Bienvenu(e) sur le site de l'Institut Necker Enfants Malades

Etudier les mécanismes cellulaires et moléculaires impliqués dans la dérégulation des réponses immunes

de la science fondamentale :
  • allergie
  • tolérance immune
à la recherche translationnelle :
  • asthme
  • diabète auto-immun
Lucienne Chatenoud
Maria Leite-De-Moraes
Immunorégulation et Immunopathologie

Lucienne CHATENOUD is Professor in Immunology at Paris Descartes University, Head of the Immunology Laboratory at Hôpital Necker-Enfants Malades and Senior Professor at the Institut Universitaire de France. Her research focused on pathogenic and regulatory immune mechanisms in transplantation and autoimmunity and on the devise of strategies to induce/restore immune tolerance. Lucienne Chatenoud pioneered the use of CD3 monoclonal antibodies to treat autoimmune diabetes, a strategy presently in clinical development.

Maria LEITE DE MORAES is Research Director (DR1) at CNRS. She made seminal discoveries on the ontogeny and function of invariant Natural Killer T (iNKT) and on their role in experimental and clinical allergic asthma. She described iNKT17 cells as a distinct lineage. Her current focus is the role of Innate Like T cells, namely iNKT, γδ T and MAIT cells, in allergy and autoimmunity.

Focus

We are primarily interested with dissecting cellular and molecular mechanisms of immunoregulation and immunopathology and how these can be harnessed, using novel biotherapies or biotherapy strategies, to develop treatments transferable to the clinic in autoimmunity, allergy, organ or cell transplantation.

Introduction

Over the last years we took advantage of the complementary expertise of the lead investigators in autoimmunity and allergy to dissect cellular and molecular mechanisms of immunoregulation and immunopathology and how these can be harnessed, using novel biotherapies or biotherapy strategies, tools and know-how to develop treatments transferable to the clinic in autoimmunity, allergy, organ or cell transplantation.

The strength of the team is that, besides conventional and genetic engineering modified mice, we also used an experimental model we have been working on for the last 25 years, the non-obese diabetic (NOD) mouse, which spontaneously develops a genetically driven autoimmune syndrome including insulin-dependent diabetes and Sjogren's syndrome.

Salient contributions include:

  1. Original description of a novel subset of invariant NKT (iNKT) cells, the IL-17-producing iNKT17 lymphocytes. They are implicated in inflammatory responses including allergic asthma and autoimmune type I diabetes. iNKT17 cells acquire their functional properties in the thymus where SAP-dependent signals are essential for the fate decisions driving their differentiation into iNKT1 (major IFNγ-producers), iNKT2 (IL-4 producers) or NKT17 cells.
  2. Initial description of the pivotal role of iNKT cells in experimental allergic asthma. The later was translated to the clinic showing the increase of iNKT cells in the brochoalveolar lavage of pediatric patients presenting severe asthma. Major efforts are presently devoted to dissect the implication of distinct innate like T lymphocytes namely, iNKT but also γδ T and MAIT (Mucosal-Associated Invariant T) cells in the physiopathology of experimental and clinical asthma.
  3. Demonstration that a single Toll Like Receptor agonist recapitulates the in vivo protection on both autoimmunity and allergy afforded by infectious agents and bacterial extracts. A new opening to a plausible explanation for the "Hygiene hypothesis" and to novel therapeutic perspectives for the prevention of these pathologies that represent a major health problem in western countries. This field of activity has been granted an European Research Council (ERC) funding (PI: J-F Bach).
  4. First clinical proof of concept of an immunointervention strategy pioneered by our team (use of CD3 monoclonal antibodies) that is successful at promoting operational immune tolerance (long-term control of pathogenic responses in absence of chronic immunosuppression) in the context of an established autoimmune disease (autoimmune type 1 diabetes) : demonstration through a long-term follow-up of patients included in a phase II randomized placebo-controlled trial, recently confirmed by a pharmaceutically-driven phase III trial.
  5. Demonstration that the tolerance-promoting ability of CD3 monoclonal antibodies can be extended from autoimmunity to organ transplantation as shown in islet, skin and cardiac transplantation. Potential use of the strategy in regenerative medicine to promote long-term survival of cardiac cell progenitors derived from embryonic stem cells.

Research objectives

Using state of the art technology, we want to re-evaluate the important problem of the penetrance of autoimmune and allergic diseases through the study of new genetic factors, of epigenetic marks and/or the influence of newly well-characterized immune regulatory mechanisms.

30 dernières publications

2019

  • Allali S, Dietrich C, Machavoine F, Rignault-Bricard R, Brousse V, de Montalembert M, Hermine O, Maciel TT, Leite-de-Moraes M. Innate-like T cells in children with sickle cell disease. PLoS One. 2019 14(6):e0219047. doi:10.1371/journal.pone.0219047
  • Belkadi A, Dietrich C, Machavoine F, Victor JR, Leite-de-Moraes M. gammadelta T cells amplify Blomia tropicalis-induced allergic airway disease. Allergy. 2019 Feb; 74(2):395-398. doi:10.1111/all.13618
  • Briand C, Fremond ML, Bessis D, Carbasse A, Rice GI, Bondet V, Duffy D, Chatenoud L, Blanche S, Crow YJ, Neven B. Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency. Ann Rheum Dis. 2019 Mar; 78(3):431-433. doi:10.1136/annrheumdis-2018-214037
  • Chatenoud L, Bertuccio P, Turati F, Galeone C, Naldi L, Chatenoud L, La Vecchia C, Bach JF, Group HS. Markers of microbial exposure lower the incidence of atopic dermatitis. Allergy. 2019 Jul 18; doi:10.1111/all.13990
  • Chatenoud L. A future for CD3 antibodies in immunotherapy of type 1 diabetes. Diabetologia. 2019 Apr; 62(4):578-581. doi:10.1007/s00125-018-4808-7
  • Courbette O, Aupiais C, Viala J, Hugot JP, Louveau B, Chatenoud L, Bourrat E, Martinez-Vinson C. Infliximab Paradoxical Psoriasis in a Cohort of Children With Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr. 2019 Aug; 69(2):189-193. doi:10.1097/MPG.0000000000002349
  • de-Oliveira MG, Lira AAL, Sgnotto FR, Inoue AHS, Santos LS, Nakamatsu BY, Duarte AJS, Leite-de-Moraes M, Victor JR. Maternal IgG impairs the maturation of offspring intrathymic IL-17-producing gammadeltaT cells: Implications for murine and human allergies. Clin Exp Allergy. 2019 Jul; 49(7):1000-1012. doi:10.1111/cea.13393
  • Duchatelet S, Join-Lambert O, Delage M, Miskinyte S, Guet-Revillet H, Lam T, Coignard-Biehler H, Ungeheuer MN, Chatenoud L, Lortholary O, Nassif X, Hovnanian A, Nassif AS. Remission of chronic acne fulminans and severe hidradenitis suppurativa with targeted antibiotherapy. JAAD Case Rep. 2019 Jun; 5(6):525-528. doi:10.1016/j.jdcr.2019.04.001
  • Lezmi G, Abou-Taam R, Garcelon N, Dietrich C, Machavoine F, Delacourt C, Adel-Patient K, Leite-de-Moraes M. Evidence for a MAIT-17-high phenotype in children with severe asthma. J Allergy Clin Immunol. 2019 Aug 16; doi:10.1016/j.jaci.2019.08.003c
  • Lozza L, Moura-Alves P, Domaszewska T, Lage Crespo C, Streata I, Kreuchwig A, Puyskens A, Bechtle M, Klemm M, Zedler U, Silviu Ungureanu B, Guhlich-Bornhof U, Koehler AB, Staber M, Mollenkopf HJ, Hurwitz R, Furkert J, Krause G, Weiner J, 3rd, Jacinto A, Mihai I, Leite-de-Moraes M, Siebenhaar F, Maurer M, Kaufmann SHE. The Henna pigment Lawsone activates the Aryl Hydrocarbon Receptor and impacts skin homeostasis. Sci Rep. 2019 Jul 26; 9(1):10878. doi:10.1038/s41598-019-47350-x
  • Neven B, Diana JS, Castelle M, Magnani A, Rosain J, Touzot F, Moreira B, Fremond ML, Briand C, Bendavid M, Levy R, Morelle G, Vincent M, Magrin E, Bourget P, Chatenoud L, Picard C, Fischer A, Moshous D, Blanche S. Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide for Primary Immunodeficiencies and Inherited Disorders in Children. Biol Blood Marrow Transplant. 2019 Jul; 25(7):1363-1373. doi:10.1016/j.bbmt.2019.03.009
  • 2018

  • Bach JF. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat Rev Immunol. 2018;18(2):105-20. doi: 10.1038/nri.2017.111. PubMed PMID: 29034905.
  • Besancon A, Demir Z, Goncalves T, Valette F, Panafieu E, Chatenoud L, You S. Differential Impact of T-bet and IFNgamma on Pancreatic Islet Allograft Rejection. Transplantation. 2018 Sep; 102(9):1496-1504. doi:10.1097/TP.0000000000002261
  • Besancon A, Goncalves T, Valette F, Mary C, Vanhove B, Chatenoud L, You S. A selective CD28 antagonist and rapamycin synergise to protect against spontaneous autoimmune diabetes in NOD mice. Diabetologia. 2018;61(8):1811-6. doi: 10.1007/s00125-018-4638-7. PubMed PMID: 29845333
  • Besancon A, Goncalves T, Valette F, Dahllof MS, Mandrup-Poulsen T, Chatenoud L, You S. Oral histone deacetylase inhibitor synergises with T cell targeted immunotherapy to preserve beta cell metabolic function and induce stable remission of new-onset autoimmune diabetes in NOD mice. Diabetologia. 2018;61(2):389-98. doi: 10.1007/s00125-017-4459-0. PubMed PMID: 29030662
  • Briand C, Fremond ML, Bessis D, Carbasse A, Rice GI, Bondet V, Duffy D, Chatenoud L, Blanche S, Crow YJ, Neven B. Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency. Ann Rheum Dis. 2018. doi: 10.1136/annrheumdis-2018-214037. PubMed PMID: 30282666
  • Delliere S, Guery R, Candon S, Rammaert B, Aguilar C, Lanternier F, Chatenoud L, Lortholary O. Understanding Pathogenesis and Care Challenges of Immune Reconstitution Inflammatory Syndrome in Fungal Infections. J Fungi (Basel). 2018 Dec 17; 4(4):doi:10.3390/jof4040139
  • Ghiasi SM, Dahllof MS, Osmai Y, Osmai M, Jakobsen KK, Aivazidis A, Tyrberg B, Perruzza L, Prause MCB, Christensen DP, Fog-Tonnesen M, Lundh M, Grassi F, Chatenoud L, Mandrup-Poulsen T. Regulation of the beta-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis. Mol Cell Endocrinol. 2018. doi: 10.1016/j.mce.2018.08.001. PubMed PMID: 30121202
  • Landon-Cardinal O, Friedman D, Guiguet M, Laforet P, Heming N, Salort-Campana E, Jouen F, Allenbach Y, Boyer O, Chatenoud L, Eymard B, Sharshar T, Benveniste O. Efficacy of Rituximab in Refractory Generalized anti-AChR Myasthenia Gravis. J Neuromuscul Dis. 2018;5(2):241-9. doi: 10.3233/JND-180300. PubMed PMID: 29865089
  • Lezmi G, Leite-de-Moraes M. Invariant Natural Killer T and Mucosal-Associated Invariant T Cells in Asthmatic Patients. Front Immunol. 2018;9:1766. doi: 10.3389/fimmu.2018.01766. PubMed PMID: 30105031; PubMed Central PMCID: PMCPMC6077286
  • Lezmi G, Abou Taam R, Dietrich C, Chatenoud L, de Blic J, Leite-de-Moraes M. Circulating IL-17-producing mucosal-associated invariant T cells (MAIT) are associated with symptoms in children with asthma. Clin Immunol. 2018;188:7-11. doi: 10.1016/j.clim.2017.11.009. PubMed PMID: 29196148.
  • Orabona C, Mondanelli G, Pallotta MT, Carvalho A, Albini E, Fallarino F, Vacca C, Volpi C, Belladonna ML, Berioli MG, Ceccarini G, Esposito SM, Scattoni R, Verrotti A, Ferretti A, De Giorgi G, Toni S, Cappa M, Matteoli MC, Bianchi R, Matino D, Iacono A, Puccetti M, Cunha C, Bicciato S, Antognelli C, Talesa VN, Chatenoud L, Fuchs D, Pilotte L, Van den Eynde B, Lemos MC, Romani L, Puccetti P, Grohmann U. Deficiency of immunoregulatory indoleamine 2,3-dioxygenase 1in juvenile diabetes. JCI Insight. 2018;3(6). doi: 10.1172/jci.insight.96244. PubMed PMID: 29563329; PubMed Central PMCID: PMCPMC5926942
  • Rignault-Bricard R, Machavoine F, Mecheri S, Hermine O, Schneider E, Dy M*, Leite-de-Moraes M*. IL-3-producing basophils are required to exacerbate airway hyper-responsiveness in a murine inflammatory model. Allergy. 2018. doi: 10.1111/all.13480. PubMed PMID: 29777594
    * corresponding authors
  • You S, Chatenoud L. Revisiting the phenotypic and genetic profiling of anergic T cells mediating long-term transplant tolerance. Curr Opin Organ Transplant. 2018;23(1):83-9. doi: 10.1097/MOT.0000000000000494. PubMed PMID: 29194071
  • Chercheur statutaire
    Christine Bodemer
    Chercheur hospitalo-Universitaire
    Lucienne Chatenoud
    Chercheur hospitalo-Universitaire
    +33 (0)1 40 61 54 44
    Stéphanie Chhun
    Enseignant Chercheur
    +33 (0)1 44 49 53 43
    Jacques De Blic
    Chercheur hospitalo-Universitaire
    +33(0)1 44 49 48 38
    Smail Hadjrabia
    Chercheur hospitalo-Universitaire
    Maria Leite-De-Moraes
    Chercheur
    +33 (0)1 40 61 54 41
    Guillaume Lezmi
    Chercheur hospitalo-Universitaire
    +33(0)1 44 49 48 38
    Chercheur non statutaire
    Baptiste Moreira
    Assistant hospitalier universitaire
    Coralie Pecquet
    Chercheur
    +33(0)1 44 49 53 69
    ITA statutaire
    Céline Dietrich
    Technicien(ne) en biologie
    +33 (0)1 40 61 54 42
    François Machavoine
    Ingénieur(e) en techniques biologiques
    +33 (0)1 40 61 54 43
    Cindy Marquet
    Ingénieur(e) en biologie
    +33 (0)1 40 61 54 45
    Fabrice Valette
    Assistant(e) en expériment.&instrument.biologiques
    +33 (0)1 44 49 53 69
    Doctorant
    Peipei Hu
    Doctorant(e)
    Etudiant
    Alix Bottier
    Master 2
    Orlagh Flanagan
    Master 2
    Eméritat
    Jean-François Bach
    Chercheur
    +33 (0)1 44 41 43 83
    Michel Dy
    Chercheur
    +33 (0)1 44 49 53 93
    Adresse

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    Parrain(s)
    S.A.R. la Princesse Caroline de Hanovre qui, à travers la Fondation Princesse Grace, soutient déjà la recherche medicale et tout ce qui contribue à soulager les enfants malades en France et dans le monde, a accepté de s'engager à nos cotés pour que ce centre de medecine moleculaire, tourné entre autres vers les pathologies des enfants, prenne de vitesse les maladies et continue à relever les defis actuels.

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