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Immunomodulation and the prevention of pathogen-driven ileitis.

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Call No.	RC862.E52 M56 2005
Author	Minns, Laurie Ann.
Title	Immunomodulation and the prevention of pathogen-driven ileitis.
Date	2005
Abstract	Oral infection with Toxoplasma gondii in susceptible C57BL/6 mice results in the morphologic, histologic and immunologic changes in the small intestine consistent with the human Inflammatory Bowel Disease (IBD) of unknown etiology, Crohn's disease. T. gondii infection induces a cascade of immunological events that involve both the components of the innate and adaptive immune responses. Both the infected enterocytes as well as the CD4+ T cells from the Lamina Propria (LP) produce chemokines and inflammatory cytokines including Interferon-γ, IFN-γ, Tumor Necrosis Factor-α (TNF-α) and Inducible Nitric Oxide Synthase (iNOS) that are necessary to clear the parasite whereas CD8+ intraepithelial lymphocytes (IELs) and regulatory CD4+ T cells secrete Transforming Growth Factor-β (TGF-β) and/or Interleukin- 10 (IL-10) that promote intestinal homeostasis. Effective strategies for preventing TH1 intestinal inflammatory events need to be developed. The data contain herein demonstrate that preventing this pathogen-driven ileitis can occur using several different targets and strategies. The identification of the Pathogen Associate Membrane Protein (PAMP), Toll Like Receptor 9 (TLR9), required for susceptibility to infection, and consequent studies using TLR9-/- mice demonstrate that targeting the initiation of inflammation, and thereby dampening the T cell response to T. gondii infection results in a complete loss of acute ileitis due to a decreased IFN-γ response by CD4+ LP T cells. Additional data presented demonstrates that IFN-γ expression by CD4+T cells is controlled in part by TGF-β producing IELs. Finally, specifically targeting the IEL population to produce TGF-β using two different immunomodulating agents, the synthetic triterpenoid, CDDO, and the capsular polysaccharide A from Bacteroides fragilis protects mice against pathogen driven ileitis. In summary, modulating the intestinal immune response by suppressing pro-inflammatory signals or by inducing "regulatory" IELs to produce TGF-β could serve as important new therapies for this debilitating disease.
Description	xii, 234 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Edward J. Usherwood
Subject	Crohn's disease -- Prevention. Crohn's disease -- Treatment. Immune response -- Regulation. Toxoplasma gondii -- Pathophysiology.
College	Dartmouth Medical School -- Department of Microbiology and Immunology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.92

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	IMMUNOMODULATION AND THE PREVENTION OF PATHOGEN-DRIVEN ILEITIS A Thesis Submitted to the Faculty In partial fulfillment of the requirements for the Degree of Doctor of Philosophy In Microbiology and Immunology By Laurie Ann Minns DARTMOUTH COLLEGE Hanover, New Hampshire May 6, 2005 Examining Committee:

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