Defining the barrier of split tolerance in allogeneic mixed chimerism

• Author / Creator

  Al-Adra, David P.

• 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.

• Subjects / Keywords

  • Bone marrow transplant
  • Non-obese diabetic mice
  • Chimerism
  • Split tolerance
  • Diabetes
  • Tolerance

• Graduation date

  Fall 2012

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3WF0D

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.