Organization

Director : Pr. Christian JORGENSEN

Office Phone : 04 67 33 06 88

Presentation of Team 2

Senior Scientists

 JM LEMAITRE (Head, DR2 INSERM), O MILHAVET (CR1 CNRS), F PELLESTOR (MCU/PH UM1),  T COMMES (PU UM2), N GILBERT (CR1 CNRS), A BOURREUX (MCU UM2), V. GATINOIS (AHU CHU),

Scientific project

The global project of the team is to explore basic genetic and epigenetic mechanisms underlying tissue regeneration, a process that takes place from early development through the entire lifetime and decreasing in the elderly. We aim to unravel and to manipulate age-related molecular pathways for efficient somatic cell reprogramming and to apply this knowledge to improve tissue regeneration in chronic and aged related diseases, which is a major objective of regenerative medicine.

Objectives of Team 2

• We aim to further understand the links between genomic stress, senescence and genomic instability which is a major hurdle to solve for the development of cell therapy as well as to validate an optimal reprogramming strategy so far demonstrated to generate stress and senescence by itself.
• We project the development of various new methods to improve reprogramming technologies and generate genetically unmodified or reprogramming “factor-free” hiPSCs. We also propose chronic and aged related disease modeling using human induced pluripotent stem cells.
• We expect that our results will provide greater insights into the mechanistic events surrounding the generation of iPSCs and will directly contribute for improving reprogramming protocols and interventions for tissues regeneration from older individuals, creating novel opportunities for the prevention and treatment of chronic or age-associated diseases.

Objective 1 : Epigenetic control of stem cell reprogramming and tissue regeneration in Ageing

JM LEMAITRE (DR2 INSERM), O MILHAVET (CR1 CNRS), F PELLESTOR (MCU/PH UMI), V COULON (MCU UM2)

• Epigenetic control of senescence
• Study of replication stress in aging and reprogramming
• Exploring Pluripotency in human cells
• Manipulating tissue regeneration in vitro an in vivo in mice models

Objective 2: Genomic instability of pluripotent stem cells

J DE VOS (PU/PH), T COMMES (PU UM2),  N GILBERT (CR1 CNRS), A BOURREUX (MCU UM2)

• Mapping mutagenic events that occur during cell culture in iPSC using whole genome sequencing and RNA-seq data
• Understanding the nature of the DNA lesions occurring in hPSC
• Understanding the dynamic and implication of L1 mobile elements in the genomic plasticity observed in hPSC

Objective 3 : Developing human developmental disease models using pluripotent stem cells reprogrammation (SAFE-iPSC core Facility Manager: R. Desprat)

J.M. LEMAITRE, O. MILHAVET, J DE VOS (PU-PH).

• Obtaining iPSCs from patients with premature aging syndroms to model diseases and to screen for molecules to delay the ageing/senescence phenotype.
• Obtaining iPSCs from patients with genetic blindness as Tools to assess gene therapy strategies
• Obtaining iPS from patients with genetic forms of Alzheimer Disease to investigate amyloid beta processing and to assess therapeutic strategies
• Obtaining iPSCs from patients with osteoarthritis to model disease

Director : Florence APPARAILLY

Phone number : 04 99 63 60 86

mailto : florence.apparailly@inserm.fr

Presentation of Team 3

Senior Scientists

F Apparailly (Head, DR2-Inserm), G. Courties (CRCN-Inserm), P Louis-Plence (CR1-Inserm), , D Geneviève (PUPH), I Touitou (PUPH), G. Sarrabay (PHU), M. Pelegrin (CRCN-CNRS)

Scientific project

Our team will perform a research program on the host immune response in vivo that is clearly translational, from bench to bedside, and vice versa, with the goal to better understand how the deregulation of the immune system leads to immune-mediated inflammatory disorders. The objective is to offer valuable new ways to combat these disorders, with a specific focus on osteoarticular diseases.

Gathering skills for genetic, functional genomic, molecular and cellular immunology, gene and cell therapy, our team aims at the following objectives:

• Identify genes associated with chronic inflammatory disorders with rheumatic tropism and study their role in pathophysiological conditions
• Better characterize distinct sub-populations of monocytes and regulatory T cells and identify pathways controlling their differentiation and function in chronic inflammatory and osteoarticular disorders
• Propose innovative strategies to restore immune tolerance using tolerogenic dendritic cells, myeloid cells or induced Treg cells.

Thematic 1 : Genetic analysis of human auto-inflammatory and chronic osteoarticular diseases

Thematic 2 : The role of the adaptive immune system in autoimmunity: the breakdown of self-tolerance

Antigen presenting cells (APCs), especially dendritic cells (DCs), play a major role in the hierarchy of the induction of immune reactions. DCs are widely accepted as the most potent APCs capable of inducing protective adaptive immune responses in addition to tolerance to self-antigens. The role of DCs is currently being investigated in the context of many disease and therapeutic settings. In response to a variety of danger stimuli, resting DCs in peripheral tissues undergo a complex maturation process that might involve the regulation of genes that control distinct DC functions.

The different functional properties of DCs are also linked to the existence of several subpopulations in humans and animals that differ in response to stimuli. On the other hand, immune reactions can be controlled by the so-called regulatory T cells that can interact with APCs such as DCs. Two main types of regulatory T cells have been identified (natural and induced) and both play significant roles in tuning down effector immune responses. Indeed, in parallel to thymus-derived natural Treg cells, induced regulatory T (iTreg) cells can develop in peripheral tissue under a variety of conditions such as antigen presentation under subimmunogenic or non inflammatory conditions.

DCs and Treg cells are currently being considered as attractive targets towards manipulation of the immune system for therapeutic purposes. With this background, the special interest of our group is focused on the immunobiology of tolerogenic DCs and Treg cells and their suppressive functions. We are studying more particularly the beneficial effect of DCs and/or Tregs in experimental models of arthritis.

Our aims are :

• Development of novel and effective immunotherapeutic tools based on DCs and/or regulatory T cells
• Development of strategies to manipulate DCs to induce more potent regulatory T cells
• Elucidating the role of DCs and/or regulatory cells in physiological and pathological conditions
•  Identifying biomarkers of immunity in response to DC and/or regulatory cells vaccines
•  Define animal models to understand in vivo suppressive mechanisms involved by tolerogenic DCs and/or Treg cells.

Contacts :

Pascale Louis-Plence, PhD, CR1 Inserm, Phone : 04 67 33 57 21

Maïlys Cren, Enginer, Phone : 04 67 33 57 22

Rita Vicente, PhD, Post-doct, Phone : 04 67 33 57 21

Main references :

1. Naila Mebarek*, Rita Vicente*, Anne Aubert-Pouëssel, Julie Quentin, Anne-Laure Mausset-Bonnefont, Jean-Marie Devoisselle, Christian Jorgensen, Sylvie Bégu and Pascale Louis-Plence. Versatile polyion complex micelles for peptide and siRNA vectorization to engineer tolerogenic dendritic cells. Eur J Pharm Biopharm. 2015 May;92:216-27.
2. H. Asnagli*, D. Martire*, N. Belmonte, J. Quentin, H. Bastian, M. Boucard-Jourdin, P. Babacar Fall, A-L. Mausset-Bonnefont, A. Mantello-Moreau, S. Rouquier, I. Marchetti, C. Jorgensen, A. Foussat* and P. Louis-Plence*. Type 1 regulatory T cells specific for collagen-type II as an efficient cell-based therapy in arthritis. Arthritis Research & Therapy.2014, 16:R115 DOI: 10.1186/ar4567 (IF=4.30)
3. A. Thiolat*, L. Semerano*, Y.M. Pers*, J. Biton, D. Lemeiter, P. Portales, J. Quentinc, C. Jorgensen, P. Decker, M-C. Boissier, P. Louis Plence, N. Bessis: IL-6 Receptor Blockade Enhances CD39+ Regulatory T-Cell Development in Rheumatoid Arthritis and in Experimental Arthritis. Arthritis & Rheum16(3): (IF 8.43)
4. A. Thiolat, L. Biton J, Decker P, Semerano L, Boissier MC, Pers YM, Jorgensen C, Plence PL, Bessis N.. Reply To PMID 24504799, Arthritis Rheumatol. 2014. ar14-0628R1 (IF 8.43)
5. Spoerl D, Duroux-Richard I, Louis-Plence P, Jorgensen C . The role of miR-155 in regulatory T cells and rheumatoid arthritis. Clin Immunol. 2013 Jul;148(1):56-65.

Thematic 3 : The role of the innate immune system in inflammatory diseases.

Main publications of Team 3

• Courties G*, Seiffart V*, Presumey J, Escriou V, Scherman D, Zwerina J, Ruiz G, Zietara N, Jablonska J, Weiss S, Hoffmann A, Jorgensen C, Gross G*, Apparailly F* (*equally contributed). In vivo RNAi-mediated silencing of TAK1 decreases inflammatory Th1 and Th17 cells through targeting of myeloid cells. Blood. 2010. 116(18):3505-16 (IF:10.5)
• J. Présumey*, G. Courties*, P. Louis-Plence, V. Escriou, D. Scherman, Y-M. Pers, H. Yssel, J. Pène, D. Kyburz, S. Gay, C. Jorgensen and F. Apparailly. NAMPT/Visfatin expression by inflammatory monocytes mediates arthritis pathogenesis. Ann Rheum Dis. 2013. 72(10):1717-24 (IF=8,72)
• Rittore C, Sanchez E, Soler S, Barat-Houari M, Albers M, Obici L, McDermott MF, Touitou I, Grandemange S. Identification of a new exon 2-skipped TNFR1 transcript: regulation by three functional polymorphisms of the TNFR-associated periodic syndrome (TRAPS) gene. Ann Rheum Dis. 2014. 73(1):290-7 (IF=8,72)
• H. Asnagli*, D. Martire*, N. Belmonte, J. Quentin, H. Bastian, M. Boucard-Jourdin, P. Babacar Fall, A-L. Mausset-Bonnefont, A. Mantello-Moreau, S. Rouquier, I. Marchetti, C. Jorgensen, A. Foussat* and P. Louis-Plence* (*equally contributed). Type 1 regulatory T cells specific for collagen-type II as an efficient cell-based therapy in arthritis. Arthritis Research & Therapy. 2014. 16:R115 (IF=4.30)
• Thiolat A*, Semerano L*, Pers YM*, Biton J, Lemeiter D, Portales P, Quentin J, Jorgensen C, Decker P, Boissier MC, Louis-Plence P, Bessis N (*equally contributed). Interleukin-6 receptor blockade enhances CD39+ regulatory T cell development in rheumatoid arthritis and in experimental arthritis. Arthritis Rheumatol. 2014. 66(2):273-83 (IF=7.48)

Presentation of Team 4

Senior Scientists

Martin VILLALBA  (DR2 INSERM), Javier HERNANDEZ (CR1 INSERM),  M. LE QUINTREC DONNETTE (PU-PH), M. DAUJATt (CRHC-Inserm), D. GITENAY (MCU-UM), C. ALEXIA (ECN-Inserm) F. IBORRA (PH-CHU), V. PERNIN (PH-CHU), S. GERBAL-CHALOIN (CRHC-Inserm), P. BLANC (PUPH-CHU), F. NAVARRO (PUPH-CHU), A. HERRERO (MCUPH-CHU)

Scientific project

Lymphocytes and phagocytes, through their adaptive and innate cytotoxic functions, contribute to the pathogenesis of autoimmune diseases and mediate transplant rejection thus hampering approaches in regenerative medicine. Furthermore, if correctly activated, they can mediate strong anti-tumor responses. Our goal is to better understand the mechanisms regulating their activation and differentiation in response to self and foreign signals. This will allow us not only to set the basis for new immunotherapeutic approaches aiming to prevent pathological responses but, also, to enhance anti-tumor cytotoxic responses.  In our laboratory, we currently develop three well-defined lines of research.