TY - JOUR A1 - Rauschenberger, Tabea A1 - Schmitt, Viola A1 - Azeem, Muhammad A1 - Klein-Hessling, Stefan A1 - Murti, Krisna A1 - Grän, Franziska A1 - Goebeler, Matthias A1 - Kerstan, Andreas A1 - Klein, Matthias A1 - Bopp, Tobias A1 - Serfling, Edgar A1 - Muhammad, Khalid T1 - T cells control chemokine secretion by keratinocytes JF - Frontiers in Immunology N2 - The massive infiltration of lymphocytes into the skin is a hallmark of numerous human skin disorders. By co-culturing murine keratinocytes with splenic T cells we demonstrate here that T cells affect and control the synthesis and secretion of chemokines by keratinocytes. While pre-activated CD8\(^+\)T cells induce the synthesis of CXCL9 and CXCL10 in keratinocytes and keep in check the synthesis of CXCL1, CXCL5, and CCL20, keratinocytes dampen the synthesis of CCL3 and CCL4 in pre-activated CD8\(^+\)T cells. One key molecule is IFN-γ that is synthesized by CD8\(^+\)T cells under the control of NFATc1 and NFATc2. CD8\(^+\)T cells deficient for both NFAT factors are unable to induce CXCL9 and CXCL10 expression. In addition, CD8\(^+\)T cells induced numerous type I IFN-inducible “defense genes” in keratinocytes encoding the PD1 and CD40 ligands, TNF-α and caspase-1. The enhanced expression of type I IFN-inducible genes resembles the gene expression pattern at the dermal/epidermal interface in lichen planus, an inflammatory T lymphocyte-driven skin disease, in which we detected the expression of CXCL10 in keratinocytes in close vicinity to the infiltration front of T cells. These data reflect the multifaceted interplay of lymphocytes with keratinocytes at the molecular level. KW - chemokine KW - keratinocytes KW - IFN KW - lichen planus KW - T cells KW - Nfatc1 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195695 SN - 1664-3224 VL - 10 IS - 1917 ER - TY - JOUR A1 - Dech, Stefan A1 - Holzwarth, Stefanie A1 - Asam, Sarah A1 - Andresen, Thorsten A1 - Bachmann, Martin A1 - Boettcher, Martin A1 - Dietz, Andreas A1 - Eisfelder, Christina A1 - Frey, Corinne A1 - Gesell, Gerhard A1 - Gessner, Ursula A1 - Hirner, Andreas A1 - Hofmann, Matthias A1 - Kirches, Grit A1 - Klein, Doris A1 - Klein, Igor A1 - Kraus, Tanja A1 - Krause, Detmar A1 - Plank, Simon A1 - Popp, Thomas A1 - Reinermann, Sophie A1 - Reiners, Philipp A1 - Roessler, Sebastian A1 - Ruppert, Thomas A1 - Scherbachenko, Alexander A1 - Vignesh, Ranjitha A1 - Wolfmueller, Meinhard A1 - Zwenzner, Hendrik A1 - Kuenzer, Claudia T1 - Potential and challenges of harmonizing 40 years of AVHRR data: the TIMELINE experience JF - Remote Sensing N2 - Earth Observation satellite data allows for the monitoring of the surface of our planet at predefined intervals covering large areas. However, there is only one medium resolution sensor family in orbit that enables an observation time span of 40 and more years at a daily repeat interval. This is the AVHRR sensor family. If we want to investigate the long-term impacts of climate change on our environment, we can only do so based on data that remains available for several decades. If we then want to investigate processes with respect to climate change, we need very high temporal resolution enabling the generation of long-term time series and the derivation of related statistical parameters such as mean, variability, anomalies, and trends. The challenges to generating a well calibrated and harmonized 40-year-long time series based on AVHRR sensor data flown on 14 different platforms are enormous. However, only extremely thorough pre-processing and harmonization ensures that trends found in the data are real trends and not sensor-related (or other) artefacts. The generation of European-wide time series as a basis for the derivation of a multitude of parameters is therefore an extremely challenging task, the details of which are presented in this paper. KW - AVHRR KW - Earth Observation KW - harmonization KW - time series analysis KW - climate related trends KW - automatic processing KW - Europe KW - TIMELINE Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246134 SN - 2072-4292 VL - 13 IS - 18 ER - TY - JOUR A1 - Klein-Hessling, Stefan A1 - Muhammad, Khalid A1 - Klein, Matthias A1 - Pusch, Tobias A1 - Rudolf, Ronald A1 - Flöter, Jessica A1 - Qureischi, Musga A1 - Beilhack, Andreas A1 - Vaeth, Martin A1 - Kummerow, Carsten A1 - Backes, Christian A1 - Schoppmeyer, Rouven A1 - Hahn, Ulrike A1 - Hoth, Markus A1 - Bopp, Tobias A1 - Berberich-Siebelt, Friederike A1 - Patra, Amiya A1 - Avots, Andris A1 - Müller, Nora A1 - Schulze, Almut A1 - Serfling, Edgar T1 - NFATc1 controls the cytotoxicity of CD8\(^{+}\) T cells JF - Nature Communications N2 - Cytotoxic T lymphocytes are effector CD8\(^{+}\) T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of Nfatc1\(^{-/-}\) cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection. Transcriptome analysis shows diminished RNA levels of numerous genes in Nfatc1\(^{-/-}\) CD8\(^{+}\) T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1\(^{-/-}\), but not Nfatc2\(^{-/-}\) CD8\(^{+}\) T cells have an impaired metabolic switch to glycolysis, which can be restored by IL-2. Genome-wide ChIP-seq shows that NFATc1 binds many genes that control cytotoxic T lymphocyte activity. Together these data indicate that NFATc1 is an important regulator of cytotoxic T lymphocyte effector functions. KW - cytotoxic T cells KW - lymphocyte activation KW - signal transduction KW - gene regulation KW - immune cells KW - NFATc1 Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170353 VL - 8 IS - 511 ER - TY - JOUR A1 - Almanzar, Giovanni A1 - Klein, Matthias A1 - Schmalzing, Marc A1 - Hilligardt, Deborah A1 - El Hajj, Nady A1 - Kneitz, Hermann A1 - Wild, Vanessa A1 - Rosenwald, Andreas A1 - Benoit, Sandrine A1 - Hamm, Henning A1 - Tony, Hans-Peter A1 - Haaf, Thomas A1 - Goebeler, Matthias A1 - Prelog, Martina T1 - Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis JF - International Archives of Allergy and Immunology N2 - Background: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. Methods: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. Results: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. Conclusions: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype. KW - methylation KW - systemic sclerosis KW - suppression KW - Tregs KW - Th17 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196577 SN - 1018-2438 SN - 1423-0097 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 171 IS - 2 ER - TY - THES A1 - Klein, Matthias Ferdinand T1 - Charakterisierung peripherer T-Zellpopulationen, regulatorischer T-Zellen und Th17 Zellen bei Patienten mit Systemischer Sklerose T1 - Characterization of peripheral T-cells, regulatory T-cells and Th17 cells in patients with Systemic Sclerosis N2 - Unklarheit herrscht bis dato über die genauen Zusammenhänge bei der Pathogenese der SSc. T-Zellen scheinen allerdings eine entscheidende Rolle in der Entstehung dieser Autoimmunerkrankung zu spielen. Zur Untersuchung dieses Aspekts wurde in dieser Arbeit eine Charakterisierung peripher zirkulierender T-Zellen sowie eine Überprüfung der Funktionalität von regulatorischen T-Zellen vorgenommen. Generell zeigte sich in den peripheren CD4+ und CD8+ T-Zellen der SSc-Patienten ein höheres Maß an Inflammationsbereitschaft und Immunoseneszenz. Dies spiegelte sich einerseits durch niedrigere Proportionen von naiven CD4+ und CD8+ T-Zellen und größeren Mengen an Gedächtnis-T-Zellen wider. Andererseits zeigte sich, dass gerade die bei SSc-Patienten vermehrt vorkommenden CD4+ Gedächtnis-T-Zellen durch Produktion von TNF-α, einem proinflammatorischen Zytokin, zur vermehrten proinflammatorische Bereitschaft der T-Zellen bei SSc-Patienten beitragen könnten. CD8+ Effektor und Gedächtniszellpopulationen zeigten im Gegensatz zu den CD4+ T-Zellen keine vermehrte Produktion von proinflammatorischen Zytokinen wie TNF-α und IFN-γ. Allerdings konnten sie als Produzenten von in der Literatur als profibrotisch beschriebenen Zytokinen wie IL-13 und IL-4 identifiziert werden. Besonders bei Patienten mit der diffusen Form der SSc zeigten sich die beschriebenen Auffälligkeiten in deutlicherem Ausmaß als bei den Patienten mit der limitierten kutanen Form, die mit einem leichteren klinischen Phänotyp einhergeht. Eine besonders in den Fokus gerückte Population der CD4+ T-Zellen sind die Th-17 Zellen, denen vor allem proinflammatorische Aspekte und Beteiligung an der Pathogenese verschiedener Autoimmunerkrankungen zugeschrieben wird. Hier konnte gezeigt werden, dass Th-17 vor allem bei SSc-Patienten mit schwereren Phänotypen der Erkrankung in vermehrtem Maße zu finden sind und dass diese im Vergleich zu gesunden Probanden auch vermehrt Interleukin-17 produzieren, was als Leitzytokin der Th17 gilt und starke inflammatorische Effekte bedingt. Regulatorische T-Zellen, die man als Gegenpol der inflammatorischen T-Zellen sieht, scheinen in Patienten mit SSc zwar vermehrt vorhanden zu sein, allerdings zeigten sich die suppressiven Effekte der Tregs bei SSc-Patienten vermindert. Dies könnte zum Beispiel an der hier gezeigten verminderten Produktion von IL-10 durch Tregs bei SSc-Patienten liegen. Eine Stabilisierung des Treg-Phänotyps, wie sie bereits experimentell bei GVHD-Patienten bzw. bei Patienten mit chronischen Abstoßungsreaktionen nach Organtransplantationen durchgeführt wird, könnte nach Interpretation unserer Ergebnisse ebenfalls bei der SSc einen Versuch wert sein. Außerdem könnten Studien zur Effektivität von bereits bei anderen Autoimmunerkrankungen erprobten Antikörpern gegen IL-17A und IL-13 bei SSc-Patienten erfolgversprechend sein, da in der Literatur der negative Einfluss dieser profibrotischen Zytokine auf das Fortschreiten der Erkrankung suggeriert wird und in dieser Arbeit die vermehrte Produktion der zwei Zytokine durch verschiedene T-Zell-Subpopulationen bei SSc-Patienten gezeigt wurde. N2 - There is still ambiguity about the exact links in the immunopathogenesis of SSc. T-cells seem to play a crucial role in the emergence of this autoimmune disease. To investigate this aspect, a characterization of circulating peripheral T-cells and examination of the functionality of regulatory T-cells was performed in this project. Generally, a higher level of disposition for inflammation, as well as immunosenescence was shown in peripheral CD4+ and CD8+ T-cells in SSc-patients. This could be reflected through lower proportions of naïve CD4+ and CD8+ T-cells and higher amounts of memory T-cells in SSc-patients. Otherwise, it was shown here, that especially CD4+ memory T-cells, which appear in higher proportions in SSc-patients, may have a significant impact on the disposition for inflammation through production of the proinflammatory cytokine TNF-α. CD8+ effector and memory T-cell populations showed no elevated levels in production of proinflammatory cytokines such as TNF-α and IFN-γ in comparison to CD4+ T-cells. Nevertheless, they could be identified as producers of the most likely profibrotic cytokines IL-13 and IL-4. Especially in patients with the diffuse form of SSc all the previously described features were seen in a larger extent, as in patients with limited cutaneous SSc, the less severe clinical phenotype of the disease. An especially interesting population of CD4+ T-cells are Th-17 cells that seem to play important roles in the development of autoimmune disorders through proinflammatory mechanisms. Here, we showed that this population of T-cells was primarily occurring in higher proportions in SSc-patients with the more severe phenotype of the disease. Also, we showed that Th-17 T-cells of SSc-patients produce larger proportions of IL-17, the most important and inflammatory cytokine of this population of T-cells. Regulatory T-cells, as a counterpart of inflammatory T-cells seemed to appear in higher proportions in SSc-patients but showed less suppressive effects in SSc-patients. This may be explained due to diminished production of IL-10 by Tregs in SSc-patients that was shown here. A stabilization of the Treg-phenotype in SSc-patients that is already beeing tested in GVHD-patients and patients with chronic organ-rejection problems after organ-transplantation, may contribute to treatment of SSc. Besides, studies to test the effectiveness of antibodies against IL-17A and IL-13 that were already tested in other autoimmune disorders should be done, because the present literature suggests a negative influence of these two cytokines on the progression of SSc and our data show the increased production of those two cytokines by T-cell-populations that were investigated in this thesis. KW - Sklerodermie KW - Systemische Sklerose KW - T-Zellen KW - regulatorische T-Zellen KW - Th17-Zellen Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-163039 ER - TY - JOUR A1 - Bender, Stephan A1 - Resch, Franz A1 - Klein, Christoph A1 - Renner, Tobias A1 - Fallgatter, Andreas J. A1 - Weisbrod, Matthias A1 - Romanos, Marcel T1 - Influence of Stimulant Medication and Response Speed on Lateralization of Movement-Related Potentials in Attention-Deficit/Hyperactivity Disorder JF - PLoS One N2 - Background: Hyperactivity is one of the core symptoms in attention deficit hyperactivity disorder (ADHD). However, it remains unclear in which way the motor system itself and its development are affected by the disorder. Movement-related potentials (MRP) can separate different stages of movement execution, from the programming of a movement to motor post-processing and memory traces. Pre-movement MRP are absent or positive during early childhood and display a developmental increase of negativity. Methods: We examined the influences of response-speed, an indicator of the level of attention, and stimulant medication on lateralized MRP in 16 children with combined type ADHD compared to 20 matched healthy controls. Results: We detected a significantly diminished lateralisation of MRP over the pre-motor and primary motor cortex during movement execution (initial motor potential peak, iMP) in patients with ADHD. Fast reactions (indicating increased visuo-motor attention) led to increased lateralized negativity during movement execution only in healthy controls, while in children with ADHD faster reaction times were associated with more positive amplitudes. Even though stimulant medication had some effect on attenuating group differences in lateralized MRP, this effect was insufficient to normalize lateralized iMP amplitudes. Conclusions: A reduced focal (lateralized) motor cortex activation during the command to muscle contraction points towards an immature motor system and a maturation delay of the (pre-) motor cortex in children with ADHD. A delayed maturation of the neuronal circuitry, which involves primary motor cortex, may contribute to ADHD pathophysiology. KW - deficit-hyperactivity disorder KW - anticipatory mechanisms KW - motor preparation KW - TIC disorder KW - children KW - ADHD KW - methylphenidate KW - contingent negative-variation KW - continuous performance-test KW - slow cortical potentials Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135262 VL - 7 IS - 6 ER - TY - THES A1 - Klein, Matthias T1 - Optische Materialien für die Additive Fertigung T1 - Optical materials for additive manufacturing N2 - In der vorliegenden Arbeit wurden neue Materialien für die additive Fertigung für opti-sche Anwendungen entwickelt. Hierbei wurde zunächst ein ORMOCER® Harz für den LCD/DLP 3D-Druck synthetisiert und charakterisiert. Das Material zeigte eine gute Druckbarkeit, gute optische Eigenschaften und eine hohe Stabilität gegenüber Belas-tungen mit UV-Licht, Temperatur und Luftfeuchtigkeit. Die prozessbedingte Stufenbil-dung für gekrümmte Oberflächen beim LDC/DLP Druck erforderte eine Weiterentwick-lung zu einem Harz, das auch mittels Inkjet-Verfahren gedruckt werden kann. Hierfür mussten die Viskosität des ORMOCER®s und die Einflüsse darauf untersucht werden. Zu diesem Zweck wurde die Synthese entsprechend verändert und die Produkte cha-rakterisiert. Variationen des Wasseranteils, des Katalysators, der Reaktionszeit, der Re-aktionsführung und der Edukte wurden durchgeführt. Harze mit resultierender niedriger Viskosität dürfen zusammenfassend nur zweifach anorganisch vernetzende Edukte mit niedrigem Reibungskoeffizienten beinhalten. Ein H2O-Verhältnis von 0,5 zu den vorlie-genden Si-O-Gruppen resultiert in akzeptablen Viskositäten und einer ausreichenden Stabilität. Als zuverlässiger Katalysator stellte sich HCl heraus. Die Reaktionszeit muss so gewählt werden, dass die Sol-Gel-Synthese abgeschlossen ist. Kürzere Zeiten füh-ren zwar zu kleineren Viskositäten, jedoch auch zu eventuell schlechter Langzeitstabili-tät. Veränderungen in der Reaktionsführung, durch Zutropfen der Edukte, resultierten jedoch vorwiegend zur Erhöhung der Viskositäten. Mit diesen Erkenntnissen wurde an-schließend ein Harz synthetisiert, das erfolgreich ohne weitere Verdünnungsschritte am Inkjet-Drucker prozessiert werden konnte. Dieses Harz ist zusätzlich auch am LCD/DLP Drucker einsetzbar. Als ergänzender Schritt konnte im Anschluss noch gezeigt werden, dass Partikel in Harze zusätzliche Eigenschaften, wie Fluoreszenz, einbringen können. N2 - In the present work, new materials for additive manufacturing for optical applications were developed. First, an ORMOCER® resin for LCD/DLP 3D printing was synthe-sized and characterized. The material showed good printability, good optical proper-ties and high stability against exposure to UV light, temperature and humidity. The process-related step formation for curved surfaces in LDC/DLP printing required fur-ther development of a resin that can also be printed by inkjet. For this purpose, the variables of the viscosity of ORMOCER®s had to be investigated. For this purpose, the synthesis was modified accordingly, and the products were characterized. Varia-tions of the water content, the catalyst, the reaction time, the way of the reaction and the reactants were carried out. In summary, resins with resulting low viscosity may contain only twofold inorganic crosslinking reactants with low friction coefficient. An H2O ratio of 0.5 to the Si-O groups present results in acceptable viscosities and suffi-cient stability. HCl turned out to be a reliable catalyst. The reaction time must be as long as the sol-gel synthesis needs to be completed. Shorter times lead to lower vis-cosities, but also to possibly poor long-term stability. However, changes in the reaction control, for example by adding reactants dropwise, resulted mainly in an increase in viscosity. These findings were then used to synthesize a resin that could be success-fully processed on the inkjet printer without further dilution steps. This resin can also be used on the LCD/DLP printer. As a complementary step, it was subsequently shown that particles can introduce additional properties, such as fluorescence, into resins. Here, quantum dots, black dyes and refractive index-increasing zirconium dioxide particles were successfully incorporated into LCD/DLP resins and characterized. KW - Additive Manufacturing KW - Inkjet KW - Quantum Dot KW - Hybrid Polymer KW - Optical Component KW - Inkjet 3D Printing KW - Ormocer(R) Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254939 ER - TY - JOUR A1 - klein Selle, Nathalie A1 - Suchotzki, Kristina A1 - Pertzov, Yoni A1 - Gamer, Matthias T1 - Orienting versus inhibition: The theory behind the ocular‐based Concealed Information Test JF - Psychophysiology N2 - When trying to conceal one's knowledge, various ocular changes occur. However, which cognitive mechanisms drive these changes? Do orienting or inhibition—two processes previously associated with autonomic changes—play a role? To answer this question, we used a Concealed Information Test (CIT) in which participants were either motivated to conceal (orienting + inhibition) or reveal (orienting only) their knowledge. While pupil size increased in both motivational conditions, the fixation and blink CIT effects were confined to the conceal condition. These results were mirrored in autonomic changes, with skin conductance increasing in both conditions while heart rate decreased solely under motivation to conceal. Thus, different cognitive mechanisms seem to drive ocular responses. Pupil size appears to be linked to the orienting of attention (akin to skin conductance changes), while fixations and blinks rather seem to reflect arousal inhibition (comparable to heart rate changes). This knowledge strengthens CIT theory and illuminates the relationship between ocular and autonomic activity. KW - arousal inhibition KW - autonomic KW - Concealed Information Test (CIT) KW - oculomotor KW - orienting response KW - response fractionation Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312626 VL - 60 IS - 3 ER - TY - JOUR A1 - Alrefai, Hani A1 - Muhammad, Khalid A1 - Rudolf, Ronald A1 - Pham, Duong Anh Thuy A1 - Klein-Hessling, Stefan A1 - Patra, Amiya K. A1 - Avots, Andris A1 - Bukur, Valesca A1 - Sahin,, Ugur A1 - Tenzer, Stefan A1 - Goebeler, Matthias A1 - Kerstan, Andreas A1 - Serfling, Edgar T1 - NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells JF - Nature Communications N2 - Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis. KW - B cells KW - psoriasis KW - interleukins KW - inflammation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173053 VL - 7 ER - TY - JOUR A1 - Glutsch, Valerie A1 - Schummer, Patrick A1 - Kneitz, Hermann A1 - Gesierich, Anja A1 - Goebeler, Matthias A1 - Klein, Detlef A1 - Posch, Christian A1 - Gebhardt, Christoffer A1 - Haferkamp, Sebastian A1 - Zimmer, Lisa A1 - Becker, Jürgen C A1 - Leiter, Ulrike A1 - Weichenthal, Michael A1 - Schadendorf, Dirk A1 - Ugurel, Selma A1 - Schilling, Bastian T1 - Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG JF - Journal for ImmunoTherapy of Cancer N2 - Merkel cell carcinoma is a rare, highly aggressive skin cancer with neuroendocrine differentiation. Immune checkpoint inhibition has significantly improved treatment outcomes in metastatic disease with response rates to programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibition of up to 62%. However, primary and secondary resistance to PD-1/PD-L1 inhibition remains a so far unsolved clinical challenge since effective and safe treatment options for these patients are lacking.Fourteen patients with advanced (non-resectable stage III or stage IV, Union international contre le cancer 2017) Merkel cell carcinoma with primary resistance to the PD-L1 inhibitor avelumab receiving subsequent therapy (second or later line) with ipilimumab plus nivolumab (IPI/NIVO) were identified in the prospective multicenter skin cancer registry ADOREG. Five of these 14 patients were reported previously and were included in this analysis with additional follow-up. Overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events were analyzed.All 14 patients received avelumab as first-line treatment. Thereof, 12 patients had shown primary resistance with progressive disease in the first tumor assessment, while two patients had initially experienced a short-lived stabilization (stable disease). Six patients had at least one systemic treatment in between avelumab and IPI/NIVO. In total, 7 patients responded to IPI/NIVO (overall response rate 50%), and response was ongoing in 4 responders at last follow-up. After a median follow-up of 18.85 months, median PFS was 5.07 months (95% CI 2.43—not available (NA)), and median OS was not reached. PFS rates at 12 months and 24 months were 42.9% and 26.8 %, respectively. The OS rate at 36 months was 64.3%. Only 3 (21%) patients did not receive all 4 cycles of IPI/NIVO due to immune-related adverse events.In this multicenter evaluation, we observed high response rates, a durable benefit and promising OS rates after treatment with later-line combined IPI/NIVO. In conclusion, our patient cohort supports our prior findings with an encouraging activity of second-line or later-line IPI/NIVO in patients with anti-PD-L1-refractory Merkel cell carcinoma. KW - Skin Neoplasms KW - CTLA-4 Antigen KW - Programmed Cell Death 1 Receptor KW - B7-H1 Antigen KW - Drug Therapy, Combination Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304613 SN - 2051-1426 VL - 10 IS - 11 ER -