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Für unser Team der Nephrologie suchen wir immer hochmotivierte Mitarbeiter... OFFENE STELLEN

Biomedical research is a focus of the division of nephrology. From cell free systems to complex in vivo analysis, ... GRUNDLAGENFORSCHUNG


Necrosis is a central pathophysiological driver of two major aspects during solid organ transplantation. Firstly, it directly results in the loss of function of parenchymal cells, resulting in organ dysfunction. Secondly, necrotic cells stimulate the immune system in a process referred to as necroinflammation. There is no more potent trigger of the adaptive immue system known than necrotic tissue. We hypothesize that antibody-mediated rejection, a paramount clinical mediator of graft loss, may be triggered by necrosis. And this, in theory, should be a very druggable process!

A novel hypothesis for the development of antibody mediated rejection (ABMR) Upon the process of transplantation of damaged (e.g. marginal) organs, naïve recipient B cells encounter massive necrosis and DAMPs during the very first passage through the graft and are being potently primed. The proliferative B cell response and the subsequent differentiation to plasma cells is prevented by the standard immunosuppression at this early time point. However, upon tapering of the immunosuppression during the first year after virtually successful transplantation, primed memory B cells progressively proliferate and terminally differentiate into plasma cells, producing donor specific antibodies and mediating ABMR. Clinically, at this stage, plasma exchange may temporarily prevent ABMR progression, but as soon as plasma exchange stops, ABMR will slowly reactivate. Our model suggests that early interference with regulated necrosis unlike HLA- or even blood group-matching possesses the capacity to prevent memory B cell priming and ABMR. Addition of necrosis blocking agents, e.g. small molecules in the machine perfusate, are predicted to prevent ABMR.

We defined the interconnection between Regulated Necrosis and inflammation as Necroinflammation. We believe that inflammation should be considered whenever necrosis is studied, simply because there is no necrosis without an immune response to it.

PD Dr. Andreas Linkermann
Principle Investigator