIP) analysis, showed that RelB-p52 dimers bound dendritic cell NF-κB consensus sequences in the IDO1 promoter region, demonstrating vaccine stimulation of NF-κB non-canonical pathway activation of IDO1 expression in human DCs in vivo. Addition of the Tumor Necrosis Factor Associated Factors (TRAF) TRAF6 and TRAF 2, 3 blocking peptides to vaccinated DCs dramatically reduced the level of IDO1 biosynthesis and stimulated DC suggesting the vaccine may function in the same signaling pathway as TNFR super-family for the up-regulation of IDO1 biosynthesis in vaccinated dendritic cells. Together, these data confirm CTB-INS vaccine activation of the non-canonical NF-κB signaling pathway TNFR receptor family up-regulation of dendritic cell IDO1 biosynthesis permitting vaccine inhibition of DC maturation leading to the suppression of type 1 diabetes development.
"],"dc:identifier":["https://scholarsrepository.llu.edu/etd/348"],"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":["Cellular and Molecular Physiology","Medical Biochemistry","Medical Cell Biology","Medical Immunology","Medical Physiology","Physiology","Dendritic Cells; Immunity; Cellular; Cell Differentiation; Diabetes Mellitus; Type 1;","Immunological Homeostasis; Chimeric Fusion Protein Vaccine; Vaccine inhibitation;"],"dc:title":["Mechanism of Chimeric Vaccine Mediated Immune Suppression of Human Dendritic Cells"],"thesis:degree_discipline":["Basic Sciences"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T02:52:38Z"}