The research areas I developed since the begining of my career at INSERM (1983), aim at caracterizing in vivo mechanisms of induction and control of pathophysiological immune responses. Since 1987 my research activities are focused on the mechanisms dictating the decision between tolerance and immunity at epithelial surfaces of the digestive tract and the skin, which are the natural site of penetration of most infectious agents and are also constantly exposed to innocuous environmental antigens from the diet or the microbiota. The current projects are gueared toward understanding and manipulation immune tolerance and homeostasis mechanisms characterizing the intestinal immune system for application in human health, especially in the diagnosis, control and treatment of allergy, chronic auto-inflammatory diseases and for development of anti-infectious vaccination strategies.
My training in Immunology started by a PhD Thesis in Immunology (docteur ès sciences at the Necker Hospital in Paris (JF. Bach, Inserm-U25) where I investigated modulation of immune responses in pathological settings including allogeneic skin graft rejection, cytolytic NK and T cell responses and metastic lung carcinomas. Besides I first documented a model of intestinal IgA deficiency with normal serum IgA, in the mutant wasted mice, which raised the issue of the gut-independent origin of serum IgA.
After my recruitment at INSERM (1983), I specialized in mucosal immunology after a 2 year sabbatical in Birmingham Alabama (Dr. J. Mestecky, UAB) and in San Diego CA (Dr.M. Kagnoff, UCSD). On return to France, I started my own team in Mucosal Immunology in Lyon ( Pr. JP Revillard, U80, Hop. E. Herriot), where I focused on antigen presenting cells in the intestinAL mucosa and caracterized the unique phenotype and antigen presentation function of small intestinal epithelial cells in mice and in human infants with food allergy and Crohn disease ; we also developed the first epithelial cell line of mouse small intestine (MODE-K) that is under MTA and is distributed worldwide.
In 1991, I participated in setting the laboratory of Immunology (where we are currently located, Tour CERVI) at the former Pasteur Institute in Lyon, which became U404 Immunity and Vaccination (Dir. F. Wild). The proximity of measles specialists prompted me to investigate the relative efficacy of different mucosal routes for vaccination against measles both in mice and later in human (patch vaccination); I also documented that measles virus infects human dendritic cells and could exploits them to induce CD4 T cell immune suppression (Cover of J. Exp.Med 1997). I also pursued extensive analysis on the mechanisms of oral tolerance using animal models of allergy and demonstrated the role of intestinal epithelial cells, dendritic cells and regulatory T cells in prevention of skin diseases. Since 1998, the main axis of research, which have been pursued after creation of the Unit-U 851(J. Marvel) and more recently the CIRI-U-1111 (FL. Cosset), to which the team is rattached.
Thanks to the training in our team of clinicians from pediatric allergy and gastroenterology departments in Lyon and to our clinical laboratory Lab at the 'Faculté de Medecine Lyon-Sud', our translational research to the clinic has expanded as well as our clinical trials with industrial partnership.
Our recent and ongoing projects include:
i) characterization of the in vivo dynamics and functional plasticity of mucosal and skin dendritic cells in initiating priming or tolerance of cytotoxic CD8 T cell responses using patho-physiological animal model of allergies and Crohn’s disease.
ii) characterizing the respective roles of T cell subsets in the initiation (CD8 CTL) and the control (Treg) of intestinal inflammation in colitis models and in patients with Crohn’s disease and their values for early diagnosis and bio-therapeutic approaches.
iii) Identification of alternative parenteral routes of vaccination and adjuvants suitable for confering anti-infectious mucosal protection and IgA responses in the respiratory, gastro-intestinal and genital tracts.
iv) Role of the liver both in mucosal and systemic immune tolerance mechanisms and in the IgA response both at homeostasis and in the context of immune evasion by hepatotropic microbes.
The gastrointestinal tract comprises more than 70% of immune cells of the body and is dominated by massive production of secretory IgA which ensures immune exclusion of pathogens. it’s huge epithelial surface permanent encounters loads of innocuous environmental antigens from the diet and the gut microbiota, while only occasionnally exposed to pathogens. The gut-associated immune system finely tunes tolerance to innocuous antigens and protective immunity to microbes. Remarkably, innocuous antigens are not simply ignored but trigger well balanced immune responses crucial for the development and function of our entire immune system. Failure of mucosal tolerance results in food allergies and chronic inflammatory bowel diseases, pathologies that are increasing in developed countries. Alternatively, oral vaccines providing robust mucosal protection against infection and transmission of microbes is hampered by tolerance.
In our team, we aim at characterizing the mechanisms of induction, expression and control of innate and adaptive immunity in the digestive tract and the skin, in response to innocuous antigens or vaccines and decipher the in vivo dynamics, plasticity and function of dendritic cells of the intestine, skin and liver in the induction of immunity versus tolerance and development of regulatory T cells. We use pre-clinical mouse models reproducing allergic diseases and Crohn’s disease, conduct clinical patho-physiological studies in humans to improve diagnosis, prognosis or treatment of intestinal diseases. Finally, to circumvent inefficacy of oral vaccination, we characterize parenteral routes of vaccination to induce IgA responses and protection against mucosal infections in the digestive and genital tracts.