Tolérances immunitaires. EA 6302
Tolérance Immunitaire. EA 6302
EA6302 Tolérance Immunitaire team is a multidisciplinary research team consisting of internationally renowned experts in mechanisms of mucosal immune regulation during early and adult life.
Two complementary axis of research are developed in the team
Axis 1 (Figure 1 et 2) : Impact of early life immune system maturation on long-term susceptibility to immune mediated disease.
Mouse models and mother-child birth cohorts are used to analyze this question with a specific focus on the role of breast milk on mechanisms of early life immune regulation. Major research accomplishments are (1) demonstration that breastfeeding affects allergic asthma risk by the presence of respiratory allergens in breast-milk which will impact immune system development1-6 (2) identification of some key allergen and neonate characteristics which will condition tolerance versus immune priming in the long term1-8 (3) demonstration that the neonate is dependent on maternal milk co-factors for successful oral tolerance induction in early life and long-term optimal immune function1-9. Ongoing research is analyzing (1) mechanisms of neonatal oral immune priming by small amounts of respiratory allergen in breastmilk (2) impact of colostrum on early life and adult immune and glucidic metabolism.
Final goal of our research is to propose innovative and efficient strategies for non communicable and infection disease prevention that are specific and adapted to the early life period.
Axis 2. Mechanism of gut barrier function and impact of its dysfunction on local and distant inflammatory disease (Figure 3)
Recently we demonstrated that respiratory allergen house dust mite (HDM), known for its etiology in allergic disease and asthma, is present in the healthy human intestine where it can immunomodulate gut function 14. In patients with irritable bowel syndrome (IBS), HDM further decreases their already-compromised gut barrier. This translational research project explores the role of HDM (as a source of exogenous proteases in the gut) in etiology of gut dysfunction, the mechanisms involved in its onset of pathophysiology of gut disease (IBS and inflammatory bowel disease, IBD) as well as potential use of protease inhibitors (such as serpin) in their ability to dampen local HDM-induced gut inflammation and restore gut homeostasis. In addition, this axis aims to examine the before unexplored role of environmental HDM in driving the lung-gut crosstalk 15 in onset of distant inflammatory diseases such as seasonal HDM-driven allergies and asthma (Figure 3).
The team is led by Valérie Verhasselt, MD, PhD, I Inserm researcher which has a long-standing experience and internationally recognized expertise on the study of immune regulation in neonates. Her research has resulted in more than 40 publications, cited more than 2500 times, including publication in Nature Medicine on mechanisms of allergy prevention by breastfeeding. Her research on immune function in early life has been acknowledged by the French Académie Nationale de Médecine (2012) and Académie des Sciences (2008).
Meri Tulic, PhD, originally from Susan Prescott’s lab at the University of Western Australia, joined the team in January 2012 and in 2013, obtained an Inserm researcher position. Meri Tulic is internationally renowned for her expertise in translational studies on ontogeny of allergy and early immune development. She has more than 80 publications including those in Lancet and JACI 10-13. She recently developed interest in the study for the role of respiratory house dust mite in the physio-pathology of gut inflammatory disease 14 and the gut-lung cross-talk in immune homeostasis 15 .
Thierry Piche, Professor, MD, PhD, is gastro-enterologist and expert in the role of gut barrier dysfunction in the syndrome of irritable bowel disease 14, 16-18 Mylène Vivinus, MD, is a clinical immunologist and contributes to translational research projects.
Local and international (Brazil, Germany, Belgium) master and PhD students contribute to the team projects. Currently (January 2016- ), Julien Boyer, MD, resident in Anatomopathology, Charlotte Isnard, MD, resident in Pediatry and Nicolas Halloin, BSc are performing a master 2 in our team and Marine Martin a BTS internship.
Engineers with permanent position contribute greatly to the success of the projects developed in our team. Akila Rekima, engeneer employed by the University of Nice sophia-Antipolis has been working with V. Verhasselt on mouse models of maternal-neonate interaction through breast milk for 8 years and has a unique technical expertise in this field 1, 3, 14. Frédéric Larbret, Inserm engeneer, is in charge of the flow cytometry platform which allows analysis of rare cell populations in early life. Frédéric Larbret is expert in the analysis of interaction between proteins by FRET technique using flow cytometry which can be used for fundamental research and high throughput drug screening19.
The team has close collaboration with neonatologist, Dr Stéphanie Desmet in a clinical project looking at the role of colostrum in premature neonate and with anthropologist, Professor Joel Candau (LAPCOS, UNS), studying perception of breastfeeding amongst different cultures. We also have multiple collaborations with neighbouring INSERM C3M research centre and in particular Jean-François Tanti's team for glucidic metabolism expertise, microbiologists (Rémy Burcelin, Inserm, Toulous), with world-leading pediatric allergologists (Susan Prescott, University of Western Australia), epidemiologists (Jon Genuneit, Ulm University, Germany; Isabella Annesi-Maesano, Paris), experts in gut mucosal inflammation (Chrystelle Bonnart and Nathalie Vergnolles, Toulouse; Gijs Van den Brink, The Netherlands), infant infectious disease immunlogy (Arnaud Marchant, Belgium and Tobias Kollmann, Canada), infantile nutrition companies (Nestlé and Nutricia) and allergy immunotherapy company (Stallergen).
Our team is hosted at the Hôpital de l’Archet and occupies a 800 m2 building with 4 culture room and 2 fully equipped experimental laboratories and a cytometry platform with FACS CANTO, FACS Vantage, FACS Aria. The laboratory is in close proximity to the C3M research centre, which is equipped of a brand new animal facility and houses mice for our research projects.
Funding. resarch is supported by UNS, INSERM, Société Française d'Allergologie, ANR, Fondation Recherche en Santé Respiratoire
EA 6302 Tolérance Immunitaire Team, Université de Nice Sophia-Antipolis
Hopital de l'Archet 1
Route Saint Antoine de Ginestière
06202 Nice Cedex 03
phone: +33 (0) 4 92 15 77 06 (office)/ +33 6 01 82 41 32 (cell phone)
Selected recent publications
Breast milk impact on immune system education
1. Verhasselt V, Milcent V, Cazareth J, Kanda A, Fleury S, Dombrowicz D, et al. Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat Med 2008; 14:170-5
2. Mosconi E, Rekima A, Seitz-Polski B, Kanda A, S. Fleury, E. Tissandie, R. Monteiro, D. D. Dombrowicz, V. Julia, N. Glaichenhaus and V. Verhasselt Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development. Mucosal Immunol 2010; 3:461-74.
3. Verhasselt V. Neonatal tolerance under breastfeeding influence. Curr Opin Immunol 2010; 22:623-30.
4. Verhasselt V. Oral tolerance in neonates: from basics to potential prevention of allergic disease. Mucosal Immunol 2010; 3:326-33.
5. Macchiaverni P, Rekima A, Turfkruyer M, Mascarell L, Airouche, P. Moingeon, K. Adel-Patient, A. Condino-Neto, I. Annesi-Maesano, S. L. Prescott, M. K. Tulic and V. Verhasselt Respiratory allergen from house dust mite is present in human milk and primes for allergic sensitization in a mouse model of asthma. Allergy 2014; 69:395-8.
6. Macchiaverni P, Ynoue LH, Arslanian C, Verhasselt V, Condino-Neto A. Early Exposure to Respiratory Allergens by Placental Transfer and Breastfeeding. PLoS One 2015; 10:e0139064.
7. Turfkruyer M, Rekima A, Macchiaverni P, Le Bourhis L, V. Muncan, G. R. van den Brink, M. K. Tulic and V. Verhasselt Oral tolerance is inefficient in neonatal mice due to a physiological vitamin A deficiency. Mucosal Immunol 2015.
8. Turfkruyer M, Verhasselt V. Breast milk and its impact on maturation of the neonatal immune system. Curr Opin Infect Dis 2015.
9. Verhasselt V. Is infant immunization by breastfeeding possible? Philos Trans R Soc Lond B Biol Sci 2015
10. Turfkruyer M, Verhasselt V. Response to "Disparity between vitamin A-induced Th1-dependent oral tolerance in newborn mice and vitamin A-induced atopic sensitization in Guinean girls". Mucosal Immunol 2016.
Ontogeny of allergic response
11. Tulic MK, Fiset PO, Manoukian JJ, Frenkiel S, Lavigne F, Eidelman DH, et al. Role of toll-like receptor 4 in protection by bacterial lipopolysaccharide in the nasal mucosa of atopic children but not adults. Lancet 2004; 363:1689-97.
12. Prescott SL, Noakes P, Chow BW, L. Breckler, C. A. Thornton, E. M. Hollams, M. Ali, A. H. van den Biggelaar and M. K. Tulic. Presymptomatic differences in Toll-like receptor function in infants who have allergy. J Allergy Clin Immunol 2008; 122:391-9, 9 e1-5.
13. Tulic MK, Hodder M, Forsberg A, McCarthy S, Richman T, D'Vaz N, et al. Differences in innate immune function between allergic and nonallergic children: new insights into immune ontogeny. J Allergy Clin Immunol 2011; 127:470-8 e1.
14. Tulic MK, Andrews D, Crook ML, Charles A, Tourigny MR, Moqbel R, et al. Changes in thymic regulatory T-cell maturation from birth to puberty: Differences in atopic children. J Allergy Clin Immunol 2012; 129:199-206 e4.
Mechanisms of gut barrier dysfunction and role in gut inflammatory disease and irritable bowel syndrom
15. Tulic MK, Vivinus-Nebot M, Rekima A, Rabelo Medeiros S, C. Bonnart, H. Shi, A. Walker, R. Dainese, J. Boyer, N. Vergnolle, T. Piche and V. Verhasselt Presence of commensal house dust mite allergen in human gastrointestinal tract: a potential contributor to intestinal barrier dysfunction. Gut 2015.
16. Tulic MK, Piche T, Verhasselt V. Lung-gut crosstalk: evidence, mechanisms and implications for the mucosal inflammatory diseases. Clin Exp Allergy 2016.
17. Piche T, Barbara G, Aubert P, Bruley des Varannes S, Dainese R, Nano JL, et al. Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators. Gut 2009; 58:196-201.
18. Piche T, Saint-Paul MC, Dainese R, Marine-Barjoan E, Iannelli A, Montoya ML, et al. Mast cells and cellularity of the colonic mucosa correlated with fatigue and depression in irritable bowel syndrome. Gut 2008; 57:468-73.
19. Vivinus-Nebot M, Frin-Mathy G, Bzioueche H, Dainese R, Bernard G, Anty R, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation. Gut 2013.
Innovation in Flow cytometry technique
20. Larbret F, Dubois N, Brau F, E. Guillemot, K. Mahiddine, S. Tartare-Deckert, V. Verhasselt and M. Deckert (2013). Technical advance: actin CytoFRET, a novel FRET flow cytometry method