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Humoral Alloimmunity in Cardiac Allograft Rejection

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Humoral Alloimmunity in Cardiac Allograft Rejection Humoral alloimmunity in cardiac allograft rejection Jawaher Alsughayyir Darwin College Department of Surgery University of Cambridge This dissertation is submitted for the degree of Doctor of Philosophy July 2018 i Declaration This dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration except where declared in the text. It has not been submitted in whole or part for a degree at any university. The length of this thesis does not exceed the 60,000 word limit i Dissertation title: Humoral alloimmunity in cardiac allograft rejection Student name: Jawaher Alsughayyir Abstract Although the short-term outcomes of solid allograft survival have improved substantially over the last few decades, there has been no significant improvement in long-term survival of solid allografts. This thesis presents the initial characterisation of alloantibody mediated rejection in a murine heart transplant model, with particular focus on the impact of the different phases of the humoral alloimmune response (follicular or germinal centre) on graft rejection. The key findings of this work are: 1) The precursor frequency of allospecific CD4 T cells determines the magnitude of the alloantibody response, with a relatively high frequency of CD4 T cells eliciting strong extrafollicular responses, while a high frequency of B cells promotes slowly-developing germinal centre responses. 2) Strong extrafollicular antibody response can mediate acute heart allograft rejection in the absence of CD8 T cells alloresponses. 3) Germinal centre humoral immunity mediates chronic antibody-mediated rejection. 4) Recipient memory, but not naïve, CD4 T cells that recognise one graft alloantigen can provide ‘unlinked’ help to allospecific B cells that recognise a different graft alloantigen for generating germinal centre alloantibody responses. ii ACKNOWLEDGEMENTS To my dearest family, friends, and colleagues. Thank you for all of your support! iii CONTRIBUTIONS OF COLLABORATORS The following section details individual collaborators and their role in this thesis. • All surgical procedures were performed by Mr. Reza Motallebzadeh and Mr. Saeed Qureshi. • Prof. Robert Brink (Garvan Institute of Medical Research, Australia) provided HEL3x 3x recombinant protein, anti-HEL hyperimmune serum, and SWHEL mice. • NIH tetramer core facility (Emory University, Atlanta, GA) for providing H2-Kd tetramers. • Thank you for Dr. Katherine Stott, Hannah Copley and Ashley Priddey for teaching me the principals of BLI and discussing my results. • Breeding and genotyping of the mouse colonies were kindly performed by Mrs Jackie Higgins and Mrs Sylvia Rehakova. • Special thanks to Mrs. Marg Negus for teaching me most of the laboratory techniques. • Mrs. Faye Hills for her endless assistance and friendship during my time in the laboratory. My sincere gratitude to my supervisor Mr. Gavin Pettigrew and to Mr. Reza Motallebzadeh for their continuous support and mentorship iv Abbreviations 2ME 2 - Mercaptoethanol 7-AAD 7 – Aminoactinomycin D Ab antibody Ag antigen ADCC antibody dependent cell-mediated cytotoxicity AMR antibody-mediated rejection APC antigen presenting cell AUC area under the curve BCR B cell receptor BM bone marrow BLI bio-layer interferometry BSA bovine serum albumin CD cluster of differentiation CMV cytomegalovirus CSR class-switch recombination CTL effector cytotoxic killer cells DC dendritic cell ELISA enzyme-linked immunosorbent assay ELISPOT enzyme-linked immunosorbent spot EVG elastin van Gieson Fc fragment crystallizable region of immunoglobulin FCS foetal calf serum FITC flourexcein isothiocynanate GC germinal centre HEL Hen egg lysozyme HLA human leukocyte antigen ICOS inducible T cell co-stimulator v IEL internal elastic lamina IFNγ interferon gamma Ig immunoglobulin Ip intraperitoneal Iv intravenous LLPC long-lived plasma cell MACS magnetic-activated cell sorting MHC major Histocompatibility Complex MST mean survival time MZ marginal zone NK natural killer PBS phosphate buffered saline PE phyocoerythrin Rag recombinase activating gene Rpm revolutions per minute RPMI Roswell Park memorial institute medium SD standard deviation SEM standard error of the mean SHM somatic hypermutation SLO secondary lymphoid organ TCR T cell receptor TCR-/- T cell receptor knock out WT wild type vi Table of contents Abstract ...................................................................................................................................... ii ACKNOWLEDGEMENTS.............................................................................................................. iii CONTRIBUTIONS OF COLLABORATORS ..................................................................................... iv Abbreviations .............................................................................................................................. v Table of contents ...................................................................................................................... vii List of Figures .............................................................................................................................xii List of Tables ............................................................................................................................. xiv Chapter 1 .................................................................................................................................... 1 1. Introduction ............................................................................................................................ 2 1.2 Allograft rejection Pathogenesis ...................................................................................... 2 1.2.1 The Major Histocompatibility Complex (MHC) ......................................................... 3 1.2.2 Allorecognition mechanisms by CD4 T cells .............................................................. 9 1.2.3 Cellular-mediated rejection ..................................................................................... 11 1.2.4 Antibody-mediated rejection .................................................................................. 12 1.3 Mechanisms underlying AMR pathogenesis .................................................................. 13 1.3.1 Complement activation ........................................................................................... 14 1.3.2 Endothelial cell activation ....................................................................................... 14 1.3.3 Antibody-dependent cell mediated cytotoxicity (ADCC) ........................................ 15 1.4 Histopathological and Immunopathological features of chronic AMR .......................... 16 1.4.1 Histopathological features of chronic AMR ............................................................ 16 1.4.2 Immunopathological features of AMR .................................................................... 17 1.5 AMR management and therapy ..................................................................................... 20 1.6 Structure and function of secondary lymphoid organs .................................................. 20 1.6.1 Lymph node structure ............................................................................................. 21 vii 1.6.2 Splenic structure ...................................................................................................... 22 1.7 Mechanisms of antibody formation ............................................................................... 24 1.7.1 B cell activation and priming ................................................................................... 24 1.7.2 Extrafollicular humoral response ............................................................................ 27 1.7.3 Germinal centre humoral response ........................................................................ 27 1.7.4 Allogenic B cell activation by unlinked CD4 T cell help ........................................... 33 1.7.5 T-dependent responses and allograft rejection ...................................................... 33 1.7.6 The potential of alloantibody affinity on allograft damage .................................... 35 1.8 Project objectives ........................................................................................................... 36 Chapter 2 .................................................................................................................................. 37 2. Materials and methods......................................................................................................... 37 2.1 Animals ........................................................................................................................... 37 2.2 Animal related techniques ............................................................................................. 40 2.2.1 Skin and heterotopic heart transplantation ............................................................ 40 2.2.1.1 Skin transplantation ............................................................................................. 40 2.2.1.2 Heterotopic heart transplantation ....................................................................... 40 2.2.2 Adoptive cell transfer and immunisation .................................................................... 41 2.2.2.1 Adoptive cell transfer ........................................................................................... 41 2.2.2.2 Immunisation
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