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Chimerism, Diabetes, non-obese diabetic mice, Tolerance, Bone marrow transplant, Split tolerance

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.





Autor: Al-Adra, David P.

Fuente: https://era.library.ualberta.ca/


Introducción



University of Alberta Defining the Barrier of Split Tolerance in Allogeneic Mixed Chimerism by David Peter Al-Adra A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Experimental Surgery Department of Surgery ©David Al-Adra Fall 2012 Edmonton, Alberta 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 authors prior written permission. For Noelle 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 aut...





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