Chemochine e Immunità Mariagrazia Uguccioni AIBT 2016 – Pesaro 1987 – Discovery of the first “chemotactic cytokine” – IL8 Marco Baggiolini Theodor Kocher Institute University of Bern (CH) The Chemokine System - 2016 CCL23 CXCL8 CCL15 CXCL7 CCL14 CXCL6 CCL13 CXCL5 CXCL8 CXCL3 CCL8 CXCL6 CCL7 CXCL11 CXCL2 CXCL1 CCL5 CCL13 CXCL10 CCL3 CCL8 CXCR1 CXCL9 CCL7 CCL26 CXCR2 CCR1 CCL2 CCL13 CXCR3 CCL11 CXCL12 CCR2 CCL8 CCL7 CXCR4 CCL5 CCR3 CXCL13 CXCR5 CCL22 CCL17 CCR4 CXCL16 CXCR6 CCL3 CCR5 CCL4 CXCL17 CXCR8 CCL5 CCL8 CCR6 CX3CR1 CCL20 CX3CL1 XCR1 CCR7 XCL1 CCL19 CCR10 CCR8 XCL2 CCR9 CCL21 CCL27 CCL1 CCL28 CCL25 Cell Migration Selectin-mediated rolling 1 Chemoattractan signalling 2 Integrin-mediated cell adhesion 3 Step 1: attachement and rolling Migration along Step 2: activation chemotactic gradient Step 3: arrest and adhesion Chemokine source Functional Modules in Cell Migration T naive IL-2 CCR7 mature DC Priming B naive IL-6 CXCR5 FDC, TFH Antibody immature DC GM-CSF CCR1, CCR5 T naive Antigen uptake TH1 IFN- CCR5 M Bacteria TH2 IL-4, IL-5 CCR3 Eos/Bas Parasites TH17 IL-17, IL-22 CCR6 Neut Fungi CTL IFN-, Perf CXCR3 M Virus From Blood to Tissue CCR1 Tissue Blood CCR2 CCR2 CCR5 CXCR3 From Tissue to Lymph Nodes CCL21 Lymph nodes are privileged sites normal for dendritic cell-naïve T cell encounters CCL21 CCR7 CCL21 inflamed CCL19 from S. Lira, Nat Immunol 2005, 6:866. Functional Modules in Cell Migration T naive IL-2 CCR7 mature DC Priming B naive IL-6 CXCR5 FDC, TFH Antibody immature DC GM-CSF CCR1, CCR5 T naive Antigen uptake TH1 IFN- CCR5 M Bacteria TH2 IL-4, IL-5 CCR3 Eos/Bas Parasites TH-17 IL-17, IL-22 CCR6 Neut Fungi CTL IFN-, Perf CXCR3 M Virus mature DC IL-12, IL-4 CCR7 T naive Priming Functional Modules in Cell Migration Bone Marrow Differentiation CXCR4 all cells CXCL12 (all tissues) and homing CCL19 CCR7 T naïve, mDC Lymph nodes Priming in LN Lymph nodes CCR7 T naïve, mDC Homing to LN CCL21 Lymphatic vessels CXCL13 CXCR5 B cells, TFH Lymph nodes Homing to LN The Chemokine System - 2016 CCL23 CXCL8 CCL15 CXCL7 CCL14 CXCL6 CCL13 CXCL5 CXCL8 CXCL3 CCL8 CXCL6 CCL7 CXCL11 CXCL2 CXCL1 CCL5 CCL13 CXCL10 CCL3 CCL8 CXCR1 CXCL9 CCL7 CCL26 CXCR2 CCR1 CCL2 CCL13 CXCR3 CCL11 CXCL12 CCR2 CCL8 CCL7 CXCR4 CCL5 CCR3 CXCL13 CXCR5 CCL22 CCL17 CCR4 CXCL16 CXCR6 CCL3 CCR5 CCL4 CXCL17 CXCR8 CCL5 CCL8 CCR6 CX3CR1 CCL20 CX3CL1 XCR1 CCR7 XCL1 CCL19 CCR10 CCR8 XCL2 CCR9 CCL21 CCL27 CCL1 CCL28 CCL25 PATHOPHYSIOLOGY - TARGET IDENTIFICATION AND VALIDATION INHIBITION OF SYNTHESIS Synergy- inducing AGONIST AGONIST BLOCKERS PHARMACOLOGY - MODELLING ANTAGONISTS l pep and sm NON-COMPETITIVE ALLOSTERIC INHIBITORS Annu Rev Immunol. 2014;32:659-702. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Griffith JW1, Sokol CL, Luster AD. Patricia Ogilvie Istituto Scientifico H San Raffaele Marcus Thelen Samantha Paoletti Milan, Italy Tiziana Apuzzo Gabriela Danelon Silvia Sebastiani Marco Bianchi Luca Varani Basil Gerber Emilie Vereneau Mattia Pedotti Vibor Petkovic Angela Raucci Elsa Livoti Ulf Panzer Barbara Celona Tamara Visekruna Andrea Cavalli Luisa Stefano Denise Bottinelli Katrin Kuscher Centro Nacional de Biotecnologia Daniel Venetz Milena Schiraldi Madrid, Spain Valentina Cecchinato Mario Mellado Lorenzo Raeli Laura Martínez-Muñoz Gianluca D’Agostino Michele Proietti Mara Ambrosini Amanda Proudfoot Funds: MUVADEN MD-THIV TIP-VAC ADITEC San Salvatore DEC-VAC TIMER Foundation DC-THERA MAIN Helmut Horten Ceschina INNOCHEM Foundation Foundation.