Date on Master's Thesis/Doctoral Dissertation

12-2019

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Matoba, Nobuyuki

Committee Co-Chair (if applicable)

Ceresa, Brian

Committee Member

Ceresa, Brian

Committee Member

Siskind, Leah

Committee Member

Yaddanapudi, Kavitha

Committee Member

Li, Chi

Author's Keywords

cholera toxin B subunit; DSS colitis; unfolded protein response; TGFβ; epithelial wound healing, IBD

Abstract

This dissertation uncovers the mechanism and explores the utility of a recombinant cholera toxin B subunit (CTB) variant containing a KDEL endoplasmic reticulum (ER) retention motif (CTB-KDEL) as a drug candidate for the treatment of inflammatory bowel disease (IBD). CTB is a mucosal immunomodulatory protein that induces robust mucosal and systemic antibody responses. This well-known biological activity has been exploited in cholera prevention (as a component of Dukoral® vaccine) and vaccine development for decades. On the other hand, several studies have investigated CTB’s immunotherapeutic potential in the treatment of inflammatory diseases such as Crohn’s disease and asthma. Here, we reveal that CTB-KDEL, in contrast to CTB, induces colon epithelial wound healing in colitis via the activation of an unfolded protein response in colon epithelial cells. Furthermore, we in a model of chronic DSS colitis we found that weekly oral administration of CTB-KDEL, dosed before or after the onset of chronic colitis, induced by repeated dextran sodium sulfate (DSS) exposure, could significantly reduce disease severity and signs of chronicity. To address the consequences of immunogenicity, mice (C57BL/6, C3H/HeJ, or Rag1-/- strains) were pre-exposed to CTB-KDEL then subjected to DSS colitis and CTB-KDEL treatment. Subsequently, we found that the immunogenicity of CTB-KDEL does not impede the protein’s mucosal healing efficacy in vivo. The results provide implications for a novel therapeutic approach for mucosal healing, a significant unmet need in IBD treatment.

Download

Share

COinS