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Date of Award

12-1998

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. Mary H. Perdue

Abstract

Food allergies are a significant clinical problem, with symptoms including diarrhea, vomiting, or systemic anaphylaxis. To elicit allergic reactions, antigens must first cross the intestinal epithelium. The purpose of my studies was to examine macromolecular transport across intestinal epithelium, and the effect of sensitization and immune activation on transepithelial antigen transport. Rats were sensitized to a model protein antigen, horseradish peroxidase (HRP) by injection with adjuvants. Intestinal segments were removed and mounted in Ussing chambers for the study for transepithelial movement of HRP. Electon microscopy analysis of HRP transport showed that specifically sensitized rats transported HRP across the epithelium in greater amounts, and more rapidly, than naive controls or rats sensitized to an irrelevant antigen. After the hypersensitivity response, there was a significant increase in HR flux across the intestinal epithelium in HRP sensitized, but not control rats. This was accompanied by an opening of the epithelial tight junctions to allow paracellular flow of antigen. Sensitized mast cell deficient rats also had an enhanced initial uptake of antigen, but did not develop a non-specific decrease in epithelial barrier function. The role of interleukin-4 (IL-4) in the regulation of transepithelial antigen transport was examined. Treatment of human epithelial monolayers with IL-4, or with serum from atopic patients, caused a significant increase in transepithelial transport of HRP. Antibodies against IL-4 abolished the effect of atopic serum on transepithelial HRP transport. Electron microscopy analysis showed an increase in both transcellular and paracellular HRP transport. These studies show that transepithelial transport of antigen is profoundly altered by sensitization, and that mast cells and interleukin-4 enhance the delivery of antigen across the intestinal epithelium.

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