The Role of TGF-β in CTB-Insulin Regulated Human Dendritic Cell Tolerance

<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>

Name thesis:degree_name

Doctor of Philosophy (Medical Science)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Earth and Biological Sciences

Year

2017

Author dc:creator

• Esebanmen, Grace Edosewe

Contributors dc:contributor

• Langridge, William H. R.
• Brand, Leonard R.
• Firek, Anthony
• Khan, Salma
• Nick, Kevin E.
• Phillips, Suzanne
• Soto, Ubaldo

• 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;

Statement 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.

Language dc:language

English

Repository record dc:identifier

https://scholarsrepository.llu.edu/etd/361

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-1354