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Immunity and Tolerance to Carbohydrate Antigens

  • Author / Creator
    Jeyakanthan, Mylvaganam
  • Access to ABO-incompatible (ABOi) organ transplantation has expanded donor availability for patients with end-stage organ failure. Determination of eligibility for safe ABOi transplantation and effective post-transplant management to deal with potential ongoing antibody production are dependent on accurate measurement of serum ABO antibodies and an understanding of ABO immunobiology. Thus, clear understanding of the structural nature of these carbohydrate antigens and immune mechanisms can help to improve patient care and devise new strategies for tolerance induction to such antigens. Immunity to carbohydrate antigens is one of the less well understood features of immunology. This class of antigens is thought to induce antibody responses by a mechanism of extensive cross-linking of B cell receptors, without the help of T cells. Antibodies produced in this fashion are considered to have low affinity and high cross-reactivity to other antigens of this class. The work in this thesis seeks to fully understand the mechanisms of immune responses to carbohydrate antigens by using clinically relevant model systems. The main objectives were to, i) study mechanisms of antibody responses to carbohydrate antigens; ii) to understand how the adaptive immune system discriminates such self and foreign antigens; iii) to characterize blood group antibodies and their specificities to minor structural differences in ABO antigens; iv) to devise a tool for the accurate determination of such antibodies in ABOi transplant patients and patients being assessed for possible ABOi transplantation; v) to establish a suitable animal model that may be used to study blood group antibodies and various strategies to induce neonatal tolerance. Studies described in chapter 2 reveal a mechanism for antibody responses to carbohydrates and, in contrast to prevailing theory, demonstrate their requirement for T cell help. The findings also provide a basis for proposing a model for self-nonself discrimination of carbohydrates. ABH subtype antigens and the differences in their expression on erythrocytes and organs are presented in chapter 3. Based on these findings, a glycan microarray for detecting antibodies against ABH subtype antigens actually expressed in the donor graft rather than in reagent erythrocytes (ie., ‘donor-specific’ antibodies) was developed and validated in an international study of heart transplant patients. Results presented in chapters 3 and 4 also reveal fundamental flaws in the ‘gold standard’ agglutination assay. Development of a large animal model of neonatal tolerance is described in chapter 5. Although naturally delayed isohemagglutinin production in piglets is analogous to the developmental kinetics in human infants, tolerance surprisingly did not develop in ABOi kidney transplant piglet recipients, despite graft A-antigen persistence long after transplant. Our studies demonstrated that in the pig, A-antigens are not expressed in vascular endothelium, in contrast to previously reported studies. These findings suggest that the impact on the host immune system of exposure to non-self ABH antigens during early life in human heart vs porcine kidney grafts may depend on expression in vascular endothelium. This model may still be valuable for studying the effects of ABO antibodies on kidney tubules where abundant expression of blood group A antigen was observed. In summary, studies presented in this thesis challenge some of the current theories related to the immune response to natural carbohydrate antigens. In addition to characterizing blood group antigens and antibodies this work also offers solutions to improve patient management in the setting of ABOi transplantation. Furthermore, these findings are also relevant to infection, autoimmunity, cancer and vaccine design.

  • Subjects / Keywords
  • Graduation date
    2014-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3R20S24Q
  • 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.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Surgery
  • Specialization
    • Experimental Surgery
  • Supervisor / co-supervisor and their department(s)
    • Lori J West (Department of Pediatrics, Surgery and Medical Microbiology & Immunology)
  • Examining committee members and their departments
    • James Shapiro (Department of Surgery)
    • Colin Anderson (Department of Surgery and Medical Microbiology & Immunology)
    • John Elliott (Department of Medicine and Medical Microbiology & Immunology)
    • Joren Madsen (Department of Surgery, Harvard Medical School)