TY  - JOUR
A1  - Weiss, Esther
A1  - Schlegel, Jan
A1  - Terpitz, Ulrich
A1  - Weber, Michael
A1  - Linde, Jörg
A1  - Schmitt, Anna-Lena
A1  - Hünniger, Kerstin
A1  - Marischen, Lothar
A1  - Gamon, Florian
A1  - Bauer, Joachim
A1  - Löffler, Claudia
A1  - Kurzai, Oliver
A1  - Morton, Charles Oliver
A1  - Sauer, Markus
A1  - Einsele, Hermann
A1  - Loeffler, Juergen
T1  - Reconstituting NK Cells After Allogeneic Stem Cell Transplantation Show Impaired Response to the Fungal Pathogen Aspergillus fumigatus
JF  - Frontiers in Immunology
N2  - Delayed natural killer (NK) cell reconstitution after allogeneic stem cell transplantation (alloSCT) is associated with a higher risk of developing invasive aspergillosis. The interaction of NK cells with the human pathogen Aspergillus (A.) fumigatus is mediated by the fungal recognition receptor CD56, which is relocated to the fungal interface after contact. Blocking of CD56 signaling inhibits the fungal mediated chemokine secretion of MIP-1α, MIP-1β, and RANTES and reduces cell activation, indicating a functional role of CD56 in fungal recognition. We collected peripheral blood from recipients of an allograft at defined time points after alloSCT (day 60, 90, 120, 180). NK cells were isolated, directly challenged with live A. fumigatus germ tubes, and cell function was analyzed and compared to healthy age and gender-matched individuals. After alloSCT, NK cells displayed a higher percentage of CD56\(^{bright}\)CD16\(^{dim}\) cells throughout the time of blood collection. However, CD56 binding and relocalization to the fungal contact side were decreased. We were able to correlate this deficiency to the administration of corticosteroid therapy that further negatively influenced the secretion of MIP-1α, MIP-1β, and RANTES. As a consequence, the treatment of healthy NK cells ex vivo with corticosteroids abrogated chemokine secretion measured by multiplex immunoassay. Furthermore, we analyzed NK cells regarding their actin cytoskeleton by Structured Illumination Microscopy (SIM) and flow cytometry and demonstrate an actin dysfunction of NK cells shown by reduced F-actin content after fungal co-cultivation early after alloSCT. This dysfunction remains until 180 days post-alloSCT, concluding that further actin-dependent cellular processes may be negatively influenced after alloSCT. To investigate the molecular pathomechansism, we compared CD56 receptor mobility on the plasma membrane of healthy and alloSCT primary NK cells by single-molecule tracking. The results were very robust and reproducible between tested conditions which point to a different molecular mechanism and emphasize the importance of proper CD56 mobility.
KW  - natural killer cell
KW  - stem cell transplantation
KW  - corticosteroids
KW  - CCL3
KW  - CCL4
KW  - CCL5
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212581
SN  - 1664-3224
VL  - 11
ER  - 
TY  - THES
A1  - Englert, Anne
T1  - Modulation der Immunantwort humaner NK-Zellen nach Stimulation mit steigenden Konzentrationen von Aspergillus fumigatus
T1  - Modulation of human NK-cells' immune response after stimulation with different concentrations of Aspergillus fumigatus
N2  - Diese Arbeit beschäftigt sich mit den antimykotischen Eigenschaften von NK-Zellen und dient der Charakterisierung der Immunantwort gegenüber A. fumigatus in Abhängigkeit der MOI (Multiplizität der Infektion). Klinisch interessant ist dies bei immunsupprimierten Patienten mit invasiver Aspergillose. Anhand von Oberflächenmarkern konnten eine an die Pilzkonzentration angepasste Bindung und Aktivierung von NK-Zellen demonstriert werden. Daneben kam es zu einer Modulation der Freisetzung ausgewählter Zytokine nach Konfrontation mit steigenden Mengen von A. fumigatus. Besonders deutlich war der Effekt bei den Chemokinen CCL3 und CCL4, deren Zusammenhang mit Pilzinfektionen bereits gezeigt wurde. Die Ergebnisse zum MOI-abhängigen Verhalten von NK-Zellen gegenüber A. fumigatus bestätigen die Relevanz bei der antimykotischen Immunantwort und verdeutlichen, weshalb ihnen zunehmende diagnostische und therapeutische Bedeutung zukommt.
N2  - The thesis focuses on the antifungal activity of NK-cells and characterizes the immune response towards A. fumigatus depending on the MOI (multiplicity of infection). This is of clinical interest regarding immunosuppressed patients suffering from invasive aspergillosis. Surface markers were used to demonstrate the binding and activation of NK cells adapted to the fungal concentration. In addition, the release of selected cytokines was modulated after confrontation with increasing amounts of A. fumigatus. The chemokine CCL3 and CCL4 that have already been described to be important during fungal infections showed the most impressive results. This study confirms the role of NK cells within the antifungal immune response and the increasing relevance for diagnosis and therapy.
KW  - Natürliche Killerzelle
KW  - Aspergillus fumigatus
KW  - natural killer cell
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202335
ER  -