Die Rolle dendritischer Zellen (DCs) für die Modulation der Angiogenese. Charakterisierung der molekularen Mechanismen in der Beeinflussung der Angiogenese

In der vorliegenden Arbeit wurde die Rolle von dendritischen Zellen für die Angiogenese untersucht. Ein besonderes Augenmerk lag darauf, zu untersuchen, welchen Effekt unreife und reife Dendritische Zellen auf die Angiogenese haben. Darüber hinaus lag ein weiterer Schwerpunkt darauf, die Rolle von Hypoxie auf die DC- getriggerte Angiogenese zu untersuchen. Folgende Erkenntnisse konnten dabei gewonnen werden: Erstens können unreife DCs eine signifikante Zunahme der Angiogenese in vivo bewirken. Diese Beobachtung konnte in zwei verschiedenen in vivo Modellen der Angiogenese gemacht werden. Einerseits konnte im Hindlimb- Ischämie Modell, einem Modell der Hypoxie- induzierten Angiogenese, beobachtet werden, dass die Depletion von DCs zu einer signifikanten Abnahme der Angiogenese im operierten Bein führt im Vergleich zum Wildtyp, bei dem keine Depletion durchgeführt worden war. Darüber hinaus konnte in einem Wachstumsfaktor getriggerten Modell der Angiogenese, dem Matrigel- Modell ebenfalls eine deutliche Zunahme der Angiogenese nach Zugabe von konditioniertem Zellkulturmedium von unreifen DCs beobachtet werden. Zweitens konnten weitere in vitro Untersuchungen von Endothelzellfunktionen wie Proliferation, Migration und Tube Formation zeigen, dass unreife DCs eine signifikante Zunahme der Proliferation und Migration von Endothelzellen bewirken. Außerdem zeigen unreife DCs eine Tendenz, die Fähigkeit von Endothelzellen, endotheliale Tubes zu bilden, zu verstärken. Drittens wurde mittels Analysen auf RNA- und Proteinebene untersucht, welche von DCs produzierten Faktoren für die Modulation der Angiogenese eine Rolle spielen könnten. Dabei fanden sich in den Untersuchungen mittels Proteome Profiling, ELISA und Real- Time- PCR mehrere mögliche Kandidaten. Zum Beispiel fand sich im Proteome Profiling CXCL10 als antiangiogen wirkendes Protein, dass vor allem von reifen DCs produziert wird. Andererseits fand sich in der Real- Time- PCR eine vermehrte Expression von FLT-1 in der Gruppe der unreifen DCs. Weitere Untersuchungen sind notwendig, um die Rolle der identifizierten Faktoren in der durch DCs getriggerten Angiogenese zu untersuchen

Trigger‐Associated Clinical Implications and Outcomes in Takotsubo Syndrome: Results From the Multicenter GEIST Registry

Stress‐induced cardiomyopathy; Takotsubo syndromeMiocardiopatía inducida por estrés; Síndrome de takotsuboMiocardiopatia induïda per l'estrès; Síndrome de takotsuboBackground Takotsubo syndrome is usually triggered by a stressful event. The type of trigger seems to influence the outcome and should therefore be considered separately. Methods and Results Patients included in the GEIST (German‐Italian‐Spanish Takotsubo) registry were categorized according to physical trigger (PT), emotional trigger (ET), and no trigger (NT) of Takotsubo syndrome. Clinical characteristics as well as outcome predictors were analyzed. Overall, 2482 patients were included. ET was detected in 910 patients (36.7%), PT in 885 patients (34.4%), and NT was observed in 717 patients (28.9%). Compared with patients with PT or NT, patients with ET were younger, less frequently men, and had a lower prevalence of comorbidities. Adverse in‐hospital events (NT: 18.8% versus PT: 27.1% versus ET: 12.1%, P<0.001) and long‐term mortality rates (NT: 14.4% versus PT: 21.6% versus ET: 8.5%, P<0.001) were significantly lower in patients with ET. Increasing age (P<0.001), male sex (P=0.007), diabetes (P<0.001), malignancy (P=0.002), and a neurological disorder (P<0.001) were associated with a higher risk of long‐term mortality, while chest pain (P=0.035) and treatment with angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker (P=0.027) were confirmed as independent predictors for a lower risk of long‐term mortality. Conclusions Patients with ET have better clinical conditions and a lower mortality rate. Increasing age, male sex, malignancy, a neurological disorder, chest pain, angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, and diabetes were confirmed as predictors of long‐term mortality

NKG2D Signaling Leads to NK Cell Mediated Lysis of Childhood AML

Natural killer cells have been shown to be relevant in the recognition and lysis of acute myeloid leukemia. In childhood acute lymphoblastic leukemia, it was shown that HLA I expression and KIR receptor-ligand mismatch significantly impact ALL cytolysis. We characterized 14 different primary childhood AML blasts by flow cytometry including NKG2D ligands. Further HLA I typing of blasts was performed and HLA I on the AML blasts was quantified. In two healthy volunteer NK cell donors HLA I typing and KIR genotyping were done. Blasts with high NKG2D ligand expression had significantly higher lysis by isolated NK cells. Grouping the blasts by NKG2D ligand expression led to a significant inverse correlation of HLA I expression and cytolysis in NKG2D low blasts. Furthermore, a significant positive correlation of NKG2D ligand expression and blast cytolysis was shown. No impact of KIR ligand-ligand mismatch was found but a significantly increased lysis of homozygous C2 blasts by KIR2DL1 negative NK cells (donor B) was revealed. In conclusion, NKG2D signaling leads to NK cell mediated lysis of childhood AML despite high HLA I expression

Acute kidney injury and tools for risk-stratification in 456 patients with hantavirus-induced nephropathia epidemica

BACKGROUND Puumala virus (PUUV) is the most common species of hantavirus in Central Europe. Nephropathia epidemica (NE), caused by PUUV, is characterized by acute kidney injury (AKI) and thrombocytopenia. The major goals of this study were to provide a clear clinical phenotyping of AKI in patients with NE and to develop an easy prediction rule to identify patients, who are at lower risk to develop severe AKI. METHODS A cross-sectional prospective survey of 456 adult patients with serologically confirmed NE was performed. Data were collected from medical records and prospectively at follow-up visit. Severe AKI was defined by standard criteria according to the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) classification. Fuller statistical models were developed and validated to estimate the probability for severe AKI. RESULTS During acute NE, 88% of the patients had AKI according to the RILFE criteria during acute NE. A risk index score for severe AKI was derived by using three independent risk factors in patients with normal kidney function at time of diagnosis: thrombocytopenia [two points; odds ratios (OR): 3.77; 95% confidence intervals (CI): 1.82, 8.03], elevated C-reactive protein levels (one point; OR: 3.02; 95% CI: 1.42, 6.58) and proteinuria (one point; OR: 3.92; 95% CI: 1.33, 13.35). On the basis of a point score of one or two, the probability of severe AKI was 0.18 and 0.28 with an area under the curve of 0.71. CONCLUSION This clinical prediction rule provides a novel and diagnostically accurate strategy for the potential prevention and improved management of kidney complications in patients with NE and, ultimately, for a possible decrease in unnecessary hospitalization in a high number of patient

The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets

Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1(−/−) mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo. In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4