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

2019

2018