@article{NiklausKlinglerWeberetal.2022, author = {Niklaus, Marius and Klingler, Philipp and Weber, Katja and Koessler, Angela and Kuhn, Sabine and Boeck, Markus and Kobsar, Anna and Koessler, Juergen}, title = {Platelet Toll-Like-Receptor-2 and -4 Mediate Different Immune-Related Responses to Bacterial Ligands}, series = {TH Open}, volume = {6}, journal = {TH Open}, number = {3}, doi = {10.1055/a-1827-7365}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301401}, pages = {e156 -- e167}, year = {2022}, abstract = {Background  Like immune cells, platelets express toll-like receptors (TLRs) on their surface membrane. TLR2 and TLR4 are able to recognize bacterial antigens and have the potential to influence hemostatic functions and classical intracellular signaling pathways. This study investigated the role of TLR2 and TLR4 for immune-related functions in human platelets. Materials and Methods  Washed platelets and neutrophils were prepared from fresh human peripheral blood. Basal-, Pam3CSK4- (as TLR2 agonist) and Lipopolysaccharides (LPS; as TLR4 agonist) -induced CD62P expression, fibrinogen binding and TLR2 or TLR4 expression, intracellular reactive oxygen species (ROS) production in H2DCFDA-loaded platelets and uptake of fluorescence-labeled TLR ligands, and fluorophore-conjugated fibrinogen were evaluated by flow cytometry. Analysis of platelet-neutrophil complexes was performed after coincubation of washed platelets and neutrophils in the presence and absence of TLR2 or TLR4 agonists on poly-L-lysine coated surfaces, followed by immunostaining and immunofluorescence imaging. Results  Pam3CSK4 rapidly and transiently increased TLR2 and TLR4 expression. Over the course of 30 minutes after activation with Pam3CSK4 and LPS, the expression of both receptors decreased. Pam3CSK4-stimulated intracellular ROS production and the uptake of TLR ligands or fibrinogen much stronger than LPS. Besides, TLR4 activation led to a significant increase of platelet-neutrophil contacts. Conclusion  Stimulation leads to rapid mobilization of TLR2 or TLR4 to the platelet surface, presumably followed by receptor internalization along with bound TLR ligands. After activation, platelet TLR2 and TLR4 mediate different immune-related reactions. In particular, TLR2 induces intracellular responses in platelets, whereas TLR4 initiates interactions with other immune cells such as neutrophils.}, language = {en} } @article{KayisogluSchlegelBartfeld2021, author = {Kayisoglu, {\"O}zge and Schlegel, Nicolas and Bartfeld, Sina}, title = {Gastrointestinal epithelial innate immunity-regionalization and organoids as new model}, series = {Journal of Molecular Medicine}, volume = {99}, journal = {Journal of Molecular Medicine}, number = {4}, doi = {10.1007/s00109-021-02043-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265220}, pages = {517-530}, year = {2021}, abstract = {The human gastrointestinal tract is in constant contact with microbial stimuli. Its barriers have to ensure co-existence with the commensal bacteria, while enabling surveillance of intruding pathogens. At the centre of the interaction lies the epithelial layer, which marks the boundaries of the body. It is equipped with a multitude of different innate immune sensors, such as Toll-like receptors, to mount inflammatory responses to microbes. Dysfunction of this intricate system results in inflammation-associated pathologies, such as inflammatory bowel disease. However, the complexity of the cellular interactions, their molecular basis and their development remains poorly understood. In recent years, stem cell-derived organoids have gained increasing attention as promising models for both development and a broad range of pathologies, including infectious diseases. In addition, organoids enable the study of epithelial innate immunity in vitro. In this review, we focus on the gastrointestinal epithelial barrier and its regional organization to discuss innate immune sensing and development.}, language = {en} } @article{LandwehrAltieriSchreineretal.2020, author = {Landwehr, Laura-Sophie and Altieri, Barbara and Schreiner, Jochen and Sbiera, Iuliu and Weigand, Isabel and Kroiss, Matthias and Fassnacht, Martin and Sbiera, Silviu}, title = {Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma}, series = {Journal for ImmunoTherapy of Cancer}, volume = {8}, journal = {Journal for ImmunoTherapy of Cancer}, doi = {10.1136/jitc-2019-000469}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229893}, year = {2020}, abstract = {Background Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Tumor-related glucocorticoid excess is present in similar to 60\% of patients and associated with particularly poor prognosis. Results of first clinical trials using immune checkpoint inhibitors were heterogeneous. Here we characterize tumor-infiltrating T lymphocytes (TILs) in ACC in association with glucocorticoids as potential explanation for resistance to immunotherapy. Methods We performed immunofluorescence analysis to visualize tumor-infiltrating T cells (CD3\(^+\)), T helper cells (CD3\(^+\)CD4\(^+\)), cytotoxic T cells (CD3\(^+\)CD8\(^+\)) and regulatory T cells (Tregs; CD3\(^+\)CD4\(^+\)FoxP3\(^+\)) in 146 ACC tissue specimens (107 primary tumors, 16 local recurrences, 23 metastases). Quantitative data of immune cell infiltration were correlated with clinical data (including glucocorticoid excess). Results 86.3\% of ACC specimens showed tumor infiltrating T cells (7.7 cells/high power field (HPF)), including T helper (74.0\%, 6.7 cells/HPF), cytotoxic T cells (84.3\%, 5.7 cells/HPF) and Tregs (49.3\%, 0.8 cells/HPF). The number of TILs was associated with better overall survival (HR for death: 0.47, 95\% CI 0.25 to 0.87), which was true for CD4\(^+\)- and CD8\(^+\) subpopulations as well. In localized, non-metastatic ACC, the favorable impact of TILs on overall and recurrence-free survival was manifested even independently of ENSAT (European Network for the Study of Adrenal Tumors) stage, resection status and Ki67 index. T helper cells were negatively correlated with glucocorticoid excess (Phi=-0.290, p=0.009). Patients with glucocorticoid excess and low TILs had a particularly poor overall survival (27 vs. 121 months in patients with TILs without glucocorticoid excess). Conclusion Glucocorticoid excess is associated with T cell depletion and unfavorable prognosis. To reactivate the immune system in ACC by checkpoint inhibitors, an inhibition of adrenal steroidogenesis might be pivotal and should be tested in prospective studies.}, language = {en} } @article{DraganovSantidrianMinevetal.2019, author = {Draganov, Dobrin D. and Santidrian, Antonio F. and Minev, Ivelina and Duong, Nguyen and Kilinc, Mehmet Okyay and Petrov, Ivan and Vyalkova, Anna and Lander, Elliot and Berman, Mark and Minev, Boris and Szalay, Aladar A.}, title = {Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers}, series = {Journal of Translational Medicine}, volume = {17}, journal = {Journal of Translational Medicine}, issn = {100}, doi = {10.1186/s12967-019-1829-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226312}, year = {2019}, abstract = {Background Previous studies have identified IFNγ as an important early barrier to oncolytic viruses including vaccinia. The existing innate and adaptive immune barriers restricting oncolytic virotherapy, however, can be overcome using autologous or allogeneic mesenchymal stem cells as carrier cells with unique immunosuppressive properties. Methods To test the ability of mesenchymal stem cells to overcome innate and adaptive immune barriers and to successfully deliver oncolytic vaccinia virus to tumor cells, we performed flow cytometry and virus plaque assay analysis of ex vivo co-cultures of stem cells infected with vaccinia virus in the presence of peripheral blood mononuclear cells from healthy donors. Comparative analysis was performed to establish statistically significant correlations and to evaluate the effect of stem cells on the activity of key immune cell populations. Results Here, we demonstrate that adipose-derived stem cells (ADSCs) have the potential to eradicate resistant tumor cells through a combination of potent virus amplification and sensitization of the tumor cells to virus infection. Moreover, the ADSCs demonstrate ability to function as a virus-amplifying Trojan horse in the presence of both autologous and allogeneic human PBMCs, which can be linked to the intrinsic immunosuppressive properties of stem cells and their unique potential to overcome innate and adaptive immune barriers. The clinical application of ready-to-use ex vivo expanded allogeneic stem cell lines, however, appears significantly restricted by patient-specific allogeneic differences associated with the induction of potent anti-stem cell cytotoxic and IFNγ responses. These allogeneic responses originate from both innate (NK)- and adaptive (T)- immune cells and might compromise therapeutic efficacy through direct elimination of the stem cells or the induction of an anti-viral state, which can block the potential of the Trojan horse to amplify and deliver vaccinia virus to the tumor. Conclusions Overall, our findings and data indicate the feasibility to establish simple and informative assays that capture critically important patient-specific differences in the immune responses to the virus and stem cells, which allows for proper patient-stem cell matching and enables the effective use of off-the-shelf allogeneic cell-based delivery platforms, thus providing a more practical and commercially viable alternative to the autologous stem cell approach.}, language = {en} } @article{GiampaoloWojcikSerflingetal.2017, author = {Giampaolo, Sabrina and W{\´o}jcik, Gabriela and Serfling, Edgar and Patra, Amiya K.}, title = {Interleukin-2-regulatory T cell axis critically regulates maintenance of hematopoietic stem cells}, series = {Oncotarget}, volume = {8}, journal = {Oncotarget}, number = {18}, doi = {10.18632/oncotarget.16377}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170947}, pages = {29625-29642}, year = {2017}, abstract = {The role of IL-2 in HSC maintenance is unknown. Here we show that Il2\(^{-/-}\) mice develop severe anomalies in HSC maintenance leading to defective hematopoiesis. Whereas, lack of IL-2 signaling was detrimental for lympho- and erythropoiesis, myelopoiesis was enhanced in Il2\(^{-/-}\) mice. Investigation of the underlying mechanisms of dysregulated hematopoiesis in Il2\(^{-/-}\) mice shows that the IL-2-T\(_{reg}\) cell axis is indispensable for HSC maintenance and normal hematopoiesis. Lack of T\(_{reg}\) activity resulted in increased IFN-γ production by activated T cells and an expansion of the HSCs in the bone marrow (BM). Though, restoring T\(_{reg}\) population successfully rescued HSC maintenance in Il2\(^{-/-}\) mice, preventing IFN-γ activity could do the same even in the absence of T\(_{reg}\) cells. Our study suggests that equilibrium in IL-2 and IFN-γ activity is critical for steady state hematopoiesis, and in clinical conditions of BM failure, IL-2 or anti-IFN-γ treatment might help to restore hematopoiesis.}, language = {en} } @article{NaseemDandekar2012, author = {Naseem, Muhammad and Dandekar, Thomas}, title = {The Role of Auxin-Cytokinin Antagonism in Plant-Pathogen Interactions}, series = {PLOS Pathogens}, volume = {8}, journal = {PLOS Pathogens}, number = {11}, doi = {10.1371/journal.ppat.1003026}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131901}, pages = {e1003026}, year = {2012}, abstract = {No abstract available.}, language = {en} }