E. Chiffoleau completed her Ph.D. degree (1999-2002) in UMR Nantes-INSERM on the identification and characterization of new molecules involved in allograft tolerance. She performed a postdoctoral position (2002-2003) at the University of Pennsylvania, Philadelphia, in the laboratory of Dr. Laurence Turka. Her research was on the study of the mechanisms and molecular pathways of molecules (TRAF6, BclXL, Notch) involved in allograft or self-tolerance. She then obtained a permanent position at the Institut National de la Santé Et de la Recherche Médicale (INSERM) in Nantes, France in INSERM U643. Her research focus now on the study of molecules involved in transplantation tolerance in rodents. She described, CLEC-1, a C-type lectin like receptor, as playing a role in antigen-presenting cell activation and the subsequent T-helper cell differentiation.
The identification of molecules that could predict or diagnose tolerance (biomarkers) or that could induce tolerance is a crucial aim of research that would allow in clinic to adapt immuno-suppressors treatment. In this regard, we have developed strategy of gene searching in a experimental model of allograft long-term tolerance to identify new molecules that could play a role in tolerance (Heslan et al. Transplantation 2006). For example, we identified IFNg and IDO as two genes up-regulated in tolerated allografts and showed their direct involvement in tolerance (Heslan et al. Transplantation 2006) (Thebault et al. Am J Transplant 2007). Thus, we started to analyze the role of one molecule, identified as up-regulated in tolerated allografts, CLEC-1, a C-type lectin like receptor. We showed in rat, that CLEC-1 is expressed by dendritic (DCs) and endothelial cells and that its expression was decreased by inflammatory mediators and enhanced by tolerogeneic molecules or by regulatory CD4+CD25+ T cells (Thebault et al. J Immunol 2009). Moreover, we showed that CLEC-1 in DCs moderates the subsequent effector T cell activation (Thebault et al. J Immunol 2009). We are now generating a fusion protein (extracellular domain of rat CLEC-1/murin IgG Fc fragment)that will help to determine the ligand of CLEC-1 (by 2D gel and chromatography), to generate a monoclonal antibody (by immunization), and to block the interaction with the ligand in in vitro and in vivo assays of T cell stimulation. Moreover, we aim to generate a KO rat by zinc-finger nucleases technique and to determine whether a soluble form of CLEC-1 exists as it is the case for other members of this family that could serve as biomarker of tolerance.
Other molecules are under study that are associated with a B cell signature observed in blood of rats or patients developing spontaneously operational tolerance following immuno-suppressive treatment (collaboration with Team S. Brouard/JPS). In the long-term, these molecules may represent a new therapeutic agent to modulate the immune response in transplantation but also in auto-immunity or cancer settings.