Date of Award

Summer 2019

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Mitzi Nagarkatti

Abstract

Dysregulated inflammation is at the heart of countless human diseases. Graft rejection is the process by which an organ from an incompatible donor is rejected by the recipient whose immune cells attack the foreign tissue. Colitis is an inflammatory disorder caused by undue chronic inflammation in the colon and rectum that can progress to cancer. Colitis incidence is on the rise, especially in developing nations and Asia; and the list of patients who need organ transplants grow by the day. Therapies for both graft rejection and colitis are limited to immunosuppressive drugs that leaves patients vulnerable to infection, heart disease, nephrotoxicity and malignancy. Thus, new strategies to address the immunological problems facing these conditions are critical. In this dissertation, we tried to identify epigenetic, molecular, and cellular pathways involved in inflammation as seen during allograft rejection or development of colitis. Data is presented regarding the expression of a pro-inflammatory microRNA cluster that is up-regulated with graft rejection, that when silenced, can provoke anti-inflammatory changes to the transplanted graft, providing a role for epigenetic modulation of inflammation. We also tested the role of cannabinoid receptors in regulating inflammation through use of natural compounds such as Δ9-tetrahydrocannabinol (THC), found in Cannabis sativa plant. THC was highly effective in suppressing colitis through complex pathways involving stimulation of colonocyte mucin production and barrier integrity mediated by tight-junction proteins to provide spatial separation between host and commensal organisms. In addition, THC modulated dendritic cell (DC) phenotype towards increased CD103 expression in the colonic lamina propria (cLP) and enhanced DC TGF-β1 expression to expand the cLP Tregs. The current study has identified novel pathways of inflammation that can be targeted to benefit patients suffering from inflammatory diseases.

Rights

© 2019, William James Becker

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