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Regulation of peripheral tolerance by mast cells.

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Call No.	Ph.D. 2010
Author	de Vries, Victor C.
Title	Regulation of peripheral tolerance by mast cells.
Date	2010
Abstract	Mast cells (MC) have until recently been regarded as pro-inflammatory, however this view changed with the observation that the absence of MC impairs the development of transplant tolerance to allografts. However, little is known about whether MC are needed to induce and/or sustain immune tolerance, the subsets of MC involved in allograft tolerance, what MC mediators contribute to tolerance, and the involvement of MC degranulation in tolerance. We find that MC can control tolerance and immunity via direct actions on the environment or indirectly by regulating the activities of dendritic cells. Because degranulation is such a central component in the biology of MC, we first asked if degranulation impacts on the ability of MC to mediate tolerance. We show that overt MC degranulation leads to acute rejection of an established allograft. This finding suggests that MC are not fixed in their ability to mediate tolerance, but their function is very much controlled by the signals they receive. Hence, mediators released by degranulating MC can break tolerance. Of the MC derived protease, MCP6 most likely changes the local levels of IL6 thereby contributing to the maintenance of a suppressive Th2 environment. Finally, immune tolerance can be maintained through the production of tryptophan hydroxylase (TPH) by MC. TPH, through its ability to metabolize tryptophan, can create a tryptophan-deficient environment which can limit T cell alloreactivity and graft rejection. In addition to the direct impact MC exert on maintaining an immunosuppressive environment, they can also maintain tolerance through regulating DC function. We contend that the maintenance of allograft tolerance requires the migration of tolerogenic DCs from the tissue site to the regional lymph node. Production of TNFα by MC within the tolerant allograft is essential in sustaining DC migration and hence graft survival. Following the migration of the graft derived DCs, their enhanced longevity appears to be a critical component in their ability to sustain tolerance. The enhanced longevity of the tolerogenic DCs is due to MC-derived GM-CSF. Hence MC-derived TNFα and GM-CSF facilitate the migration and longevity of tolerogenic DCs which is critical to maintain graft survival. In conclusion, MC contribute directly and indirectly to graft tolerance by nutrient deprivation and local modulation of the cytokine environment and through controlling the behaviour of tolerogenic DCs. Although a lot of questions are still unanswered, this work provides some novel insights in how MC positively contribute to peripheral tolerance.
Description	xiv, 228 leaves : ill. (some col.) ; 28 cm.
Format	application/pdf
Advisor	Randolph J Noelle, Mary Jo Turk, Charles Sentman, Terry B Strom
Subject	Mast cells -- Immunology. Mast cells -- Physiology. Dendritic cells. Immunological tolerance -- Molecular aspects. Medical Term Cell Degranulation.
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.384

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	_____________________ Brian W. Pogue, PhD Dean of Graduate Studies Regulation of peripheral tolerance by mast cells A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Department of Microbiology and Immunology by Victor C. de Vries DARTMOUTH COLLEGE Hanover, New Hampshire April, 2010 Examining Committee: ______________________________ Mary Jo Turk, PhD (Chair) ______________________________ Charles Sentman, PhD ______________________________ Terry B. Strom, MD ______________________________ Randolph J. Noelle, PhD (advisor)

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Regulation of peripheral tolerance by mast cells.