Descrizione del progetto
Fare luce sul puzzle immunitario
Attualmente la nostra comprensione dei processi che agevolano la rimozione efficiente degli auto-antigeni dalle cellule apoptotiche e necrotiche, che consente al sistema immunitario di rispondere efficacemente agli agenti patogeni invasori, è limitata. La mancanza di tecniche adeguate ha ostacolato l’identificazione e la localizzazione di specifiche sottopopolazioni di fagociti responsabili della rimozione simultanea di cellule morenti e agenti patogeni all’interno di un organismo vivente. Per ovviare a queste limitazioni, il progetto SOS, finanziato dal CER, si propone di sviluppare strumenti innovativi che facciano luce sugli intricati meccanismi coinvolti nella rimozione delle cellule morenti e degli agenti patogeni, in particolare in presenza di infiammazione. Il progetto intende approfondire le nostre conoscenze sulle cause alla base delle malattie autoimmuni e infettive, nonché promuovere l’elaborazione di approcci terapeutici innovativi.
Obiettivo
During inflammation and infection, we are simultaneously confronted with both self and non-self in form of dying cells and microbes, respectively. Mechanisms that facilitate the non-immunogenic clearance of self-antigens derived from apoptotic and necrotic cells and that, in parallel, allow the initiation of an immune response against invading pathogens are incompletely understood.
Recent data from our laboratory show that the immune system actively sorts apoptotic cells (ACs) and bacteria into distinct subspecies of macrophages and dendritic cells thereby enabling a segregated processing of self and non-self as well as a differential immune response against these two entities. Incorrect sorting and aberrant uptake of AC-derived self-antigens by pro-inflammatory and antigen-presenting dendritic cells, however, results in the break of self-tolerance and autoimmunity.
Due to technical limitations, the identification and fate-mapping of specific phagocyte subsets that mediate the simultaneous clearance of dying cells and pathogens in vivo has remained largely elusive. We thus plan to develop novel tools that are based on cutting-edge technologies to comprehensively elucidate the sorting of dying cells and pathogens under inflammatory conditions in vivo. We plan to generate TAT-Cre transgenic mice and bacteria that will be used in conjunction with R26-eYFP reporter animals to permanently track phagocytes after ingestion of endogenously accumulated dying cells and pathogens, respectively. These approaches will enable us to characterize the involved phagocytes, study molecular mechanisms underlying the differential processing of self and non-self and follow the phagocyte’s migratory behaviour and its subsequent differentiation. The obtained data will not only provide insights into the pathogenesis of autoimmune and infectious diseases, but will also foster the development of novel therapeutic strategies for the treatment of such disorders.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
91054 Erlangen
Germania