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The Contribution of T Cell-Derived Cytokines and Proteases to Chronic Inflammation in the Human Intestine

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The Contribution of T Cell-Derived Cytokines and Proteases to Chronic Inflammation in the Human Intestine The contribution of T cell-derived cytokines and proteases to chronic inflammation in the human intestine by Paolo Biancheri A thesis submitted for the Degree of Doctor of Philosophy Supervisor: Prof Thomas T MacDonald Second supervisor: Prof Andrew Silver Queen Mary University of London Barts and The London School of Medicine and Dentistry London - United Kingdom 2016 This work is dedicated to the memory of my grandparents Margherita, Luigi, Bianca, and Paolo 2 Statement of originality I, Paolo Biancheri, confirm that the research included within this thesis is my own work or that, where it has been carried out in collaboration with, or supported by others, this is duly acknowledged below and my contribution indicated. Previously published material is also acknowledged below. I attest that I have exercised reasonable care to ensure that the work is original, and does not to the best of my knowledge break any UK law, infringe any third party’s copyright or other Intellectual Property Right, or contain any confidential material. I accept that the College has the right to use plagiarism detection software to check the electronic version of the thesis. I confirm that this thesis has not been previously submitted for the award of a degree by this or any other university. The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author. Signature: Date: 28.02.2016 Details of collaboration I declare that the work presented in this thesis is my own, with the exception of some of the experiments reported in Chapters 3, 4 and 6, which, upon obtaining approval from the owners of the data, have been included in this thesis and have been listed in the Note at the beginning of the Chapters. 3 Details of publications – Original papers Biancheri P, Pender SL, Ammoscato F, Giuffrida P, Sampietro G, Ardizzone S, Ghanbari A, Curciarello R, Pasini A, Monteleone G, Corazza GR, Macdonald TT, Di Sabatino A. The role of interleukin 17 in Crohn's disease-associated intestinal fibrosis. Fibrogenesis Tissue Repair 2013;6:13. Biancheri P, Di Sabatino A, Ammoscato F, Facciotti F, Caprioli F, Curciarello R, Hoque SS, Ghanbari A, Joe-Njoku I, Giuffrida P, Rovedatti L, Geginat J, Corazza GR, Macdonald TT. Absence of a role for interleukin-13 in inflammatory bowel disease. Eur J Immunol 2014;44:370-85. Biancheri P, Brezski RJ, Di Sabatino A, Greenplate AR, Soring KL, Corazza GR, Kok KB, Rovedatti L, Vossenkämper A, Ahmad N, Snoek SA, Vermeire S, Rutgeerts P, Jordan RE, MacDonald TT. Proteolytic Cleavage and Loss of Function of Biologic Agents that Neutralize Tumor Necrosis Factor in the Mucosa of Patients with Inflammatory Bowel Disease. Gastroenterology 2015;149:1564- 74. Blaydon DC, Biancheri P, Di WL, Plagnol V, Cabral RM, Brooke MA, van Heel DA, Ruschendorf F, Toynbee M, Walne A, O'Toole EA, Martin JE, Lindley K, Vulliamy T, Abrams DJ, MacDonald TT, Harper JI, Kelsell DP. Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med 2011;365:1502-8. Details of publications – Review papers Di Sabatino A, Biancheri P, Rovedatti L, Macdonald TT, Corazza GR. Recent advances in understanding ulcerative colitis. Intern Emerg Med 2012;7:103-11. Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev 2014;13:3-10. Di Sabatino A, Biancheri P, Rovedatti L, Macdonald TT, Corazza GR. New pathogenic paradigms in inflammatory bowel disease. Inflamm Bowel Dis 2012;18:368-71. Biancheri P, Di Sabatino A, Corazza GR, MacDonald TT. Proteases and the gut barrier. Cell Tissue Res 2013;351:269-80. Biancheri P, Giuffrida P, MacDonald TT. Proteases and small intestinal barrier function in health and disease. Curr Opin Gastroenterol 2014;30:147-53. 4 Biancheri P, Giuffrida P, Docena G, MacDonald TT, Corazza GR, Di Sabatino A. The role of transforming growth factor (TGF)- in modulating the immune response and fibrogenesis in the gut. Cytokine Growth Factor Rev 2014;25:45-55. Biancheri P, Powell N, Monteleone G, Lord G, MacDonald TT. The challenges of stratifying patients for trials in inflammatory bowel disease. Trends Immunol 2013;34:564-71. 5 Details of presentations Biancheri P, Di Sabatino A, Ammoscato F, Giuffrida P, Salvatore C, Guerci M, Massari A, MacDonald TT, Corazza GR. Interleukin-17A but not interleukin-17E is profibrotic in the gut of patients with Crohn’s disease. Gut 2012;61(Suppl.3):A156. Biancheri P, Joe-Njoku I, Rovedatti L, Vossenkaemper A, Di Sabatino A, Corazza GR, MacDonald TT. Is Ulcerative Colitis an Atypical Th2-mediated Disease Characterised by Excess Production of IL-13? “15th International Congress of Mucosal Immunology (ICMI 2011)”, Paris, France, July 05-09, 2011, Abstract Supplement:107. Biancheri P, Ammoscato F, Di Sabatino A, Joe-Njoku I, Rovedatti L, Corazza GR, MacDonald TT. Does interleukin (IL)-13 have a role in sustaining the mucosal pro-inflammatory immune response in ulcerative colitis and in promoting intestinal fibrogenesis in Crohn’s disease? Gastroenterology 2012;142(Suppl.1):S872. Biancheri P, Di Sabatino A, Rovedatti L, Ahmad N, Corazza GR, MacDonald TT. Differential Degradation of Anti-Tumor Necrosis Factor- Agents by Matrix Metalloproteinase-12 in Inflammatory Bowel Disease. Gastroenterology 2010;138(Suppl.1):S422. Biancheri P, Di Sabatino A, Snoek S, Joe-Njoku I, Rovedatti L, Ahmad N, Corazza GR, MacDonald TT. Differential Degradation of Anti-tumor Necrosis Factor-alpha Agents by Matrix Metalloproteinase (MMP)-3 and MMP-12 in Inflammatory Bowel Disease (IBD). “15th International Congress of Mucosal Immunology (ICMI 2011)”, Paris, France, July 05-09, 2011, Abstract Supplement:112. 6 Abstract This Thesis explores aspects of disease pathogenesis in Crohn’s disease (CD) and ulcerative colitis (UC), investigates mechanisms of responsiveness to biologic treatment in inflammatory bowel disease (IBD), and describes the clinical and immunologic phenotype associated with a homozygous deletion in a disintegrin and a metalloproteinase (ADAM)17 gene. The role of interleukin (IL)-17A, IL-17E and IL-13 in human intestinal inflammation is not clear. IL-13 plays an important role in experimental colitis and in intestinal experimental fibrosis. However, contrasting observations exist on the levels and the role of IL-13 in inflamed IBD mucosa, and limited information is available on the role of IL-13 in CD intestinal fibrosis. We observed that IL-13 is not up-regulated in UC intestinal mucosa, and that it is unlikely to play a functional role in the mucosal pro-inflammatory response in the majority of patients with UC. Conversely, IL-17A is up-regulated in fibrostenosing CD intestine, and may contribute to intestinal fibrosis in CD. Our results indicate that IL-17E and IL-13 are not up-regulated in CD intestinal strictures, and are unlikely to play a role in intestinal fibrosis in CD. A considerable proportion of IBD patients do not respond to anti-tumour necrosis factor (TNF)- agents. Anti-TNF- agents exert their action in inflamed tissues, rich in matrix metalloproteinase (MMP)-3 and MMP-12, which in turn can degrade immunoglobulin (Ig)G1. We observed that MMP-3, MMP-12, and protein extracts from inflamed IBD mucosa, but not MMP-9, degrade the anti-TNF- agents infliximab, adalimumab and etanercept, however etanercept shows a higher susceptibility than infliximab and adalimumab. We also observed that a subgroup of IBD patients who did not respond to anti-TNF- agents have particularly high serum levels of MMP-3-/MMP-12-cleaved endogenous IgG and anti-hinge autoantibodies compared to IBD patients who subsequently responded to biologic therapy. 7 Finally, we observed that homozygous deletion in ADAM17 in humans is associated with a complex, neonatal-onset, multi-organ syndrome affecting mainly the skin, the intestine, and the cardiovascular system. In this condition, ADAM17 expression is down-regulated in the skin and in the duodenum, and soluble TNF- release by peripheral blood mononuclear cells (PBMCs) is substantially impaired. These results underline the heterogeneity characterising chronic intestinal inflammation, and may form the basis for subsequent studies with the aim to identify accurate serum biomarkers of disease progression and responsiveness to biologic therapy, and ultimately to develop effective strategies of patient stratification in IBD. 8 Acknowledgements First and foremost I would like to thank Prof Tom MacDonald for giving me the opportunity to do research in his lab and for supervising me during the PhD. His enthusiasm and guidance have been an invaluable source of motivation and support for me. I am deeply grateful to Prof Gino R Corazza and Dr Antonio Di Sabatino for their supervision during my clinical training in Pavia and for allowing me to undertake my research experience in London. I would like to thank Prof Andy Silver, who first encouraged me to start the PhD, and Prof Dan Pennington, who has been a precious advisor on both scientific and non-scientific questions. I am grateful to Prof Alastair Watson and Prof Alastair Forbes for their helpful feedback during the revision of the Thesis. I would like to express my appreciation and thanks to Dr Cinzia Papadia for her patience and continuous guidance in teaching me clinical skills and for her positive and cheerful attitude. I am grateful to Dr Claire Walshe and Dr Steve Webber from Topivert for supporting my research activity during the PhD. I would like to thank Prof David P Kelsell for allowing me to study the immunologic consequences of the ADAM17 mutation described in this thesis, and Dr Federica Facciotti for her help on the project about IL-13 in IBD. I would like to thank Dr Eleanor Wood, Dr Laura Marelli, Dr Nora Thoua and Joy Sadeghian for their help and advice during my time at the Homerton Hospital.
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