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Hematopoietic Progenitor Populations for Cell Therapy of Autoimmune Hematopoietic progenitor populations for cell therapy of autoimmune diseases : characterization and comparison of their mechanism of action in Type I Diabetes and Experimental Autoimmune Encephalomyelitis Sarantis Korniotis To cite this version: Sarantis Korniotis. Hematopoietic progenitor populations for cell therapy of autoimmune diseases : characterization and comparison of their mechanism of action in Type I Diabetes and Experimental Autoimmune Encephalomyelitis. Immunology. Université René Descartes - Paris V, 2014. English. NNT : 2014PA05T015. tel-01236622 HAL Id: tel-01236622 https://tel.archives-ouvertes.fr/tel-01236622 Submitted on 2 Dec 2015 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. KORNIOTIS Sarantis – Thèse de doctorat - 2014 Université Paris Descartes Ecole Doctorale Génétique Cellules Immunologie Infectiologie Développement Institut Necker Enfants Malades INSERM U1151 CNRS 8253 Hematopoietic progenitor populations for cell therapy of autoimmune diseases : Characterization and comparison of their mechanism of action in Type I Diabetes and Experimental Autoimmune Encephalomyelitis Sarantis KORNIOTIS Thèse de doctorat d’Immunologie Dirigée par Dr. Flora ZAVALA Présentée et soutenue publiquement le 24 Juin 2014 Devant un jury composé de : Pr. Pierre-Olivier COURAUD Président du Jury Dr. Sophie BROUARD Rapporteur Dr. Abdelhadi SAOUDI Rapporteur Dr. Simon FILLATREAU Examinateur Dr. José COHEN Examinateur Dr. Flora ZAVALA Directeur de thèse 1 KORNIOTIS Sarantis – Thèse de doctorat - 2014 Acknowledgements This thesis was carried out within the team of Dr. ZAVALA Flora in ‘Hopital Necker Enfants Malades’ and Institut Necker at the previous scientific unit of CNRS UMR8147 and more recently in the unit of Physiology and differentiation of T lymphocytes, under the direction of Dr. EZINE Sophie and Dr. ROCHA Benedita. It was funded by DIM Stem Pole-Region Ile de France and ARSEP. My sincere regards to Dr. ZAVALA Flora for receiving me in her team, for giving me the opportunity to start a beautiful thesis, for her confidence and support, availability and coaching. It is with her presence and encouragement that I could achieve my goals. I thank her for letting me share her scientific knowledge. Her remarks, requirements and guidance helped me to improve my work. She always gave me the right conditions for the realization of my thesis. I am very grateful to her for the international conferences and trips abroad in which I participated. Flora was more than an example for me with all her passion and enthusiasm for research. She taught me to believe in my abilities and give the best to myself. She will be always my scientific mentor. In addition to that, I feel lucky to work with a good-manered person who was close to me not only scientifically but also as an original human. Thank you for all the moments we shared together all these four years. I would like to thank all the members of the jury who have agreed to judge my thesis: Sophie Brouard, Abdelhadi Saoudi, Simon Fillatreau, Jose Cohen and Pierre-Olivier Couraud. In particular, I thank Sophie Brouard and Abdelhadi Saoudi who gave me the honour to be the reporters of my thesis. My thanks to Sophie Ezine for being always willing to discuss and to help me in every step of my PhD. I thank all my colleagues for their support and good humor, for our fruitful discussions and for the happy times we shared during these four years. In particular, Sophia, Irini, Mira, Ruddy, Esther, Christophe, Alicia, Helene, Emmanuelle, Chantal, Myriam, Rasha, Karim, Francine and Benedicte. Many thanks to all my friends that have aroused in me the perseverance necessary to enable the completion of my thesis. Thank you for being an important part of my life for these 4 years in Paris. In particular: Alexandros, Vasilis, Alexandra, Katerina, Joanna, Tassos, Danai, Marialena, Myrto, Venia, Kostas, Kiki, Antonis, Marina, Maya, Agni, Faidonas, Stavros and Daphni. I would like also to express my sincere thanks to all my friends in Greece, either in Athens or in my homeland, Lemnos. My thanks to : Thanasis, Lena, Konstantinos, Michalis, Nikos, Aggelos, Giota, Eleni, Dimitra, Pantelis and Roula. My special thanks to : Elisavet Fotiadou and Roe Moschoudi. This work is dedicated to my family, to my dear parents Nikos and Stavroula, my dear brother Dimitris and my dear aunt Victoria. I do not know if just a thank is enough in order to express my love for you. What I know is that, without you, I would not be here. Paris, thank you for making me live a dream. ‘’Life is a continuous ascent to higher and higher removable peaks together with the ecstatic but painful knowledge that there are no extreme peaks’’ (Nikos Kazantzakis) 2 KORNIOTIS Sarantis – Thèse de doctorat - 2014 TABLE OF CONTENTS Abbreviations.........................................................................................................................................8 Introduction...........................................................................................................................................12 Chapter I: Hematopoiesis ....................................................................................................................... 12 I-1 Normal Hematopoiesis ................................................................................................................. 12 I-1-1 Hematopoietic Stem Cells (HSCs) ....................................................................................... 12 I-1-2 Multipotent Progenitors (MPPs) ........................................................................................... 16 I-1-3 Development of B lymphocytes ........................................................................................... 18 A) Early B cell development .................................................................................................. 18 B) Migration of B cells from the bone marrow to the secondary lymphoid organs ............... 20 C) B cell maturation ............................................................................................................... 20 D) Other important markers of B cells ................................................................................... 21 E) Main Subtypes of B cells ................................................................................................... 22 E1) B-1 cells .......................................................................................................................... 22 E2) Follicular B cells ............................................................................................................ 23 E3) Transitional B cells ......................................................................................................... 25 E4) Marginal Zone B cells .................................................................................................... 25 E5) Memory B cells .............................................................................................................. 26 E6) Plasma Cells ................................................................................................................... 27 I-1-4 Regulation of Hematopoiesis ................................................................................................ 27 A) Hematopoeitic stem cell niches ............................................................................................ 27 A1) Role of c-kit and CXCL12 ............................................................................................. 28 A2) Hypoxia and the stem cell niche .................................................................................... 29 A3) Osteolineage cells .......................................................................................................... 30 A4) The role of N-cadherin in the stem cell niche ................................................................ 30 A5) Other cells and factors involved in HSC maintenance .................................................. 31 3 KORNIOTIS Sarantis – Thèse de doctorat - 2014 I-1-5 Influence of Infections – Adaptive Hematopoiesis ............................................................... 32 A1) Role of cytokines produced during an infection ................................................................ 32 A2) Effector functions of hematopoietic stem and/or progenitor cells ..................................... 34 Α3) Regulatory hematopoietic stem and/or progenitor cells ..................................................... 34 Ι-2 Toll Like receptors ....................................................................................................................... 37 Ι-2-1 Toll-like Receptors – General ............................................................................................... 37 I-2-2 Types of TLRs and their ligands ........................................................................................... 38 A) TLRs of cell surface ............................................................................................................
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