The Immunomodulatory Effects of Arsenic Trioxide in Autoimmunity and Alloreactivity Yishan Ye To cite this version: Yishan Ye. The Immunomodulatory Effects of Arsenic Trioxide in Autoimmunity and Alloreactivity. Immunology. Sorbonne Université, 2019. English. NNT : 2019SORUS426. tel-03233559 HAL Id: tel-03233559 https://tel.archives-ouvertes.fr/tel-03233559 Submitted on 25 May 2021 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. Sorbonne Université Ecole doctorale 394: Physiologie, Physiopathologie et Thérapeutique Centre de recherche Saint Antoine / Equipe Mohty The Immunomodulatory Effects of Arsenic Trioxide in Autoimmunity and Alloreactivity Par Yishan YE Thèsededoctoratdebiologie Spécialité : Immunologie Dirigée par Mohamad Mohty Présentée et soutenue publiquement le 23 Mai 2019 Devant un jury composé de : AUCOUTURIER Pierre, PU-PH, Président du Jury BAZARBACHI Ali, Professeur, Rapporteur SAAS Philippe, Professeur, Rapporteur HERMINE Olivier, PU-PH, Examinateur MALARD Florent, MCU-PH, Co-directeur de thèse MOHTY Mohamad, PU-PH, Directeur de thèse 1 Acknowledgments First I would like to thank the jury members, Professor Pierre Aucouturier, Professor Ali Bazarbachi, Professor Philippe Saas, Professor Olivier Hermine for having accepted to evaluate my work. I can still remember the day in 2014 when I asked my distinguished guest from France, the president of the European Society for Blood and Marrow Transplantation, to write me a recommendation letter for a future PhD. The answer was ‘Perhaps you can come to my lab’, which opened the door to a long and fascinating journey. To Professor Mohty, despite tons of work that you are dealing with on a daily basis, you are always the first to respond to my requirements, and the first to congratulate me when something good happens. Your global vision, leadership nature, passion towards work, great care and patience for me make you a role model that I will always follow. Thank you Professor Mohty, with my greatest appreciation. To Dr. Florent Malard, you are really the most outstanding young physician scientist that I have ever had the privilege to meet. You are in charge of all the detailsofmy project, and always help me make correct choice when problem happens. It is my honor to have you, a man with sharp mind, accurate choice, impartial judgement as my co-director. Thank you Florent. To Dr. Béatrice Gaugler, you were the first person who gave me greetings during my first visit to the hospital, the moment that I will always remember. As the scientific leader of the lab, you offered me the first idea for my project, and later became the main body of this thesis. I can’t finish this thesis without the ideas, and the continuous and unselfish intellectual supports from you. Thank you Béatrice. To Dr. Laure Ricard and Dr. Nicolas Stocker, my greatest colleagues, for fighting together, for creating a really welcoming and harmonious atmosphere, for helping and encouraging me during the hard time of research. Thank you! To Prof. Arsène 2 Mekinian, for great support on the clinical samples and suggestions offered during my PhD study. Thank you! To Dr. Lama Siblany, an excellent start and I am sure that you will do great academic work in the near future. Good luck! Nevertherless, toDr. Charlotte Laurent, Mr. Maxime Tenon, Mr. Christophe de Vassoigne, and all the other people that I have had the chance to meet in the lab, thank you so much. To Dr. Baptiste Lamarthée, Mr. Frédéric de Vassoigne, and Dr. Ruoping Tang, you were the first who offered me, a nervous foreigner without any lab techniques, the warmest welcome and the orientation courses with great patience. Thank youso much. It is impossible to list all the people who have helped and supported me during the three years. France has become so warm and lovely because of you. To Prof. He Huang and all the colleagues in Hangzhou, for offering me the best clinical training, and continuous care during my PhD study. Thank you. To China Scholarship Council for the financial support. Finally, I would like to extend my most sincere thanks to my parents, my girlfriend, my friends, and all the other people who cared and supported me continuously, far away in China. Love you forever, and see you soon. 3 List of abbreviations ABT-199: chemical name of venetoclax G-CSF: granulocyte-colony stimulating aGVHD: acute graft-versus-host disease factor AHR: airway hyperresponsiveness GM-CSF: granulocyte-macrophage AP3: adapter protein-3 colony-stimulating factor APCs: antigen presenting cells GRFS: GVHD-free/relapse-free survival APL: acute promyelocytic leukemia GVHD: graft-versus-host disease As(III): trivalent arsenicals GVL: graft-versus-leukemia As2O3: arsenic trioxide H2O2: hydrogen peroxide ATG: antithymocyte globulin HEVs: high endothelial venules ATL: adult T-cell leukemia/lymphoma HLA: human leukocyte antigen ATRA: all-trans retinoic acid HMGB1: high mobility group box 1 BALF: broncho-alveolar lavage fluid HSC: hematopoietic stem cell BST2: bone marrow stromal antigen 2 HCT: hematopoietic cell transplantation BU: busulfan iAs: inorganic arsenic compounds cDC: conventional dendritic cell IBD: inflammatory bowel disease CDP: common DC progenitor ID2: Inhibitor Of DNA Binding 2 cGAMP: cyclic guanosine IDO: indoleamine 2,3-dioxygenase monophosphate-adenosine IFNAR: IFN-I receptor monophosphate IFN-I: type-I interferons CLP: common lymphoid precursor IKK: IĸB kinase CMP: common myeloid precursor IRF7: interferon regulatory factor 7 CNI: calcineurin inhibitor LAK: lymphokine activated killer CpG-ODN: CpG LAP: LC3-associated phagocytosis oligodeoxyribonucleotides LC3: microtubule-associated protein CsA: cyclosporine 1A/1B-light chain 3 G-CSF: granulocyte-colony stimulating LFA-1: Lymphocyte function-associated factor antigen 1 M-CSFR: macrophage Lin: lineage markers colony-stimulating factor receptor LMPP: lymphoid-primed multi-potent CX3CR1: CX3C chemokine receptor 1 progenitor CY: cyclophosphomide LP: lymphoid precursor DAMPs: damage-associated molecular LPS: lipopolysaccharide patterns MA: myeloablative DC: dendritic cell mAb: monoclonal antibodies EC50: half maximal effective MAPKs: mitogen-activated protein concentration kinases ER: endoplasmic reticulum MCMV: mouse cytomegalovirus FKBP12: FK506-binding protein 12 MDDC: monocyte derived dendritic cell Flt3L: Fms-like tyrosine kinase 3 ligand MDP: macrophage and DC precursor GC: glucocorticoid MHC: major histocompatibility complex GI: gastrointestinal tract miHA: minor histocompatibility antigen 4 miRNA: microRNA STAT3: signal transducer and activator MM: multiple myeloma of transcription 3 MMF: mycophenolate mofetil Syk: spleen tyrosine kinase MP: myeloid precursor TBI: total body irradiation mRNA: messenger RNA TCF4: transcription factor 4 mTOR: mammalian target of rapamycin Th: T helper cell MTX: methotrexate TLR: toll-like receptor MYD88: myeloid differentiation TNF: tumor necrosis factor primary response protein 88 Treg: regulatory T cell NaAsO2: sodium arsenite UPR: unfolded protein response NADPH: nicotinamide adenine dinucleotide phosphate NBs: nuclear bodies NETs: neutrophil extracellular traps Nf-κB: nuclear factor-κB NK cell: natural killer cell NOD: non-obese diabetic Nrf2: nuclear factor erythroid 2-related factor 2 NRM: non-relapse mortality PAMPs: pathogen-associated molecular patterns PBMC: peripheral blood mononuclear cell pDC: plasmacytoid dendritic cell PML: promyelocytic leukemia PTCy: posttransplantation cyclophosphomide RA: rheumatoid arthritis RARE: retinoic acid response elements RARα: retinoic acid receptor-α RIC: reduced-intensity conditioning RNS: reactive nitrogen species ROR: retinoic-related orphan receptor ROS: reactive oxygen species RXR: retinoid X receptor Sca-1: stem cells antigen-1 Siglec-H: sialic acid-binding immunoglobulin-like lectin H SLE: systemic lupus erythematosus SPF: specific pathogen-free SSc: systemic sclerosis 5 List of Figures Figure 1 . Reaction of vicinal sulfhydryl groups in a protein structure with trivalent arsenic (Emadi et al., Blood Rev, 2010)...............................................................10 Figure 2 . Dual targeting of PML-RARα and PML by As2O3 lead to APL cell differentiation and loss of self-renewal (de Thé., Nat Rev Cancer, 2018) .........11 Figure 3 . Diverse functions of As(III) on immune cells............................................. 15 Figure 4 . Mechanisms of action: As2O3 effects on CD4+ T cell............................... 20 Figure 5 . The proposed spectrum between pDC and cDC (Reizis, Immunity, 2019) 30 Figure 6 . Possible pathways of plasmacytoid dendritic cell development (modified from Shortman et al, Adv Immunol, 2013)..........................................................34 Figure 7 . Factors involved in pDC trafficking (modified from Swiecki et al,NatRev Immunol, 2015)....................................................................................................36 Figure 8 . TLR9 signaling (Swiecki et al, Nat Rev Immunol, 2015)........................... 40 Figure 9 . Cell-intrinsic and cooperative sensing