ERA

Download the full-sized PDF of Defining the barrier of split tolerance in allogeneic mixed chimerismDownload the full-sized PDF

Analytics

Share

Permanent link (DOI): https://doi.org/10.7939/R3WF0D

Download

Export to: EndNote  |  Zotero  |  Mendeley

Communities

This file is in the following communities:

Graduate Studies and Research, Faculty of

Collections

This file is in the following collections:

Theses and Dissertations

Defining the barrier of split tolerance in allogeneic mixed chimerism Open Access

Descriptions

Other title
Subject/Keyword
Chimerism
Diabetes
non-obese diabetic mice
Tolerance
Bone marrow transplant
Split tolerance
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Al-Adra, David P.
Supervisor and department
Anderson, Colin (Medical Microbiology and Immunology and Surgery)
Examining committee member and department
Mueller, Thomas (Medicine)
Shapiro, James (Surgery)
Elliot, John (Medical Microbiology and Immunology)
Cattral, Mark (Surgery)
Department
Department of Surgery
Specialization
Experimental Surgery
Date accepted
2012-07-09T11:19:06Z
Graduation date
2012-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Establishing mixed hematopoietic chimerism is a promising approach to develop donor-specific tolerance to transplanted organs. Establishing tolerance may eliminate the need for long-term immunosuppressive therapy, prevent chronic rejection and in the case of Type 1 Diabetes (T1DM), reverse autoimmunity. However, even in the long-lasting presence of a donor organ or donor hematopoietic cells, some allogeneic tissues from the same donor can be rejected; a phenomenon known as split tolerance. With the current goal of creating mixed chimeras using clinically feasible amounts of donor bone marrow and with minimal conditioning, split tolerance may become more prevalent and its mechanisms need to be explored. The work in this thesis can be broadly divided into four components. First, we discuss chimerism and its potential as an adjuvant for islet transplantation for the treatment of T1DM. Second, using the relevant autoimmune non-obese diabetic (NOD) mouse model, we demonstrate that NOD NK cells are a substantial barrier to allogeneic chimerism in the presence or absence of adaptive immunity. Third, we use radiation chimeras to show that the split tolerance NOD mice develop has contributing components from both radiation sensitive and radiation resistant cellular compartments. Furthermore, we have identified T cells, but not NK or B cells, as cells that both resist chimerism induction and mediate split tolerance. We then developed a successful non-myeloablative chimerism induction protocol based on recipient NOD T cell depletion. Finally, we examined the role of MHC class I expression on recipient vascular endothelial cells in CD8 T cell mediated indirect allograft rejection. Our results suggest that the commonly held notion that recipient MHC class I expression on recipient vasculature ingrowth into non-vascularized allografts cannot be the primary explanation for indirect rejection by CD8 T cells and that additional mechanisms of indirect recognition by CD8 T cells must be involved. This work has identified cells that resist chimerism induction and cells that mediate split tolerance in NOD mice. This has allowed the generation of a successful chimerism induction protocol that produces tolerance towards fully allogeneic islets. In addition, we have challenged the previously accepted mechanisms of indirect rejection by CD8 T cells. Combined, this work has highlighted some of the mechanisms of split tolerance and has developed means to mitigate its occurrence.
Language
English
DOI
doi:10.7939/R3WF0D
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Al-Adra, D.P. and C.C. Anderson. (2011) Mixed chimerism and split tolerance: Mechanisms and clinical correlations. Chimerism 2(4):89-101.Al-Adra, D.P., Chan, W.F. and C.C. Anderson. (2011) Nonobese diabetic natural killer cells: a barrier to allogeneic chimerism that can be reduced by rapamycin. Transplantation 15;92(9):977-984.

File Details

Date Uploaded
Date Modified
2014-05-01T01:12:54.675+00:00
Audit Status
Audits have not yet been run on this file.
Characterization
File format: pdf (Portable Document Format)
Mime type: application/pdf
File size: 4083474
Last modified: 2015:10:12 17:03:43-06:00
Filename: Al-Adra David Fall 2012.pdf
Original checksum: 634fbfcc241863de1f0ed97782e585af
Well formed: true
Valid: true
File title: -
File author: David
Page count: 248
File language: en-CA
Activity of users you follow
User Activity Date