A7: Role of myeloid-derived suppressor cells (MDSCs) in trauma

PI: G. Strauß

The clinical course after trauma depends on the balance or imbalance of pro-and anti-inflammatory responses.  While predominance of a pro-inflammatory response leads to ”systemic inflammatory response syndrome” (SIRS) and overwhelming immune reactions, inhibition of the immune response induces the ”compensatory anti-inflammatory response syndrome“ (CARS) connected with immunosuppression and an enhanced risk for all types of infections. Traumatic injuries are associated with the release of pro-inflammatory factors such as TNF-α, IL-6 or glucocorticoids, which shape the immune response. Several types of inflammation such as tumors, autoimmunity, and bacterial infections are known to induce a population of immature myeloid cells, which suppress T cell-mediated immune responses such as T cell activation, proliferation, and cytotoxicity. These heterogeneous populations of immature myeloid cells are defined as myeloid-derived suppressor cells (MDSCs) and are characterised by the co-expression of surface molecules CD11b and Gr-1. At present, the impact of MDSCs on the course of disease and the innate and adaptive immune responses after traumatic injuries are not well defined. A few studies point to a beneficial effect of MDSC appearance for the injured host, however, their precise effects on innate and cellular immunity are unclear. Therefore, we will use different trauma models preferentially blunt chest trauma and blunt chest trauma in combination with femur osteotomy to define the kinetics of MDSC induction after injury and determine their influence on innate immunity and T cell functions. Using MDSC-depleting antibodies or the injection of in vitro-generated MDSCs will show at which time point after trauma, MDSCs interfere with the trauma-induced immune response and whether induction of MDSCs is detrimental or advantageous for the injured host. A major focus of the studies will be the modulation of T cell functions by trauma-induced MDSCs. Immune suppression and susceptibility for opportunistic infections after trauma is often associated with a skewing towards Th2 immunity and the loss of Th1-specific cytotoxicity. Whether and how MDSCs influence the Th1/Th2 balance after traumatic injuries will be analysed. Since pro-inflammatory factors such IL-6 and glucocorticoids are strongly induced after blunt chest trauma and are known to be required for the expansion and maturation of MDSCs, we will delineate the role of IL-6 and GC for MDSCs induction and T cell immune responses. Analysis of MDSCs induction and function and their influence on T cell-mediated immune responses in other trauma models will further clarify whether MDSCs have a general impact on the course of traumatic injuries and how they influence SIRS and CARS. The anticipated results will define the role of MDSCs after traumatic injury and might help to clarify whether interference with MDSC development is a possible therapeutic option after trauma induction.

Video

Projektleiter

Prof. Dr. Gudrun Strauß
Universitätsklinik für Kinder- und Jugendmedizin
Forschungslabor
Eythstr. 24, Haus 16
89075 Ulm
Tel.: +49 731 500-57033
Fax: +49 731 500-57042
gudrun.strauss(at)uniklinik-ulm.de
Homepage

Model for trauma-induced MDSC modulation of the immune response