Kurzfassung

Polymorphonuclear neutrophils (PMN) play an essential role in innate inflammatory processes. Beside toll-like receptors and NOD-like receptors Triggering receptor expressed on myeloid cells (TREM)-1 is implicated in innate immune activation of these cells and plays a role in infectious as well as non-infectious conditions. Amongst others, activation of TREM-1 results in release of pro-inflammatory chemokines and cytokines and degranulation. Studies on TREM-1 downstream pathways and regulation...Polymorphonuclear neutrophils (PMN) play an essential role in innate inflammatory processes. Beside toll-like receptors and NOD-like receptors Triggering receptor expressed on myeloid cells (TREM)-1 is implicated in innate immune activation of these cells and plays a role in infectious as well as non-infectious conditions. Amongst others, activation of TREM-1 results in release of pro-inflammatory chemokines and cytokines and degranulation. Studies on TREM-1 downstream pathways and regulation of TREM-1 expression revealed an involvement of protein kinase A, phosphatidylinositide 3-kinase (PI3K), mitogen-activated protein kinases and phospholipase C. Apart from the membrane-bound form, a soluble TREM-1 variant (sTREM-1) has been detected in body fluids of various diseases but the exact mechanism and function of sTREM-1 release is unknown so far.
During the last years different small-molecule inhibitors for target therapy were approved for the treatment of hematological and oncological disease. Current data suggest that idelalisib, a selective PI3Kδ inhibitor, influences innate immune defense. Thus, idelalisib serving as a selective inhibitor can be used to gain deeper insights into the involvement of PI3K in TREM-1 signaling and sTREM-1 release in vitro. Furthermore, in vivo studies can elucidate if this plays a relevant clinical role in immune responses of patients receiving idelalisib treatment. Therefore we are first planning to perform in vitro experiments using healthy human PMN regarding effector functions like phagocytosis and oxidative burst after pretreatment with idelalisib and elucidate signal transduction pathways by Western blot analysis. Secondly, studies on a mouse model of invasive pulmonary aspergillosis will be performed to gain insights into susceptibility and completion of infections under idelalisib treatment. Thirdly, we are planning to follow up data and blood samples of patients receiving idelalisib treatment to investigate PMN functions. Fourthly, to receive deeper insights into sTREM-1 release ELISA on cell supernatants and blood samples will be performed. Finally, we expect our results to lead to a deeper understanding of innate immune response concerning TREM-1 signaling. Experimental data will be connected to clinical aspects of patients receiving treatment with small-molecule inhibitors and therefore contribute to improved medical care.
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