Bedeutung dendritischer Zellen für die Tumortherapie mit Immunkontrollpunkt-Inhibitoren

Neben Operation, Chemotherapie oder Bestrahlung nimmt die Bedeutung der Immuntherapie in den letzten Jahren als neue Therapiesäule bei Tumorerkrankungen weiter zu. Einer der dabei zu Grunde liegenden Mechanismen zielt auf die Blockade der Immunkontrollpunkte CTLA-4 und PD-1 mittels monoklonaler Antikörper wie Ipilimumab bzw. Nivolumab oder Pembrolizumab ab. Gerade durch den kombinierten Einsatz dieser Kontrollpunktinhibitoren wurden nicht nur bei soliden Tumoren, wie dem malignen Melanom oder dem Mammakarzinom, sondern auch bei Tumoren, welche sich innerhalb des Immunsystems bilden, große klinische Erfolge verzeichnet. Lange Zeit wurde als Mechanismus der Therapie fast ausschließlich die Reaktivierung der im Tumormilieu supprimierten T-Zell-Funktionen vermutet. Mittlerweile hat man herausgefunden, dass der therapeutische Effekt der Immunkontrollpunkt-Inhibition zusätzlich von weiteren Immunzellen und deren Zytokinsekretion abhängt. Unter der Therapie mit anti-CTLA-4- und anti-PD-1-Antikörpern produzieren T-Zellen und vor allem NK-Zellen vermehrt Interferon-γ (Ahmetlic et al., 2021). Ausgangspunkt dieser Arbeit ist, dass dies wiederum Einfluss auf die Eigenschaften dendritischer Zellen (DZ) ausüben sollte. Diese spielen als Antigen-präsentierende Zellen (APZ) eine Schlüsselrolle in der Bekämpfung von Tumorzellen. Allerdings scheinen ihre phänotypischen und funktionellen Eigenschaften in der Tumorumgebung verändert bzw. unterdrückt zu werden (Naujoks et al., 2014). Es wurde daher untersucht, ob der Einsatz der therapeutischen Antikörper zu einem Wechsel der inhibitorischen Eigenschaften tumor-infiltrierender DZ (TIDZ) hin zu einer gewünschten inflammatorischen Reaktionskaskade führt. Als Untersuchungsmodell wurden transgene λ-MYC-Mäuse verwendet, welche nach 80 bis 120 Tagen endogene B-Zell-Lymphome entwickeln. Zunächst wurde der Reifegrad der TIDZ aus mit Antikörpern behandelten λ-MYC-Mäusen anhand der Expression von Oberflächenmarkern charakterisiert. Dabei war das Verhältnis der CD11cniedrig zur CD11choch Population im Vergleich zur unbehandelten Kontrollgruppe signifikant verringert. Dies ist in funktioneller Hinsicht von Bedeutung, da die CD11cniedrig Population als regulatorische und eher unreife Subgruppe bezeichnet wird, welche Anergie und Tumorzelltoleranz in T-Zellen induziert (Perrot et al., 2007). Zudem kam es unter Therapie insbesondere in der CD11cniedrig Gruppe zu einer Hochregulation der kostimulatorischen Marker CD80, CD86 und des Haupthistokompatibilitätskomplex-II (MHC-II), welche essentiell für eine erfolgreiche T-Zell-Stimulation sind. Auch konnte gezeigt werden, dass es durch IFN-γ zu einer Umkehr des im Tumormilieu verringerten IL-12-/IL-10-Verhältnis in DZ kam, wodurch eine TH1-gesteuerte Antitumor-Antwort begünstigt werden sollte. Die Steigerung des IL12-/IL-10-Verhältnisses konnte darüber hinaus auch durch die direkte Interaktion der therapeutischen Antikörper mit DZ erreicht werden. Von besonderer Bedeutung war schließlich die klar verbesserte Fähigkeit der TIDZ zur allogenen und auch peptidspezifischen T-Zell-Stimulation in vitro, welche aus Mäusen gewonnen wurden, die zuvor mit α-CTLA-4- und α-PD-1-Antikörpern behandelt worden waren. Zusammenfassend zeigt diese Arbeit, dass dendritische Zellen unter Therapie mit Immunkontrollpunktinhibitoren ihre im Tumormilieu unterdrückten Funktionen wieder erlangen können. Gemeinsam mit NK-Zellen unterstützen DZ die Antitumor-Aktivität der T-Zellen und tragen daher maßgeblich zum therapeutischen Erfolg von α-CTLA-4- und α-PD-1-Antikörpern im λ-MYC-Lymphommodell bei

Inspecting PV-plants using aerial, drone-mounted infrared thermography system

Paper presented to the 3rd Southern African Solar Energy Conference, South Africa, 11-13 May, 2015.Worldwide more than 140 GW photovoltaic plants are installed. The demand for testing methods for quality control of installed photovoltaic modules is increasing. Imaging techniques, like infrared imaging, are very popular. There are several advantages, providing two-dimensional images, measuring during operating conditions, fast and contactless as well as non-destructive. Mounting an infrared camera to a drone enhances the inspection but some specialties have to be considered. There are several factors influencing the image quality, as the observation angle, the flight altitude, the flight velocity which have to be chosen properly. Besides the influence of the measurement parameters, IR-images of PV-plants and single modules will be shown. Depending on the temperature distribution evidence for specific failure modes are given. Thus, cell fracture, soldering failure, short-circuited cells, by-passed substrings, can be distinguished easily using IR-imaging. Further analyses verify the negative impact of the identified defects on the module performance.cf201

Development and Projected Performance of the Red Kite Sounding Rocket Motor

Averaging about ten launches per year, DLR Mobile Rocket Base (MORABA) has been supporting rocket borne research for more than five decades. Major fields of experimentation include atmospheric physics, microgravity-based research in material physics and biology as well as hypersonic flight research and technology development. Over the last decade, a sustained demand has evolved for sounding rocket vehicles with the capacity to deliver payloads in the order of 400 kg gross mass into trajectories with apogees beyond 250 km or extended dwell time in the hypersonic regime. To leverage cost efficient and reliable military surplus motors such as the Improved Malemute for use in this regime, DLR has contracted Bayern-Chemie GmbH for a joint development and delivery of a suitable solid propellant motor to be used as a first stage. Currently in project phase C, the definition of the motor performance, materials and design are completed and manufacturing of first components has begun. The paper gives an overview of the motor performance and safety characteristics, applications of the motor in vehicle combinations with their projected performances and a schedule of tasks until qualification flight

Main Achievements of the Rocket Technology Flight Experiment ROTEX-T

Based on experience gathered during the hypersonic flight experiments SHEFEX-I and SHEFEX-II the German Aerospace Center (DLR) performed the extensively instrumented flight experiment ROTEX-T (ROcket Technology EXperiment-Transition). ROTEX-T was successfully launched on 19th July 2016 at 06:05 am CEST from the Esrange Space Center near Kiruna in northern Sweden. Students of the RWTH Aachen University supported the design of the project with numerical simulations. ROTEX-T was a low cost flight experiment mission without inertial measurement unit, reaction control and parachute system. The payload reached an altitude of 183 kilometers, performed a ballistic re-entry with a total flight time of approximately 446 seconds and was afterwards recovered by helicopter. An unique and modular data acquisition system with sampling rates of 20 Hz, 1 kHz, 10 kHz and 2000 kHz was developed for ROTEX-T to study also instationary aerothermal phenomena

Dopamine transporter (DAT1) and dopamine receptor D4 (DRD4) genotypes differentially impact on electrophysiological correlates of error processing

Peer reviewedPublisher PD

Structural alterations in a type IV pilus subunit protein result in concurrent defects in multicellular behaviour and adherence to host tissue

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72384/1/j.1365-2958.2001.02629.x.pd

Neisseria meningitidis Differentially Controls Host Cell Motility through PilC1 and PilC2 Components of Type IV Pili

Neisseria meningitidis is a strictly human pathogen that has two facets since asymptomatic carriage can unpredictably turn into fulminant forms of infection. Meningococcal pathogenesis relies on the ability of the bacteria to break host epithelial or endothelial cellular barriers. Highly restrictive, yet poorly understood, mechanisms allow meningococcal adhesion to cells of only human origin. Adhesion of encapsulated and virulent meningococci to human cells relies on the expression of bacterial type four pili (T4P) that trigger intense host cell signalling. Among the components of the meningococcal T4P, the concomitantly expressed PilC1 and PilC2 proteins regulate pili exposure at the bacterial surface, and until now, PilC1 was believed to be specifically responsible for T4P-mediated meningococcal adhesion to human cells. Contrary to previous reports, we show that, like PilC1, the meningococcal PilC2 component is capable of mediating adhesion to human ME180 epithelial cells, with cortical plaque formation and F-actin condensation. However, PilC1 and PilC2 promote different effects on infected cells. Cellular tracking analysis revealed that PilC1-expressing meningococci caused a severe reduction in the motility of infected cells, which was not the case when cells were infected with PilC2-expressing strains. The amount of both total and phosphorylated forms of EGFR was dramatically reduced in cells upon PilC1-mediated infection. In contrast, PilC2-mediated infection did not notably affect the EGFR pathway, and these specificities were shared among unrelated meningococcal strains. These results suggest that meningococci have evolved a highly discriminative tool for differential adhesion in specific microenvironments where different cell types are present. Moreover, the fine-tuning of cellular control through the combined action of two concomitantly expressed, but distinctly regulated, T4P-associated variants of the same molecule (i.e. PilC1 and PilC2) brings a new model to light for the analysis of the interplay between pathogenic bacteria and human host cells

Pathogenic Neisseria Hitchhike on the Uropod of Human Neutrophils

Polymorphonuclear neutrophils (PMNs) are important components of the human innate immune system and are rapidly recruited at the site of bacterial infection. Despite the effective phagocytic activity of PMNs, Neisseria gonorrhoeae infections are characterized by high survival within PMNs. We reveal a novel type IV pilus-mediated adherence of pathogenic Neisseria to the uropod (the rear) of polarized PMNs. The direct pilus-uropod interaction was visualized by scanning electron microscopy and total internal reflection fluorescence (TIRF) microscopy. We showed that N. meningitidis adhesion to the PMN uropod depended on both pilus-associated proteins PilC1 and PilC2, while N. gonorrhoeae adhesion did not. Bacterial adhesion elicited accumulation of the complement regulator CD46, but not I-domain-containing integrins, beneath the adherent bacterial microcolony. Electrographs and live-cell imaging of PMNs suggested that bacterial adherence to the uropod is followed by internalization into PMNs via the uropod. We also present data showing that pathogenic Neisseria can hitchhike on PMNs to hide from their phagocytic activity as well as to facilitate the spread of the pathogen through the epithelial cell layer