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    T-cell tolerance, biomarkers and therapies in type 1 diabetes.

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    Team leaders

    Our research work focuses on Type 1 diabetes (T1D), an autoimmune disease resulting from the destruction of insulin-producing pancreatic β cells by the immune system, in particular by autoreactive T lymphocytes. Interestingly, we all harbor these autoreactive T lymphocytes but they are in most cases “benign”. So why do they turn into a pathological and aggressive state in diabetic patients? To answer this question, we are exploring the mechanisms that (1) fail to keep autoreactive T lymphocytes inoffensive and (2) make the β cells more visible and vulnerable to the autoimmune attack. This research will allow us to identify novel therapeutic targets to prevent T1D. In this perspective, we have already launched several clinical studies to screen for T1D risk in affected families. 

    Objectives

    Our aim is to understand how the autoimmunity against pancreatic β cells develops and progresses toward type 1 diabetes (T1D), and how to halt this progression, before β-cell destruction and clinical disease. β-cell destruction involves the recognition of peptide-HLA Class I (pHLA-I) complexes on the surface of β cells by autoreactive CD8+ T cells. Surprisingly, we observed that CD8+ T cells recognizing known and novel β-cell peptides, that we identified by HLA peptidomics and transcriptomics strategies, circulate at a similar frequency in T1D and healthy donors and display a largely naïve phenotype (Culina et al. Sci Immunol 2018, Gonzalez-Duque et al. Cell Metab 2018). Thus, a universal state of ‘benign’ islet autoimmunity exists in all individuals, to a much larger extent than previously appreciated.

    The overall objective of our Laboratory is to decipher the mechanisms by which this benign autoimmunity progresses toward T1D in few individuals, and not in many others. We propose that such progression may rely on two non-mutually exclusive mechanisms: a) loss of immune ignorance toward β-cell antigens that are normally invisible to T cells (β-cell-centric hypothesis); and b) loss of the immune regulation that controls autoreactive T cells (T-cell-centric hypothesis).

    Aim #1. Loss of immune ignorance. We are investigating whether progression to T1D involves a different vulnerability of β cells in the face of a naïve autoimmune repertoire that is similar across individuals. This vulnerability may be modulated by a different pHLA presentation by β cells or dendritic cells in the T1D and healthy conditions. In this context, we are studying:

    #1.1: the peptide antigen display of β cells under resting versus inflammatory conditions, or upon infection by Enteroviruses (which are the most credited environmental triggers for T1D).

    #1.2: the role of other surface molecules that may further modulate this vulnerability.

    Aim #2. Loss of immune regulation. We are focusing on the immune mechanisms that regulate this autoimmune T-cell repertoire that we all harbor and that may be lost in T1D. We are currently exploring:

    #2.1: Pathways involved in the preferential priming of islet-reactive T cells in T1D patients.

    #2.2: Increased resistance of effector T cells to TGF-β-mediated regulation.

    #2.3: Defective production/signaling of pro-resolving lipid mediators.

    Aim #3. Innovative therapies to restore “benign” autoimmunity. The challenge is to be selective, to avoid global immune suppression; and non-invasive, to intervene as early as possible in children at risk of developing T1D. We have devised a novel oral vaccine using Fc-fused preproinsulin (PPI-Fc) that meets these criteria, and we are currently exploring its therapeutic efficacy for T1D prevention.

     

    Main publications

    1: Gonzalez-Duque S, Azoury ME, Colli ML, Afonso G, Turatsinze JV, Nigi L, Lalanne AI, Sebastiani G, S. Pinto, Carré A, Pinto S, Culina S, Corcos N, Bugliani M, Marchetti P, Armanet M, Diedisheim M, Kyewski B, Steinmetz LM, Buus S, You S, Dubois-Laforgue D, Larger E, Beressi JP, Bruno G, Dotta F, Scharfmann R, Eizirik DL, Verdier Y, Vinh J, R. Mallone. Conventional and neo-antigenic peptides presented by β cells are targeted by circulating naïve CD8+ T cells in type 1 diabetic and healthy donors. Cell Metab (2018), 28:946-960.e6

    2: Culina S, Lalanne A.I, Afonso G, Cerosaletti K, Pinto S, Sebastiani G, Kuranda K, Nigi L, Eugster A, Østerbye T, Maugein A, McLaren J.E, Ladell K, Larger E, Beressi J.P, Lissina A, Appay V, Davidson H.W, Buus S, Price D.A, Kuhn M, Bonifacio E, Battaglia M, Caillat-Zucman S, Dotta F, Scharfmann R, Kyewski B, Mallone R, the ImMaDiab Study Group. Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetes from healthy donors. Sci Immunol (2018), 3:eaao4013

    3: Besançon 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):1811-1816

    4: Besançon A, Goncalves T, Valette F, Dahllöf 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):389-398.

    5: Culina S, Gupta N, Boisgard R, Afonso G, Gagnerault MC, Dimitrov J, Østerbye T, Justesen S, Luce S,Attias M, Kyewski B, Buus S, Wong FS, Lacroix-Desmazes S, Mallone R. Materno-fetal transfer of preproinsulin through the neonatal Fc receptor protects from autoimmune diabetes. Diabetes (2015), 64:3532-42

    Team’s news

    Prix, distinctions, labellisations:

    2019: Directeur de Recherche 1 (DR1) promotion to Roberto Mallone
    2019: EFSD travel fellowship to Zhicheng Zhou
    2017: The Helmsley Charitable Trust George S. Eisenbarth nPOD Award for Team Science

    Liens

    www.dearlab.org
    www.innodia.eu

    Projets collaboratifs

    - EU IMI2 INNODIA ‘Translational approaches to disease modifying therapy of type 1 diabetes: An innovative approach towards understanding and arresting Type 1 diabetes’

    - ANR DIAPOP ‘Resetting self-tolerance in autoimmune diabetes by pro-resolving mediators derived from apoptotic cell efferocytosis’

    - JDRF nPOD ‘Network for pancreatic organ donors with diabetes’

    - Clinical Networks: ImMaDiab (NCT01747967), TiBet, INNODIA, TRAKR (NCT02184676)

    Brevets

    Pending patents “Antigenic peptides deriving from Secretogranin V, PCSK2, Urocortin 3 and uses thereof for the diagnosis and treatment of type 1 diabetes” (EP18305286, EP18305287, EP18305288).

    WO/2017/046335 “T cell receptors (TCR) and uses thereof for the diagnosis and treatment of diabetes”.

    WO/2017/012959 “Methods and pharmaceutical compositions for inducing immune tolerance by mucosal vaccination with Fc-coupled antigens”.

    Provisional US patent “Prenatal therapy to induce immune tolerance” (US62/188,004).

    WO/2016/180852 “Methods for preparing antigen-specific T cells from an umbilical cord blood sample”.

    WO/2015/110397 “Methods for testing T cell priming efficacy in a subject”.

    European patent “Method for stimulating antigen-specific T cell responses”.

    WO/2013/061353 “Use of Mycobacterium avium paratuberculosis peptides to diagnose type 1 diabetes”.

    WO/2010/119033 “Method for stimulating antigen-specific T cells using accelerated co-cultured DCs”.

    Multimedia, interview

    R. Mallone. Communiqué de presse Inserm. ‘Diabète de type 1 : le rôle du thymus n’est pas celui que l’on croyait !’. February 2018.

    R. Mallone. Magazine Equilibre de la Fédération Française des Diabetiques. Interview to R. Mallone by B. Blond ‘Diabète de type 1 : les dessous de l’auto-immunité’. December 2017.  

    R. Mallone. Inserm ‘Science et Santé’ magazine. Article ‘Maladies auto-immunes : dompter le système immunitaire’. January 2017.

    R. Mallone. La revue de l’AJD (Aide aux Jeunes Diabétiques).  Article ‘L’auto-immunité du diabète de type 1 et les nouvelles pistes pour une prévention à l’aide de vaccins’. June 2017.

    R. Mallone. Patient newsletters. Three-monthly newsletters for patients participating in our cohort studies (ImMaDiab, TRAKR). Dossiers ‘Parlons Science’ at www.dearlab.org. Since October 2012.

    R. Mallone. Pariscience, Festival International du Film Scientifique. Intervention to the projection of the movie ‘Sugar Blues’ d’A. Culkova. Paris, France, October 2015.

    S. You. Invitée de l’émission de radio « La Méthode Scientifique » sur France Culture le 07/01/2019 sur le thème « Greffe : l’impossible puzzle biologique ».

    S. You. Contribution à un article de presse du journal « Le Monde », section Science/Médecine du 27/01/2017 « Greffe : des animaux incubateurs d’organes ».

    S. You. Reportage pour le Magazine de la Santé, France 5, diffusé le Jeudi 05/02/2015.

    S. You. INSERM Actualités Recherche du 30/10/2014 : une nouvelle piste contre le rejet de greffe.