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Clinical and Experimental Studies on the Cellular Mediators of Corneal Allograft Rejection

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Clinical and Experimental Studies on the Cellular Mediators of Corneal Allograft Rejection Clinical and experimental studies on the cellular mediators of corneal allograft rejection by Thomas Henry Flynn A thesis submitted to University College London for the degree of Doctor of Philosophy Department of Ocular Immunology UCL Institute of Ophthalmology Bath Street London May 2010 1 STATEMENT OF ORIGINALITY I, Tom Flynn, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis 2 ACKNOWLEDGEMENTS The work described in this thesis could not have been done without the support of a number of people and organisations and it is a pleasure to thank them now. I would like to thank my supervisors Mr Frank Larkin and Professor Santa J Ono for offering me the opportunity to undertake this work and for their guidance and support throughout my studentship. I am grateful to the special trustees of Moorfields Eye Hospital, Pfizer, The Irish College of Ophthalmologists and Fight for Sight for supporting my research. I would like to thank all of my colleagues in the laboratory but especially Dr Masaharu Ohbayashi for his help with immunohistochemistry and the mouse model of allergic conjunctivitis and Professor Avrion Mitchison for his friendship and guidance during my project. I would like to express my gratitude to my parents for all their support and encouragement over the years. I owe my deepest gratitude to my wife Joanne for her unwavering and unconditional support and patience throughout this project. I dedicate this thesis to her and to our son David. 3 ABSTRACT Despite significant advances in our knowledge of the cellular and molecular elements of transplant immunology the 10 year survival probability for all human corneal grafts is 0.73. In some ―high-risk‖ recipients it is as low as 0.37. To date almost all our knowledge about the cellular events during acute corneal graft rejection comes from animal models. In mice, the presence of pre-existing host corneal vascularisation confers ―high- risk‖ status on a graft and has been shown to accelerate rejection. In the first part of this thesis the effect on survival of grafting to an inflamed conjunctival bed was investigated. Using a mouse model of allergic conjunctivitis significantly reduced survival was seen in graft recipients with perioperative conjunctival inflammation. This appeared to be due to the local effects of conjunctivitis rather than systemic effects of allergy/ atopy. Subsequent experiments investigated the effect of perioperative allergic conjunctivitis on the cellular components of both early (surgical trauma-induced, alloantigen-independent) and late (alloantigen-dependent; rejection) post- keratoplasty anterior segment inflammation and demonstrated significant effects on both. Grafts recipients with allergic conjunctivitis had significantly greater early post-operative corneal inflammation and associated corneal and conjunctival lymphangiogenesis. Analysis of graft infiltrating cells during rejection in mice confirmed that large numbers of CD4+ cells, CD8+ cells and macrophages were recruited. Flow cytometric analysis of human aqueous during acute endothelial rejection demonstrated for the first time the presence of CD4+ cells, CD8+ cells and a surprisingly high proportion of macrophages therein. In mouse recipients with allergic conjunctivitis eosinophils were found in both the graft itself and the ciliary body during rejection although the role of these cells during rejection is uncertain. Chemokine analysis during both murine and human corneal graft rejection demonstrated increased expression of the chemokine IP-10 (CXCL-10) suggesting a potentially important role for this protein in the rejection process. 4 TABLE OF CONTENTS Title……………………………………………………………………………………….1 Statement of originality…………………………………………………………………2 Acknowledgements……………………………………………………………………..3 Abstract…………………………………………………………………………………..4 Table of contents………………………………………………………………………..5 List of figures…………………………………………………………………………...16 List of tables………………………………………………………………………...….20 Abbreviations……………………………………………….....……………………….22 5 CHAPTER 1: General Introduction .................................................................. 25 1.1. CORNEAL ANATOMY AND PHYSIOLOGY ......................................... 26 1.1.1. Anatomy ........................................................................................ 26 1.1.2. Corneal function ............................................................................ 26 1.1.3. Endothelium .................................................................................. 27 1.2. PENETRATING KERATOPLASTY ....................................................... 28 1.2.1. Penetrating Keratoplasty: Epidemiology ....................................... 28 1.2.2. Penetrating Keratoplasty: Indications ........................................... 28 1.2.3. Penetrating Keratoplasty: Survival ................................................ 29 1.3. CLINICAL FEATURES OF CORNEAL GRAFT REJECTION ............... 30 1.3.1. Epithelial Rejection ........................................................................ 30 1.3.2. Stromal Rejection .......................................................................... 31 1.3.3. Endothelial rejection ...................................................................... 31 1.4. INNATE IMMUNITY .............................................................................. 32 1.4.1. Barrier function .............................................................................. 32 1.4.2. Cellular mediators .......................................................................... 33 1.4.3. Humoral mediators ........................................................................ 34 1.5. ACQUIRED IMMUNITY ........................................................................ 34 1.5.1. Cellular mediators .......................................................................... 34 1.5.2. Humoral mediators ........................................................................ 35 1.5.3. Major Histocompatibility Complex .................................................. 35 1.5.4. T cell tolerance .............................................................................. 37 1.6. IMMUNOBIOLOGY OF CORNEAL ALLOGRAFT REJECTION ........... 38 1.6.1. Genes v Environment .................................................................... 38 1.6.2. Surgical trauma and the innate response ...................................... 40 1.6.3. Sensitisation .................................................................................. 42 1.6.4. Clonal expansion ........................................................................... 45 1.6.5. Effector Mechanisms: Lymphocytes .............................................. 46 1.6.6. Effector Mechanisms: TH1/Th2 balance ........................................ 49 1.6.7. Effector Mechanisms: Eosinophils ................................................. 54 1.6.8. Effector Mechanisms: Monocyte/macrophage ............................... 56 6 1.6.9. Effector Mechanisms: Natural Killer cell ........................................ 56 1.7. CORNEAL IMMUNE PRIVILEGE ......................................................... 57 1.7.1. Clinical tolerance v immunological tolerance ................................. 57 1.7.2. Avascularity of the cornea ............................................................. 58 1.7.3. Lack of mature APCs ..................................................................... 58 1.7.4. Low MHC expression .................................................................... 60 1.7.5. Blood aqueous barrier ................................................................... 60 1.7.6. Immunosuppresive factors in aqueous humour ............................. 60 1.7.7. ACAID ........................................................................................... 61 1.8. CORNEAL TRANSPLANTATION IN SETTINGS CONFERRING HIGH REJECTION RISK .............................................................................................. 61 1.9. TREATMENT OF ESTABLISHED REJECTION ................................... 65 1.10. PREVENTION OF REJECTION ........................................................... 66 1.11. CHEMOKINES AND THEIR RECEPTORS .......................................... 67 1.11.1. Chemokine biology ........................................................................ 67 1.11.2. Chemokine and chemokine receptor expression in vascularised organ transplantation ....................................................................................... 72 1.11.3. Chemokine and chemokine receptor expression in corneal transplantation ................................................................................................. 73 1.11.4. Chemokines and APCs ................................................................. 75 1.11.5. Chemokines as therapeutic targets in transplantation ................... 77 1.12. LYMPHANGIOGENESIS ...................................................................... 78 1.12.1. History ........................................................................................... 78 1.12.2. Vascular Endothelial Growth Factor .............................................. 83 1.12.3. Corneal lymphangiogenesis .......................................................... 84 1.13. ALLERGIC CONJUNCTIVITIS ............................................................. 86 1.13.1. Atopy ............................................................................................
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