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Article ; Online: Effects of Receptor Specificity and Conformational Stability of Influenza A Virus Hemagglutinin on Infection and Activation of Different Cell Types in Human PBMCs.

Dorna, Jens / Kaufmann, Andreas / Bockmann, Viktoria / Raifer, Hartmann / West, Johanna / Matrosovich, Mikhail / Bauer, Stefan

Frontiers in immunology

2022 Volume 13, Page(s) 827760

Abstract: Humans can be infected by zoonotic avian, pandemic and seasonal influenza A viruses (IAVs), which differ by receptor specificity and conformational stability of their envelope glycoprotein hemagglutinin (HA). It was shown that receptor specificity of the ...

Abstract	Humans can be infected by zoonotic avian, pandemic and seasonal influenza A viruses (IAVs), which differ by receptor specificity and conformational stability of their envelope glycoprotein hemagglutinin (HA). It was shown that receptor specificity of the HA determines the tropism of IAVs to human airway epithelial cells, the primary target of IAVs in humans. Less is known about potential effects of the HA properties on viral attachment, infection and activation of human immune cells. To address this question, we studied the infection of total human peripheral blood mononuclear cells (PBMCs) and subpopulations of human PBMCs with well characterized recombinant IAVs differing by the HA and the neuraminidase (NA) but sharing all other viral proteins. Monocytes and all subpopulations of lymphocytes were significantly less susceptible to infection by IAVs with avian-like receptor specificity as compared to human-like IAVs, whereas plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells were equally susceptible to IAVs with avian-like and human-like receptor specificity. This tropism correlated with the surface expression of 2-3-linked sialic acids (avian-type receptors) and 2-6-linked sialic acids (human-type receptors). Despite a reduced infectivity of avian-like IAVs for PBMCs, these viruses were not less efficient than human-like IAVs in terms of cell activation as judged by the induction of cellular mRNA of
MeSH term(s)	Animals ; Dogs ; Hemagglutinin Glycoproteins, Influenza Virus/genetics ; Hemagglutinins ; Humans ; Influenza A virus/genetics ; Leukocytes, Mononuclear/metabolism ; Madin Darby Canine Kidney Cells ; Membrane Proteins/genetics ; RNA, Messenger/metabolism ; RNA-Binding Proteins/metabolism ; Sialic Acids/metabolism ; Virus Replication/genetics
Chemical Substances	Hemagglutinin Glycoproteins, Influenza Virus ; Hemagglutinins ; IFITM3 protein, human ; Membrane Proteins ; RNA, Messenger ; RNA-Binding Proteins ; Sialic Acids
Language	English
Publishing date	2022-03-14
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.827760
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Flt3L, LIF, and IL-10 combination promotes the selective in vitro development of ESAM

Cyran, Laura / Serfling, Julia / Kirschner, Luisa / Raifer, Hartmann / Lohoff, Michael / Hermanns, Heike M / Kerstan, Andreas / Bodem, Jochen / Lutz, Manfred B

European journal of immunology

2022 Volume 52, Issue 12, Page(s) 1946–1960

Abstract: The development of two conventional dendritic cells (DC) subsets (cDC1 and cDC2) and the plasmacytoid DC (pDC) in vivo and in cultures of bone marrow (BM) cells is mediated by the growth factor Flt3L. However, little is known about the factors that ... ...

Abstract	The development of two conventional dendritic cells (DC) subsets (cDC1 and cDC2) and the plasmacytoid DC (pDC) in vivo and in cultures of bone marrow (BM) cells is mediated by the growth factor Flt3L. However, little is known about the factors that direct the development of the individual DC subsets. Here, we describe the selective in vitro generation of murine ESAM
MeSH term(s)	Mice ; Animals ; Interleukin-10 ; Bone Marrow ; CDC2 Protein Kinase ; Cytidine Diphosphate ; Cell Adhesion Molecules
Chemical Substances	Interleukin-10 (130068-27-8) ; CDC2 Protein Kinase (EC 2.7.11.22) ; Cytidine Diphosphate (63-38-7) ; Esam protein, mouse ; Cell Adhesion Molecules
Language	English
Publishing date	2022-04-14
Publishing country	Germany
Document type	Journal Article
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202149663
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Reciprocal crosstalk between Th17 and mesothelial cells promotes metastasis-associated adhesion of ovarian cancer cells.

Clinical and translational medicine

2024 Volume 14, Issue 4, Page(s) e1604

Abstract: Background: IL-17A and TNF synergistically promote inflammation and tumorigenesis. Their interplay and impact on ovarian carcinoma (OC) progression are, however, poorly understood. We addressed this question focusing on mesothelial cells, whose ... ...

Abstract	Background: IL-17A and TNF synergistically promote inflammation and tumorigenesis. Their interplay and impact on ovarian carcinoma (OC) progression are, however, poorly understood. We addressed this question focusing on mesothelial cells, whose interaction with tumor cells is known to play a pivotal role in transcoelomic metastasis formation. Methods: Flow-cytometry and immunohistochemistry experiments were employed to identify cellular sources of IL-17A and TNF. Changes in transcriptomes and secretomes were determined by bulk and single cell RNA sequencing as well as affinity proteomics. Functional consequences were investigated by microscopic analyses and tumor cell adhesion assays. Potential clinical implications were assessed by immunohistochemistry and survival analyses. Results: We identified Th17 cells as the main population of IL-17A- and TNF producers in ascites and detected their accumulation in early omental metastases. Both IL-17A and its receptor subunit IL-17RC were associated with short survival of OC patients, pointing to a role in clinical progression. IL-17A and TNF synergistically induced the reprogramming of mesothelial cells towards a pro-inflammatory mesenchymal phenotype, concomitantly with a loss of tight junctions and an impairment of mesothelial monolayer integrity, thereby promoting cancer cell adhesion. IL-17A and TNF synergistically induced the Th17-promoting cytokines IL-6 and IL-1β as well as the Th17-attracting chemokine CCL20 in mesothelial cells, indicating a reciprocal crosstalk that potentiates the tumor-promoting role of Th17 cells in OC. Conclusions: Our findings reveal a novel function for Th17 cells in the OC microenvironment, which entails the IL-17A/TNF-mediated induction of mesothelial-mesenchymal transition, disruption of mesothelial layer integrity and consequently promotion of OC cell adhesion. These effects are potentiated by a positive feedback loop between mesothelial and Th17 cells. Together with the observed clinical associations and accumulation of Th17 cells in omental micrometastases, our observations point to a potential role in early metastases formation and thus to new therapeutic options.
MeSH term(s)	Humans ; Female ; Th17 Cells ; Interleukin-17/metabolism ; Cytokines/metabolism ; Ovarian Neoplasms/metabolism ; Inflammation/metabolism ; Tumor Microenvironment
Chemical Substances	Interleukin-17 ; Cytokines
Language	English
Publishing date	2024-04-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2697013-2
ISSN	2001-1326 ; 2001-1326
ISSN (online)	2001-1326
ISSN	2001-1326
DOI	10.1002/ctm2.1604
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Article ; Online: A Novel Approach for Glioblastoma Treatment by Combining Apoptosis Inducers (TMZ, MTX, and Cytarabine) with E.V.A. (Eltanexor, Venetoclax, and A1210477) Inhibiting XPO1, Bcl-2, and Mcl-1.

Zhao, Kai / Braun, Madita / Meyer, Leonie / Otte, Katharina / Raifer, Hartmann / Helmprobst, Frederik / Möschl, Vincent / Pagenstecher, Axel / Urban, Hans / Ronellenfitsch, Michael W / Steinbach, Joachim P / Pesek, Jelena / Watzer, Bernhard / Nockher, Wolfgang A / Taudte, R Verena / Neubauer, Andreas / Nimsky, Christopher / Bartsch, Jörg W / Rusch, Tillmann

Cells

2024 Volume 13, Issue 7

Abstract: Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due to an excess of anti-apoptotic XPO1/Bcl-2-family ... ...

Abstract	Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due to an excess of anti-apoptotic XPO1/Bcl-2-family proteins. We assessed TMZ, Methotrexate (MTX), and Cytarabine (Ara-C) (apoptosis inducers) combined with XPO1/Bcl-2/Mcl-1-inhibitors (apoptosis rescue) in GB cell lines and primary GB stem-like cells (GSCs). Using CellTiter-Glo
MeSH term(s)	Animals ; Mice ; Temozolomide/pharmacology ; Glioblastoma/drug therapy ; Glioblastoma/metabolism ; Methotrexate/pharmacology ; Methotrexate/therapeutic use ; Cytarabine/pharmacology ; Cytarabine/therapeutic use ; Antineoplastic Agents, Alkylating/pharmacology ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology ; Apoptosis ; Amides ; Pyrimidines ; Sulfonamides ; Bridged Bicyclo Compounds, Heterocyclic
Chemical Substances	Temozolomide (YF1K15M17Y) ; Methotrexate (YL5FZ2Y5U1) ; venetoclax (N54AIC43PW) ; Cytarabine (04079A1RDZ) ; Eltanexor ; Antineoplastic Agents, Alkylating ; Antineoplastic Agents ; Amides ; Pyrimidines ; Sulfonamides ; Bridged Bicyclo Compounds, Heterocyclic
Language	English
Publishing date	2024-04-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells13070632
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Article: T-cell-derived TNF-α and a cluster of immunological parameters from plasma allow a separation between SARS-CoV-2 convalescent versus vaccinated elite athletes.

Palmowski, Jana / Kohnhorst, Sarah / Bauer, Pascal / Puta, Christian / Haunhorst, Simon / Gebhardt, Kristina / Reichel, Thomas / Keller, Christian / Huber, Magdalena / Raifer, Hartmann / Krüger, Karsten

Frontiers in physiology

2023 Volume 14, Page(s) 1203983

Abstract: Guidelines for medical clearing after SARS-CoV-2 infection in elite athletes do not include T-cell immunity aspects despite its relevance in the course of COVID-19 disease. Therefore, we aimed to analyze T-cell-related cytokines before and ... ...

Abstract	Guidelines for medical clearing after SARS-CoV-2 infection in elite athletes do not include T-cell immunity aspects despite its relevance in the course of COVID-19 disease. Therefore, we aimed to analyze T-cell-related cytokines before and after
Language	English
Publishing date	2023-06-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2023.1203983
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Article ; Online: Subpopulations of regulatory T cells are associated with subclinical atherosclerotic plaques, levels of LDL, and cardiorespiratory fitness in the elderly.

Böttrich, Tim / Bauer, Pascal / Gröβer, Vincent / Huber, Magdalena / Raifer, Hartmann / Frech, Torsten / Nolte, Svenja / Dombrowski, Theresa / Cemic, Franz / Sommer, Natascha / Ringseis, Robert / Eder, Klaus / Krüger, Karsten / Weyh, Christopher

Journal of sport and health science

2023 Volume 13, Issue 3, Page(s) 288–296

Abstract: Background: Atherosclerosis forms the pathological basis for the development of cardiovascular disease. Since pathological processes initially develop without clinically relevant symptoms, the identification of early markers in the subclinical stage ... ...

Abstract	Background: Atherosclerosis forms the pathological basis for the development of cardiovascular disease. Since pathological processes initially develop without clinically relevant symptoms, the identification of early markers in the subclinical stage plays an important role for initiating early interventions. There is evidence that regulatory T cells (Tregs) are involved in the development of atherosclerosis. Therefore, the present study aimed to identify and investigate associations with Tregs and their subsets in a cohort of healthy elderly individuals with and without subclinical atherosclerotic plaques (SAP). In addition, various lifestyle and risk factors, such as cardiorespiratory fitness, were investigated as associated signatures. Methods: A cross-sectional study was performed in 79 participants (male: n = 50; age = 63.6 ± 3.7 years; body mass index = 24.9 ± 3.1 kg/m²; mean ± SD) who had no previous diagnosis of chronic disease and were not taking medication. Ultrasound of the carotids to identify SAP, cardiovascular function measurement for vascular assessment and a cardiorespiratory fitness test to determine peak oxygen uptake were performed. Additionally, tests were conducted to assess blood lipids and determine glucose levels. Immunophenotyping of Tregs and their subtypes (resting (rTregs) and effector/memory (mTregs)) was performed by 8-chanel flow cytometry. Participants were categorized according to atherosclerotic plaque status. Linear and logistic regression models were used to analyze associations between parameters. Results: SAP was detected in a total of 29 participants. The participants with plaque were older (64.8 ± 3.6 years vs. 62.9 ± 3.5 years) and had higher peripheral systolic blood pressure (133.8 ± 14.7 mmHg vs. 125.8 ± 10.9 mmHg). The participants with SAP were characterized by a lower percentage of rTregs (28.8% ± 10.7% vs. 34.6% ± 10.7%) and a higher percentage of mTregs (40.3% ± 14.7% vs. 30.0% ± 11.9%). Multiple logistic regression identified age (odds ratio (OR) = 1.20 (95% confidence interval (95%CI): 1.01-1.42)) and mTregs (OR = 1.05 (95%CI: 1.02-1.10)) as independent risk factors for SAP. Stepwise linear regression could reveal an association of peak oxygen uptake (β = 0.441), low-density lipoprotein (LDL) (β = -0.096), and SAP (β = 6.733) with mTregs and LDL (β = 0.104) with rTregs. Conclusion: While at an early stage of SAP, the total proportion of Tregs gives no indication of vascular changes, this is indicated by a shift in the Treg subgroups. Factors such as serum LDL or cardiopulmonary fitness may be associated with this shift and may also be additional diagnostic indicators. This could be used to initiate lifestyle-based preventive measures at an early stage, which may have a protective effect against disease progression.
MeSH term(s)	Humans ; Male ; T-Lymphocytes, Regulatory/immunology ; Cross-Sectional Studies ; Middle Aged ; Plaque, Atherosclerotic/blood ; Female ; Cardiorespiratory Fitness ; Aged ; Risk Factors ; Cholesterol, LDL/blood ; Atherosclerosis/blood ; Lipoproteins, LDL/blood ; Life Style
Chemical Substances	Cholesterol, LDL ; Lipoproteins, LDL
Language	English
Publishing date	2023-11-10
Publishing country	China
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2673028-5
ISSN	2213-2961 ; 2095-2546
ISSN (online)	2213-2961
ISSN	2095-2546
DOI	10.1016/j.jshs.2023.11.004
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Article ; Online: IL18 Receptor Signaling Regulates Tumor-Reactive CD8+ T-cell Exhaustion via Activation of the IL2/STAT5/mTOR Pathway in a Pancreatic Cancer Model.

Lutz, Veronika / Hellmund, Veronique M / Picard, Felix S R / Raifer, Hartmann / Ruckenbrod, Teresa / Klein, Matthias / Bopp, Tobias / Savai, Rajkumar / Duewell, Peter / Keber, Corinna U / Weigert, Andreas / Chung, Ho-Ryun / Buchholz, Malte / Menke, André / Gress, Thomas M / Huber, Magdalena / Bauer, Christian

Cancer immunology research

2023 Volume 11, Issue 4, Page(s) 421–434

Abstract: Intratumoral cytotoxic CD8+ T cells (CTL) enter a dysfunctional state characterized by expression of coinhibitory receptors, loss of effector function, and changes in the transcriptional landscape. Even though several regulators of T-cell exhaustion have ...

Abstract	Intratumoral cytotoxic CD8+ T cells (CTL) enter a dysfunctional state characterized by expression of coinhibitory receptors, loss of effector function, and changes in the transcriptional landscape. Even though several regulators of T-cell exhaustion have been identified, the molecular mechanisms inducing T-cell exhaustion remain unclear. Here, we show that IL18 receptor (IL18R) signaling induces CD8+ T-cell exhaustion in a murine pancreatic cancer model. Adoptive transfer of Il18r-/- OT-1 CD8+ CTLs resulted in enhanced rejection of subcutaneous tumors expressing ovalbumin (OVA) as a model antigen (PancOVA), compared with wild-type OT-1 CTLs. Transferred intratumoral IL18R-deficient CTLs expressed higher levels of effector cytokines TNF and IFNγ and had reduced expression of coinhibitory receptors (PD-1, TIM-3, 2B4, LAG-3) and the transcription factors Eomes and TOX. Lower expression of coinhibitory receptors and TOX on IL18R-deficient versus IL18R-sufficient CD8+ T cells were confirmed in an orthotopic KPC model. IL18R-induced T-cell exhaustion was regulated by IL2/STAT5 and AKT/mTOR pathways, as demonstrated in an in vitro exhaustion assay. Concordantly, mice deficient in NLRP3, the molecular complex activating IL18, had decreased expression of coinhibitory receptors on intratumoral T cells and similar changes in signaling pathways at the transcriptome level. Thus, molecular pathways promoting T-cell exhaustion indicate an involvement of an NLRP3-expressing tumor microenvironment, which mediates IL18 release. The Cancer Genome Atlas analysis of patients with pancreatic carcinoma showed an association between NLRP3-mediated IL18 signaling and shorter survival. These findings indicate NLRP3-mediated IL18R signaling as a regulator of intratumoral T-cell exhaustion and a possible target for immunotherapy. See related Spotlight by Stromnes, p. 400.
MeSH term(s)	Mice ; Animals ; Interleukin-18 ; Interleukin-2 ; T-Cell Exhaustion ; Receptors, Interleukin-18 ; STAT5 Transcription Factor ; NLR Family, Pyrin Domain-Containing 3 Protein ; CD8-Positive T-Lymphocytes/immunology ; Pancreatic Neoplasms/genetics ; TOR Serine-Threonine Kinases ; Inflammation ; Tumor Microenvironment ; Pancreatic Neoplasms
Chemical Substances	Interleukin-18 ; Interleukin-2 ; Receptors, Interleukin-18 ; STAT5 Transcription Factor ; NLR Family, Pyrin Domain-Containing 3 Protein ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2023-02-09
Publishing country	United States
Document type	Research Support, Non-U.S. Gov't ; Journal Article
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-22-0398
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Zs.A 7022: Show issues

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Article: Eltanexor Effectively Reduces Viability of Glioblastoma and Glioblastoma Stem-Like Cells at Nano-Molar Concentrations and Sensitizes to Radiotherapy and Temozolomide.

Otte, Katharina / Zhao, Kai / Braun, Madita / Neubauer, Andreas / Raifer, Hartmann / Helmprobst, Frederik / Barrera, Felipe Ovalle / Nimsky, Christopher / Bartsch, Jörg W / Rusch, Tillmann

Biomedicines

2022 Volume 10, Issue 9

Abstract: Current standard adjuvant therapy of glioblastoma multiforme (GBM) using temozolomide (TMZ) frequently fails due to therapy resistance. Thus, novel therapeutic approaches are highly demanded. We tested the therapeutic efficacy of the second-generation ... ...

Abstract	Current standard adjuvant therapy of glioblastoma multiforme (GBM) using temozolomide (TMZ) frequently fails due to therapy resistance. Thus, novel therapeutic approaches are highly demanded. We tested the therapeutic efficacy of the second-generation XPO1 inhibitor Eltanexor using assays for cell viability and apoptosis in GBM cell lines and GBM stem-like cells. For most GBM-derived cells, IC
Language	English
Publishing date	2022-08-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10092145
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Book ; Thesis: Untersuchung der Signaltransduktion in den Strobila-Stadien von Aurelia aurita

Raifer, Hartmann

2006

Author's details	vorgelegt von Hartmann Raifer
Language	German
Size	95 S, Ill., graph. Darst
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Univ., Diss.--Köln, 2006
Database	Special collection on veterinary medicine and general parasitology

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Book ; Thesis: Untersuchung der Signaltransduktion in den Strobila-Stadien von Aurelia aurita

Raifer, Hartmann

2006

Author's details	vorgelegt von Hartmann Raifer
Language	German
Size	95 S, Ill., graph. Darst
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Univ., Diss.--Köln, 2006
Database	Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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