Kurzfassung

Ruxolitinib (RUX) is the first specific Janus kinase (JAK) inhibitor approved for the treatment of myelofibrosis (MF) or polycythaemia vera (PV), as the pathogenesis of these myeloproliferative neoplasms is linked to a dysregulation of the JAK signalling pathway. In clinical trials, RUX demonstrates a profound reduction of splenomegaly and constitutive symptoms along with an improved quality of life. The most frequent adverse events of RUX include anemia and thrombocytopenia. Beyond this,...Ruxolitinib (RUX) is the first specific Janus kinase (JAK) inhibitor approved for the treatment of myelofibrosis (MF) or polycythaemia vera (PV), as the pathogenesis of these myeloproliferative neoplasms is linked to a dysregulation of the JAK signalling pathway. In clinical trials, RUX demonstrates a profound reduction of splenomegaly and constitutive symptoms along with an improved quality of life. The most frequent adverse events of RUX include anemia and thrombocytopenia. Beyond this, severe infectious complications have been reported in association with RUX, such as C. neoformans pneumonia, toxoplasmosis retinitis and hepatitis B virus reactivation, indicating immunosuppressive effects of this drug on the innate as well as the adaptive immune system. On the cellular level, RUX has yet been characterized as a negative regulator for NK- and T-cell functions, possibly accounting for the side effects observed. In our present work, we focused on the impact of RUX on polymorphonuclear neutrophil (PMN) activation as important regulators of the innate immune response. Preliminary experiments performed in our lab revealed a direct influence of RUX on PMN effector functions that need to be further analysed. Therefore we plan to determine the impact of RUX pretreatment on the full spectrum of effector functions elucidated after TLR- and non-TLR-stimulation. This will provide further insights into the quality of innate immune response under RUX treatment. In further continuation we will perform western blot analysis to determine differences in the intracellular signalling cascade. Finally we plan to transfer the collected results to the situation in patients under RUX treatment in comparison to healthy controls. These data provide deeper insights on the impact of RUX as an immunosuppressant of innate immunity on the cellular level and may help to explain the severe infectious complications observed in RUX-treated patients and possibly lead to enhanced medical care.
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