|Immunobiology of Dendritic Cells - INSERM U818|
|HEAD||Dr ALBERT Matthew, MD, PhD / firstname.lastname@example.org|
|MEMBERS||Claire BIOT, PhD student / Aurélie BISIAUX, Engineer / Isabelle BOUVIER, M2 training / PhD / Maryse BRANDT, Secretary / Dr Matthew BUCKWALTER, postoc / Armanda CASROUGE, Engineer / Huey Hsuan CHANG, PhD student / Jérémie DECALF, PhD student (left in September 08) / Dr Melissa LAIRD, Postdoc / Dr. Anton KRAXNER (arrived January 2009) / Hélène SAKLANI, Engineer / Clémentine SCHILTE, PhD Student / Stéphanie THOMAS, Projects manager
The lab focuses on the characterization of the cellular and molecular mechanisms underlying the cross-priming of tumor and viral-specific cytolytic T lymphocytes (CTLs). To achieve this goal and maintain a strong link to physiologically and pathologically relevant problems, we are using a ‘bedside-to-bench’ approach to translational research. Regarding our scientific work, it derives in part from our study of patients with naturally occurring tumor immunity. We have found that dendritic cells (DCs) engulf apoptotic tumor cells and process the internalized material for the generation of MHC I / peptide complexes. We expect that with a better understanding of this pathway, it will be possible to design methods for boosting CTL responses in which apoptotic cells are used as a source of antigen for purposes of tumor immunotherapy.
To further our understanding of the cross-presentation pathway, we aim:
1) To define the direct and indirect influence of apoptotic and autophagic cell death on immunity. This involves the use of mouse models to precisely define the mechanism by which type II PCD results in robust tumor and viral immune responses. In addition, we are utilizing cell biology and siRNA knock-down to characterize the path antigen travels as it moves from within the dying cell into the MHC I processing pathway of the dendritic cell.
ii) To identify mechanisms of tumor immunity in patients with superficial transitional cell carcinoma of the bladder. Bladder cancer patients offer an unique opportunity to define the mechanism of a successful immunotherapy intervention. We have initiated a clinical study with the objective being a proteomic analysis utilizing a platform called Multi-Analyte Profiling (MAP). The goal is to identify novel molecular markers that predict clinical
responsiveness to therapy in patients with transitional cell carcinoma (TCC) of the bladder. In defining prognostic or surrogate markers for treatment response, two things will become immediately evident: first, we will identify patients for whom BCG therapy will offer the most benefit and possibly allow for the extension of this useful therapy to a subset of patients with muscle invasive disease thus sparing them the resection of their bladder (the standard therapy for T2-T4 lesions); in addition, if our prediction is correct, the marker analyte will also offers insight into the mechanism of tumor immunity and establish a path for developing new therapeutics for those patient that do not mount a proper anti-tumor immune response following the intravesical instillation of BCG. Cross-over with our basic science aims include the evaluation of candidate molecules for their ability to influence the immunologic outcome of cross-presentation; and the definition of how BCG kills urothelial cells – this seems to be the the means of initiating the anti-tumor immune response.
iii) To characterize the complex role of type I IFNs and inferferon stimulated genes (ISGs) in HCV disease pathogenesis and treatment. HCV is controlled by CD8+ T cells, yet dendritic cells are not directly infected. Thus, to achieve priming, antigen must be cross-presented. Specific to this part of the project, we aim to determine the in vivo pro- and counter-inflammatory effect of IFN and IFN-induced gene products in the cross-priming of CD8<+ T cells. This work will capitalize on the efforts we have made to establish mouse models for the study of cell-associated antigen. In addition, we will generate new tools to control the production of IFNs in vivo thus permitting us to test our hypotheses regarding the dual effect of type I IFNs in tumor and viral immunity. We continue our clinical collaborations in Cairo, Egypt and Paris where it has become possible to test our ideas about the mechanism of action of IFN and ISGs in disease pathogenesis.
Keywords: Antigen, bladder, cross-presentation, dendritic cells, hepatitis, immunotherapy, interferon
Hélène Jusforgues-Saklani, Martin Uhl, Nathalie Blachère, Fabrice Lemaître, Olivier Lantz, Philippe Bousso, Deborah Braun and Matthew L. Albert. 2008. Antigen persistence is required for efficient cross-priming of minor histocompatibility antigen specific CD8+T cells. Journal of Immunology181(5):3067-76 .
Decalf J, Fernandes S, Longman R, Ahloulay M, Audat F, Lefrerre F, Rice CM, Pol S, Albert ML.2007. Plasmacytoid dendritic cells initiate a complex chemokine and cytokine network and are a viable drug target in chronic HCV patients. The Journal of Experimental Medicine. 204(10):2423-37.
Nathalie Blachère, Heather K. Morris, Deborah Braun, Hélène Saklani, James P. Di Santo, Robert B. Darnell and Matthew L. Albert. 2006. Interleukin-2 is required for the activation of memory CD8+ T cells via antigen cross-presentation. J Immunol.176: 7288-300.
Nathalie Blachère, Robert B. Darnell andMatthew L. Albert. 2005. Apoptotic cells deliver processed antigen to dendritic cells for cross-presentation. PLoS Biology.3:e185.
Matthew L. Albert. 2004. Death-defying immunity: do apoptotic cells influence antigen processing and presentation. Nature Reviews Immunology,4: 223-31.
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Activity Reports 2009 - Institut Pasteur
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