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Membrane Attack and Therapy in Autoimmune Disease: Modulating Pathology Whilst Retaining Physiology Membrane attack and therapy in autoimmune disease: modulating pathology whilst retaining physiology By Marieta Milkova Ruseva A thesis submitted to Cardiff University in Candidature for the Degree of Doctor of Philosophy. Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff Wales, United Kingdom December 2010 UMI Number: U564B00 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U564300 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 DECLARATION This work has not previously been accepted in substance for any degree and is not concurrently submitted in candidature for any degree. Signed... Date JS,. 93; M i / ........... STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of PhD. Signed .. Date . l . i .......... STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. Signed .. Date . Q??:pU?.. i i ............. STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed ............................................................. Date........................................ STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loans after expiry of a bar on access previously approved by the Graduate Development Committee. Signed ............................................................. Date........................................ 2 Acknowledgments This thesis would not have been possible without the guidance and the help of several individuals who in one way or another contributed and extended their valuable assistance in the preparation and completion of this study. First and foremost, my utmost gratitude to my supervisor, Dr. Claire Harris, whose sincerity and encouragement I will never forget. Her truly scientist intuition and passion of science exceptionally inspire and enrich my growth as a researcher and scientist. I am heartily thankful to Professor Paul Morgan, whose guidance and support from the initial to the final level enabled me to develop an understanding of the Complement. I offer my regards and blessings to all of those who supported me in any respect during the completion of the project. My special thanks go to Danielle Paixao-Cavalcante, Meike Heurich, Ruth Lewis and James Hindley for their friendship and help. I convey special acknowledgement to Dr. Tim Hughes for his help with the model of atherosclerosis. Words fail me to express my appreciation to Martin for his dedication, love and persistent confidence in me. I dedicate this thesis to you, Martin! Where would I be without my family? My Mum, Dad and Ivo deserve special mention for their inseparable support. Finally, I would like to thank everybody who was important to the successful realization of thesis, as well as expressing my apology that I could not mention personally one by one. 3 Summary The complement system is implicated in a number of diseases where it exacerbates or triggers pathology. The majority of the anti-complement agents inhibit systemically, risking infection and immune complex disease with long-term use in humans. Many of these have a short half-lifein vivo, necessitating repetitive administration. To overcome these limitations, two types of reagents were generated. Both target late stages of complement activation, preventing membrane attack complex (MAC) formation, which is implicated in many diseases. The saliva of the soft tick, Ornithodoros moubata, contains a powerful complement inhibitor (OmCI) which has been developed by others for therapy. Recombinant OmCI rapidly binds circulating C5 when given to animals, completely inhibiting complement. However, excess agent is excreted within minutes, making long-term therapy with this agent problematic. To overcome this, I fused OmCI to the Fc domain of murine IgG2a, generating OmCI-Fc, an anti-complement therapeutic with extended in vivo half-life. OmCI-Fc efficiently inhibited the terminal pathway in vitro and, by binding C5 following resynthesis, also provided prolonged inhibition in vivo. A second group of agents comprised CD59, a powerful MAC inhibitor, and the murine complement receptor of the immunoglobulin superfamily (CRIg). CRIg binds complement activation fragments, thus has potential to deliver therapy directly to tissues attacked by complement. An antibody hinge domain was engineered between the two moieties in CD59-CRIg to promote dimerisation and increase avidity for target tissue. The dimeric agent localised efficiently to the surface of complement-attacked cells in vitro and specifically targeted diseased tissue ex vivo. I have created novel anti-complement reagents designed to deliver effective therapy locally, or where inhibition is long-term, to target only the terminal stages of complement. These agents have exciting potential to effectively treat complement-mediated diseases and to retain other crucial biological functions of complement such as opsonisation and immune complex solubilisation. 4 Abbreviations Ab: Antibody AChR: Acetylcholine receptor ADEAE: Antibody-dependent experimental autoimmune encephalomyelitis ADP: Adenosine-5 '-diphosphate aHUS: Atypical haemolytic uremic syndrome AIA: Antigen-induced arthritis AMD: Age-related macular degeneration AP: Alternative pathway ApoE: Apolipoprotein E (main apoprotein of the chylomicron) ATP: Adenosine-5 '-triphosphate BBB: Blood brain barrier BSA: Bovine serum albumin C4bp: C4b-binding protein CAIA: Anti-collagen type II Ab transfer cDNA: Complementary deoxyribonucleic acid CDRs: Complementarity determining regions CFA: Complete Freund's adjuvant CFD: Complement fixation diluent CHO: Chinese hamster ovary cells CIA: Collagen type II-induced arthritis CNS: Central nervous system CNV: Choroidal neovascularisation CPB: Cardiopulmonary bypass CP: Classical pathway CR: Complement receptor CRIg: Complement receptor of the immunoglobulin superfamily CRP: C-reactive protein Crry: Complement receptor 1-related/gene protein y CSF: Cerebrospinal fluid CVF: Cobra venom factor DAF: Decay accelerating factor 5 DAPI: Diamidino-2-phenylindole DDD: Dense deposit disease DMSO: Dimethylsulphoxide DNA: Deoxyribonucleic acid dNTP: Deoxynucleotidetriphosphates DTT: Dithiothreitol EAE: Experimental autoimmune encephalomyelitis EArb: Antibody-sensitised rabbit erythrocytes EAsh: Antibody-sensitised sheep erythrocytes EDTA: Ethylene diamine tetraacetic acid EGTA: Ethylene glycol tetraacetic acid ELISA: Enzyme-linked immunosorbent assay Epo: Erythropoetin Fc: Fragment crystallisable FcR: Fc receptor FCS: Foetal calf serum FDC: Follicular dendritic cells fH: Factor H fHL: Factor H-like protein fHR: Factor H-related protein GPE: Guinea pig erythrocytes GPI: Glycosylphosphatidylinositol HAT: Hypoxanthine, aminopterin and thymidine HEPES: 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid HRPO: Horseradish peroxidase HRV: Human rhinovirus HT: Hypoxanthine and thymidine i.n.\ Intranasal IC: Immune complex IFA: Incomplete Freund's adjuvant ip: Intraperitoneal IR Ischaemia reperfusion iv: Intravenous Kd: Equilibrium dissociation constant LB: Lauria-Bertani LDL: Low-density lipoprotein LHR: Long homologous repeats LP: Lectin pathway LPS: Lipopolysaccharide mAb: Monoclonal antibody MAC: Membrane attack complex MASPs: Mannan binding lectin-associated serine proteases MBL: Mannan binding lectin MCP: Membrane cofactor protein MPGN: Membranoproliferative glomerulonephritis MS: Multiple sclerosis OCT: Optimum cutting temperature compound OmCI: Omithodores moubata Complement Inhibitor OPD: O-Phenylenediamine dihydrochloride pAb: Polyclonal antibody PBS: Phosphate buffered saline PCR: Polymerase chain reaction PEG: Polyethylene glycol PE: Phycoerythrin PNH: Paroxysmal nocturnal haemoglobinuria PS: ProteinS PTEC: Proximal tubule epithelial cells RA: Rheumatoid arthritis RCA: Regulators of complement activation rMOG: Recombinant myelin oligodendrocyte glycoprotein RNA: Ribonucleic acid RPMI-1640: Roswell Park Memorial Institute 1640 RU: Resonance unit SAP: Serum amyloid protein SAP: Shrimp alkaline phosphatase SCR: Short consensus repeat sCRl: Soluble complement receptor 1 sc: Subcutaneous SDS PAGE: Sodium dodecyl sulphate polyacrylamide gel electrophoresis SDS: Sodium dodecyl sulphate Serpin: Serine protease inhibitor SLE: Systemic lupus erythematosus SPR: Surface plasmon resonance TBS: Tris buffered saline TfR: Transferrin receptor 1 THP: Tris (hydroxypropyl) phosphine v/v: Volume to volume VSIG4: V-set and Ig domain-containing 4 w/v: Weight to volume Table of contents Chapter 1. Introduction ..........................................................................................................15 1.1. The Complement system.............................................................................................15
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