TY  - JOUR
A1  - Bäuerlein, Carina A.
A1  - Qureischi, Musga
A1  - Mokhtari, Zeinab
A1  - Tabares, Paula
A1  - Brede, Christian
A1  - Jordán Garrote, Ana-Laura
A1  - Riedel, Simone S.
A1  - Chopra, Martin
A1  - Reu, Simone
A1  - Mottok, Anja
A1  - Arellano-Viera, Estibaliz
A1  - Graf, Carolin
A1  - Kurzwart, Miriam
A1  - Schmiedgen, Katharina
A1  - Einsele, Hermann
A1  - Wölfl, Matthias
A1  - Schlegel, Paul-Gerhardt
A1  - Beilhack, Andreas
T1  - A T-Cell Surface Marker Panel Predicts Murine Acute Graft-Versus-Host Disease
JF  - Frontiers in Immunology
N2  - Acute graft-versus-host disease (aGvHD) is a severe and often life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). AGvHD is mediated by alloreactive donor T-cells targeting predominantly the gastrointestinal tract, liver, and skin. Recent work in mice and patients undergoing allo-HCT showed that alloreactive T-cells can be identified by the expression of α4β7 integrin on T-cells even before manifestation of an aGvHD. Here, we investigated whether the detection of a combination of the expression of T-cell surface markers on peripheral blood (PB) CD8\(^+\) T-cells would improve the ability to predict aGvHD. To this end, we employed two independent preclinical models of minor histocompatibility antigen mismatched allo-HCT following myeloablative conditioning. Expression profiles of integrins, selectins, chemokine receptors, and activation markers of PB donor T-cells were measured with multiparameter flow cytometry at multiple time points before the onset of clinical aGvHD symptoms. In both allo-HCT models, we demonstrated a significant upregulation of α4β7 integrin, CD162E, CD162P, and conversely, a downregulation of CD62L on donor T-cells, which could be correlated with the development of aGvHD. Other surface markers, such as CD25, CD69, and CC-chemokine receptors were not found to be predictive markers. Based on these preclinical data from mouse models, we propose a surface marker panel on peripheral blood T-cells after allo-HCT combining α4β7 integrin with CD62L, CD162E, and CD162P (cutaneous lymphocyte antigens, CLA, in humans) to identify patients at risk for developing aGvHD early after allo-HCT.
KW  - acute graft-versus-host disease
KW  - alloreactive T cells
KW  - transplantation
KW  - prediction
KW  - mouse models
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224290
SN  - 1664-3224
VL  - 11
ER  - 
TY  - JOUR
A1  - Rapp, Christina K.
A1  - Van Dijck, Ine
A1  - Laugwitz, Lucia
A1  - Boon, Mieke
A1  - Briassoulis, George
A1  - Ilia, Stavroula
A1  - Kammer, Birgit
A1  - Reu, Simone
A1  - Hornung, Stefanie
A1  - Buchert, Rebecca
A1  - Sofan, Linda
A1  - Froukh, Tawfiq
A1  - Witters, Peter
A1  - Rymen, Daisy
A1  - Haack, Tobias B.
A1  - Proesmans, Marijke
A1  - Griese, Matthias
T1  - Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy
JF  - Clinical Genetics
N2  - Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA, MIM#618278) is a rare clinical condition caused by bi‐allelic variants in NHL repeat containing protein 2 (NHLRC2, MIM*618277). Pulmonary disease may be the presenting sign and the few patients reported so far, all deceased in early infancy. Exome sequencing was performed on patients with childhood interstitial lung disease (chILD) and additional neurological features. The chILD‐EU register database and an in‐house database were searched for patients with NHLRC2 variants and clinical features overlapping FINCA syndrome. Six patients from three families were identified with bi‐allelic variants in NHLRC2. Two of these children died before the age of two while four others survived until childhood. Interstitial lung disease was pronounced in almost all patients during infancy and stabilized over the course of the disease with neurodevelopmental delay (NDD) evolving as the key clinical finding. We expand the phenotype of FINCA syndrome to a multisystem disorder with variable severity. FINCA syndrome should also be considered in patients beyond infancy with NDD and a history of distinct interstitial lung disease. Managing patients in registers for rare diseases helps identifying new diagnostic entities and advancing care for these patients.
KW  - cerebropulmonary disease
KW  - childhood interstitial lung disease
KW  - cholesterol pneumonia
KW  - FINCA
KW  - lung fibrosis
KW  - lipoid pneumonitis
KW  - multi‐organ disease
KW  - NHLRC2
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262732
VL  - 100
IS  - 4
SP  - 453
EP  - 461
ER  - 
TY  - JOUR
A1  - Schuch, Luise A.
A1  - Forstner, Maria
A1  - Rapp, Christina K.
A1  - Li, Yang
A1  - Smith, Desiree E. C.
A1  - Mendes, Marisa I.
A1  - Delhommel, Florent
A1  - Sattler, Michael
A1  - Emiralioğlu, Nagehan
A1  - Taskiran, Ekim Z.
A1  - Orhan, Diclehan
A1  - Kiper, Nural
A1  - Rohlfs, Meino
A1  - Jeske, Tim
A1  - Hastreiter, Maximilian
A1  - Gerstlauer, Michael
A1  - Torrent‐Vernetta, Alba
A1  - Moreno‐Galdó, Antonio
A1  - Kammer, Birgit
A1  - Brasch, Frank
A1  - Reu‐Hofer, Simone
A1  - Griese, Matthias
T1  - FARS1‐related disorders caused by bi‐allelic mutations in cytosolic phenylalanyl‐tRNA synthetase genes: Look beyond the lungs!
JF  - Clinical Genetics
N2  - Aminoacyl‐tRNA synthetases (ARSs) catalyze the first step of protein biosynthesis (canonical function) and have additional (non‐canonical) functions outside of translation. Bi‐allelic pathogenic variants in genes encoding ARSs are associated with various recessive mitochondrial and multisystem disorders. We describe here a multisystem clinical phenotype based on bi‐allelic mutations in the two genes (FARSA, FARSB) encoding distinct subunits for tetrameric cytosolic phenylalanyl‐tRNA synthetase (FARS1). Interstitial lung disease with cholesterol pneumonitis on histology emerged as an early characteristic feature and significantly determined disease burden. Additional clinical characteristics of the patients included neurological findings, liver dysfunction, and connective tissue, muscular and vascular abnormalities. Structural modeling of newly identified missense mutations in the alpha subunit of FARS1, FARSA, showed exclusive mapping to the enzyme's conserved catalytic domain. Patient‐derived mutant cells displayed compromised aminoacylation activity in two cases, while remaining unaffected in another. Collectively, these findings expand current knowledge about the human ARS disease spectrum and support a loss of canonical and non‐canonical function in FARS1‐associated recessive disease.
KW  - aminoacyl‐tRNA synthetases
KW  - cholesterol pneumonitis
KW  - FARS1
KW  - children´s interstitial lung disease (chILD) lipoid pneumonia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238827
VL  - 99
IS  - 6
SP  - 789
EP  - 801
ER  - 
TY  - JOUR
A1  - Peindl, Matthias
A1  - Göttlich, Claudia
A1  - Crouch, Samantha
A1  - Hoff, Niklas
A1  - Lüttgens, Tamara
A1  - Schmitt, Franziska
A1  - Pereira, Jesús Guillermo Nieves
A1  - May, Celina
A1  - Schliermann, Anna
A1  - Kronenthaler, Corinna
A1  - Cheufou, Danjouma
A1  - Reu-Hofer, Simone
A1  - Rosenwald, Andreas
A1  - Weigl, Elena
A1  - Walles, Thorsten
A1  - Schüler, Julia
A1  - Dandekar, Thomas
A1  - Nietzer, Sarah
A1  - Dandekar, Gudrun
T1  - EMT, stemness, and drug resistance in biological context: a 3D tumor tissue/in silico platform for analysis of combinatorial treatment in NSCLC with aggressive KRAS-biomarker signatures
JF  - Cancers
N2  - Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRAS\(^{G12C}\) or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-β. To investigate further determinants of drug response, we tested several drugs in combination with a KRAS\(^{G12C}\) inhibitor in KRAS\(^{G12C}\) mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures.
KW  - EMT
KW  - drug resistance
KW  - invasion
KW  - stemness
KW  - 3D lung tumor tissue models
KW  - KRAS biomarker signatures
KW  - boolean in silico models
KW  - targeted combination therapy
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270744
SN  - 2072-6694
VL  - 14
IS  - 9
ER  - 
TY  - JOUR
A1  - Seal, Rishav
A1  - Schwab, Lara S. U.
A1  - Chiarolla, Cristina M.
A1  - Hundhausen, Nadine
A1  - Klose, Georg Heinrich
A1  - Reu-Hofer, Simone
A1  - Rosenwald, Andreas
A1  - Wiest, Johannes
A1  - Berberich-Siebelt, Friederike
T1  - Delayed and limited administration of the JAKinib tofacitinib mitigates chronic DSS-induced colitis
JF  - Frontiers in Immunology
N2  - In inflammatory bowel disease, dysregulated T cells express pro-inflammatory cytokines. Using a chronic azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis model resembling ulcerative colitis, we evaluated whether and when treatment with the Janus kinase (JAK) inhibitor tofacitinib could be curative. Comparing the treatment with two and three cycles of tofacitinib medication in drinking water – intermittently with DSS induction – revealed that two cycles were not only sufficient but also superior over the 3-x regimen. The two cycles of the 2-x protocol paralleled the second and third cycles of the longer protocol. T cells were less able to express interferon gamma (IFN-γ) and the serum levels of IFN-γ, interleukin (IL)-2, IL-6, IL-17, and tumor necrosis factor (TNF) were significantly reduced in sera, while those of IL-10 and IL-22 increased under the 2-x protocol. Likewise, the frequency and effector phenotype of regulatory T cells (Tregs) increased. This was accompanied by normal weight gain, controlled clinical scores, and restored stool consistency. The general and histologic appearance of the colons revealed healing and tissue intactness. Importantly, two phases of tofacitinib medication completely prevented AOM-incited pseudopolyps and the hyper-proliferation of epithelia, which was in contrast to the 3-x regimen. This implies that the initial IBD-induced cytokine expression is not necessarily harmful as long as inflammatory signaling can later be suppressed and that time-restricted treatment allows for anti-inflammatory and tissue-healing cytokine activities.
KW  - anti-inflammatory cytokines
KW  - AOM/DSS
KW  - pro-inflammatory cytokines
KW  - effector Treg (eTreg)
KW  - chronic IBD model
KW  - JAK inhibitor
KW  - tofacitinib
KW  - treatment regimens
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-317815
VL  - 14
ER  -