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    'Humanized' mouse models

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    Principal investigator: Christian Boitard

    Contact: christian.boitard@cch.aphp.fr; christian.boitard@inserm.fr

    Phone : +33 1 58 41 24 40 / +33 1 58 41 21 94

     

    Objectives

    The lab focuses is on interactions between immune cells and the islet of Langerhans in type 1 diabetes: 1- the role of local islet factors, in particular of costimulation T cell signals, in immune tolerance and its failure in diabetes; 2- the identification of major T lymphocyte epitopes on preproinsulin, a major autoantigen in diabetes development; 3- the development of preclinical models to develop new strategies in the diagnosis and treatment of type 1 diabetes; 4- the development of immunotherapy in human type 1 diabetes.

     

    The group

    Pamela Alhoueiss, Master student, ARDRM; Rasha Barakat, Doctoral student, INSERM; Chantal Becourt, Engineer Assistant, INSERM; François Lemonnier, Director of research, emeritus, INSERM; Sandrine Luce, Post-doctoral fellow, AP-HP.

     

    Research interests

    We have demonstrated the central role of insulin-secreting cells in the failure of immune tolerance that leads to type 1 diabetes, and further the key role of preproinsulin as a major autoantigen in NOD mice that were deficient in the expression of either the insulin 1 or the insulin 2 gene (Larger E et al. J Exp Med 1995, 181:1635). Along the same line, we have characterized insulin epitopes recognized by T lymphocytes and have shown in the mouse that the expression of insulin in the thymus controls the repertoire of T lymphocytes that are selected in the periphery (7). In the human, we have characterized insulin epitopes that are recognized by CD4+ and CD8+ T lymphocytes along the diabetes process (6; 5; 3). The present goal is to develop new diagnostic tools and vaccination strategies in the treatment of type 1 diabetes.  Along this line, we have obtained a new preclinical model of type 1 diabetes by generating humanized mouse that lack the expression of murine class I, class II and insulin genes and express HLA-A*0201, HLA-DQ8 and human insulin (hINS) transgenes (1). Finally, the role of T cell costimulation is studied in NOD mice that lack the expression of either ICOS or its ligand. ICOS-/- and ICOSL-/- NOD mice are protected from diabetes, but develop an autoimmune disease that affects neural and muscular cells, pointing to local T cell interactions within the islet environment as a key factor in immune tolerance (4, 2).

     

     

     

    Main publications and patents

    1: Luce S, Guinoiseau S, Gadaul A, Letourneur F, Blondeau B, Nitschke P, Pasmant E, Vidaud M, Lemmonier F, Boitard C. A Humanized Mouse Model to Study Type 1 Diabetes.  Diabetes. 2018 Sep;67(9):1816-1829.

    2 : Briet, C., Bourdenet, G., Rogner, U. C., Becourt, C., Tardivel, I., Drouot, L., Arnoult, C., do Rego, J. C., Prevot, N., Massaad, C., Boyer, O., Boitard, C. The Spontaneous Autoimmune Neuromyopathy in ICOSL-/- NOD Mice Is CD4+ T-Cell and Interferon-gamma Dependent Front Immunol 2017; 8:287.

    3 : Luce S, Lemonnier F, Briand JP, Coste J, Lahlou N, Muller S, Larger E, Rocha B, Mallone R, Boitard C. Single insulin-specific CD8+ T cells show characteristic gene expression profiles in human type 1 diabetes. Diabetes. 2011;60:3289-99.

    4 : Prevot N, Briet C, Lassmann H, Tardivel I, Roy E, Morin J, Mak TW, Tafuri A, Boitard C. Abrogation of ICOS/ICOS ligand costimulation in NOD mice results in autoimmune deviation toward the neuromuscular system. Eur J Immunol. 2010 Aug;40(8):2267-76.

    5 : Toma A, Laïka T, Haddouk S, Luce S, Briand JP, Camoin L, Connan F, Lambert M, Caillat-Zucman S, Carel JC, Muller S, Choppin J, Lemonnier F, Boitard C. Recognition of human proinsulin leader sequence by class I-restricted T-cells in HLA-A*0201 transgenic mice and in human type 1 diabetes. Diabetes. 2009;58:394-402.

    6 : Toma A, Haddouk S, Briand JP , Camoin L, Gahery H, Connan F, Dubois-Laforgue D, Caillat-Zucman S, Guiullet  JG, Carel JC, Muller S, Choppin J, Boitard C. Recognition of a subregion of human proinsulin  by class-I restricted T cells in type 1 diabetic patients. Proc Natl Acad Sci USA, 2005;102: 10581-6.

    7 :  Thébault-Baumont K, Dubois-Laforgue D, Krief P, Briand JP, Halbout P, Vallon-Geoffroy K, Morin J, Laloux V, Lehuen A, Carel JC, Jami J, Muller S, Boitard C. Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J Clin Invest. 2003;111:851-7.

     

    Financial supports

    These programs are supported by INSERM, University Paris Descartes, EFSD, ANR, FP7, AFM.