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1. 1 Skin targeting for vaccine efficacy Laboratory of « Immunity and Infection » INSERM Paris, France Behazine COMBADIERE, PhD Director of research INSERM
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4. Skin, Mucosa sites Intensity Quality (T cells: cytokine released, cytotoxicity, B cells: IgG, IgA) Persistence of Memory Localization (mucosa, skin, liver) CD4 T cells Dendritic cells B cells CD8 T cells
5. SKIN TARGETING OF APC DICTATES IMMUNOLOGICAL OUTCOMES Lymph nodes HAIR FOLLICLE Stratum corneum Langerhans cells Lymph node Micro- environments Epidermis Lymphatic vessels Dermal- epidermal junction Dermal DC Dermis Differential targeting of antigen-presenting cells dictates the immunological outcomes (intensity, quality, localization) Lymphatic and blood capillary vessels Hypodermis Leukocytes recruitment(neutrophils, monocytes, pDC) CD4 T cells Dendritic cells B cells CD8 T cells Blood vessels
6. Stratum corneum Follicular cast Hair fibre + cyanoacrylate glue + follicular casts+ ca. 30% of stratum corneum HAIR FOLLICLE TARGETING OF COMPOUNDS TO LANGERHANS CELLS Stratum corneum Epidermis Dermis Lymphatic and blood capillary vessels Hypodermis Vogt et al. J Invest Dermatology 2006 and Mahe J Invest Dermatology 2008
7. Suitable size of vaccine compounds intofollicularducts 1500-700 nm 200 nm 40 nm 37°C Suitable size for Langerhans cells up-take of vaccine : biodegradable or solid nanoparticles, virus like particles, small viruses, DNA, protein/peptide-carrier Skin purified human CD1a+ cells (+40nm) 5
8. PROOF OF CONCEPT: PHASE I TRIAL OF AN INFLUENZA VACCINE Influenza-specific CD8 TC route Vogt et al. J Immunol 2008 and Combadiere et al Plos One 2010 IM route Hair follicle Langerhans cells favors CD8 responses and also mucosal immunity but not IgG responses Influenza-specific CD4
9. FROM HUMANIZED MICE TO CLINICAL TRIALS “tailor-cut” immunization strategies could be proposed for infectious diseases: HIV, Malaria, Tuberculosis, emerging diseases and cancer EU-FP7 large-scale coordination : CUT’HIVAC project 2010-2014 Pre-clinical models Humanized mice CLINICAL TRIALS Human skin Explants Human immune cells Immunodeficient mice
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