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Developing clinically translatable chimerism induction protocols in a stringent murine model

  • Author / Creator
    Lin, Jiaxin
  • Allogeneic hematopoietic chimerism induction via bone marrow transplantation (BMT) is thus far the most robust method for inducing donor antigen specific tolerance to allogeneic grafts. However, limited by the toxicity of the reagents used in conditioning the recipients, the demand of a high dose hematopoietic stem cells, and the risk of graft versus host disease (GVHD), the current conditioning protocols cannot be applied for islet transplantation in patients with brittle type 1 diabetes. We aimed to generate clinical translational chimerism induction protocols for these recipients by using non-obese diabetic (NOD) mice, a mouse model for type 1 diabetes, which is also a stringent model for testing chimerism induction conditioning protocols. Our lab has previously recognized that recipient T cells in the NOD mice were responsible for the split tolerance after induction of mixed hematopoietic chimerism. Here, we overcame the resistance to tolerance induction and the requirement of toxic reagents and a high dose bone marrow cells in chimerism induction in NOD mice with a maximized T cell depletion approach. This protocol led to full chimerism and tolerance to fully allogeneic donor skin in NOD mice. We further tested this protocol in spontaneously diabetic NOD mice, which have previously been shown to be challenging recipients for chimerism induction. We found that the enhanced resistance to chimerism induction in spontaneously diabetic NOD mice was confounded by age. We showed that a modified protocol with infusion of donor CD8α+ cells generated full chimerism and tolerance to fully allogeneic islets in autoimmune diabetic NOD mice. Lastly, we tried to generate chimerism in recipients that had been immunized with donor cells. We overcame the high lightened anti-donor immune response in these primed recipients with enzymes that block functions of mouse IgG. This work has generated a protocol that is potentially translatable for clinical islet transplantation. We also identified that aging has an important role in chimerism induction in NOD mice. Our work on IgG blockade in presensitized recipients supports the further application of this new treatment to bone marrow transplantation in patients with pre-existing antibodies towards donor antigens.

  • Subjects / Keywords
  • Graduation date
    Spring 2020
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/r3-mm3e-b091
  • License
    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.