All ETDs from UAB

Advisory Committee Chair

Phillip D Smith

Advisory Committee Members

Robinna G Lorenz

Jiri Mestecky

Lou B Justement

Charles O Elson

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Extracellular matrix (stroma) regulation of mucosal T-cell function is incompletely understood. Here we uncovered a role for intestinal stromal products in the innate regulation of effector T-cells. Stroma-conditioned media (S-CM) derived from normal human intestinal stroma (TGF-&betahi/IL-6lo/IL-1ßlo) significantly down-regulated T-cell proliferation and IFN-&gamma production compared to S-CM derived from inflamed Crohn's mucosa (TGF-&betahi/IL-6hi/IL-1&betahi). Antibody neutralization studies showed that TGF-&beta in normal S-CM inhibited T-cell proliferation and IFN-&gamma production, whereas IL-6 plus IL-1&beta in Crohn's S-CM promoted T-cell proliferation, and the IL-1&beta alone promoted IFN-γ and IL-17 release. Importantly, stromal cells in normal tissue produce TGF-&beta and contribute to mucosal homeostasis and tolerance to antigenic stimulation. In contrast, stromal cells in Crohn's mucosa produce high levels of IL-6 and IL-1&beta in addition to TGF-&beta and are hyper-responsive to antigenic stimulation. These findings implicate an important role for stromal regulation of immune responses in normal mucosa through the production of TGF-&beta and in promoting inflammatory responses in Crohn's disease through the production of IL-6 and IL-1&beta and TGF-&beta

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