Istituto di Ricerca in Biomedicina
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Istituto di Ricerca in Biomedicina
Chemokine ed Immunità
Panoramica
Il nostro interesse di ricerca rimane focalizzato sul traffico cellulare nella fisiologia e patologia umana, con particolare attenzione ai meccanismi che regolano la modulazione dell’espressione e dell’attività delle chemochine, molecole chiave nel controllo della migrazione cellulare, e dei loro recettori. Gli effetti delle chemochine sono mediati da recettori a sette domini transmembrana che sono differenzialmente espressi in una vasta gamma di cellule del sangue e non solo. La diversità di espressione dei recettori e la loro reattività alle chemochine garantiscono la corretta distribuzione tissutale dei diversi tipi di globuli bianchi sia in condizioni normali che patologiche. L’orientamento delle cellule nell’organismo è assicurato attraverso gradienti di chemochine. Numerose evidenze sperimentali mostrano il diretto coinvolgimento di recettori delle chemochine in molte condizioni patologiche, e rendendo questa famiglia di recettori un possibile bersaglio di una nuove e mirate terapie farmacologiche.
Fin dall’inizio della risposta infiammatoria ed anche nel caso delle malattie autoimmuni, il rilascio sequenziale di agenti esogeni (ad esempio prodotti batterici e virali) e l’induzione di mediatori endogeni (ad esempio citochine, chemochine e allarmine) contribuiscono al reclutamento di globuli bianchi circolanti nel sito infiammatorio. Vari meccanismi regolano la risposta infiammatoria e il reclutamento di globuli bianchi. Il nostro gruppo ha descritto un meccanismo di regolazione della migrazione leucocitaria che mostra come diverse molecole possano indurre i globuli bianchi a rispondere a concentrazioni di chemochine che per sé sarebbero inattive, abbassando così la loro “soglia migratoria”. Tuttavia, sappiamo ancora poco sulle caratteristiche di questi complessi formati da molecole infiammatorie e chemochine e sulle loro interazioni. I nostri studi si stanno ora concentrando sulle malattie infiammatorie croniche, come ad esempio l’Artrite Reumatoide e la Spondilite Anchilosante, sul ruolo che questi complessi hanno nello sviluppo della malattia e su come si possa intervenire per favorire la risoluzione dell’infiammazione. Recentemente abbiamo dimostrato che anche l’attività dei recettori per le chemochine può essere influenzata da uno stato di attivazione cronica del sistema immunitario. Questi ulteriori studi sul traffico leucocitario, possono favorire lo sviluppo di nuove terapie in pazienti con infezioni persistenti, favorendo il ripristino delle funzioni di popolazioni cellulari attive nella risposta immunitaria.
Progetti
Researchers
Mariagrazia Uguccioni – Group Leader
Gabriela Danelon Sargenti – Technician
Status: in progress
Overview
Chemokines have emerged as key controllers of integrin function and cell locomotion. A vast range of in situ experiments has revealed that a variety of chemokines can be concomitantly produced in physiology, as well as in tumours. This renders the chemokine system a good target for therapy, and has increased the search, by pharmaceutical companies, for chemokine antagonists. While we understand well the effects of different chemokines one by one, much less was known about the potential consequences of the expression of multiple chemokines, cytokines, toll like receptor ligands or different inflammatory molecules, on cell responses to chemokines. Chemokine structure/function studies led us to identify chemokines that can act as natural antagonists by preventing natural agonist binding and the subsequent activation of the receptor. Recently, we have described chemokines that can act in synergism with chemokine receptor agonists, forming heterocomplexes able to induce functional responses at lower agonist concentration. There is no more doubt that the synergism between chemokines is crucial at the very early stage of inflammation, while the study of the role of molecules, such as the alarmin High Mobility Group Box 1 (HMGB1), that can synergise with chemokines is at its infancy.
Researchers
Mariagrazia Uguccioni – Group Leader
Gabriela Danelon Sargenti – Technician
Status: in progress
Overview
We have recently provided evidence that HMGB1, a damage associated molecular pattern protein (DAMP), can synergise with the CXCR4 agonist, CXCL12, promoting immune cell influx in injured tissues and enhancing immune cell responses. Cell income is blocked by glycyrrhizin, the sweet tasting compound of liquorice root, able to abolish the synergistic effect of HMGB1 on CXCL12-dependent migration, without affecting CXCL12/CXCR4 interaction. Given the fact that CXCL12 is strongly expressed in many tissues, favouring cell influx and egression, we aim to characterize in vitro and in vivo the mechanisms of action of chemokine synergy-inducing molecules on cell trafficking.
These studies might pave the way to establish novel approaches for controlling leukocyte migration and activities.
Group leaders: Mariagrazia Uguccioni
Researchers: Valentina Cecchinato – Scientist, Gabriela Danelon Sargenti – Technician
Status: In progress
Researchers
Mariagrazia Uguccioni – Group Leader
Valentina Cecchinato – Scientist
Gabriela Danelon Sargenti – Technician
Status: in progress
Overview
30 years after the discovery of human immunodeficiency virus (HIV) as the causative agent of AIDS, the mechanisms governing pathogenesis and disease progression are still not fully understood. Indeed, a progressive impairment of the immune system, with alterations that affect both innate and adaptive immunity, characterizes the infection with HIV‑1 in humans and with simian immunodeficiency virus (SIV) in macaques. It has been proposed that a state of chronic immune activation contributes to the loss of CD4+ T cells and to alterations of immune responses, ultimately leading to disease progression.
The loss of CD4+CCR5+ T cells in the gut associated lymphoid tissue (GALT) has been well documented both in the natural host and in pathogenic models of SIV infection. A decrease in the frequency of Th17 cells, a subset of effector T cells involved in the immune response against extracellular bacteria, has been described by Dr. Cecchinato in the mucosa of SIV infected animals. Nevertheless, the migratory capacity of this T cell subpopulation has not been investigated so far.
Chemokines are important mediators of leukocyte trafficking and function, and deregulation of their expression might contribute in part to the pathogenesis of HIV-1/SIV infection. In the frame of a projects funded by the European Community and by the Swiss HIV Cohort Study, we are investigating the mechanisms that mediate CCR6+/Th17 cells trafficking and activities at mucosal sites together with their decrease in frequency during HIV/SIV infection in order to better understand the pathogenesis of AIDS and in view of generating efficient vaccines.
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