Foxp3+ regulatory T cells protect the liver from immune damage and compromise virus control during acute experimental hepatitis B virus infection in mice

The strength of antiviral T cell responses correlates with clearance of hepatitis B virus (HBV) infection, but the immunological mechanisms mitigating or suppressing HBV-specific T cells are still poorly understood. In this study, we examined the role of CD4(+) Foxp3(+) regulatory T cells (Tregs) in a mouse model of acute HBV infection. We initiated HBV infection via an adenoviral vector transferring a 1.3-fold overlength HBV genome (AdHBV) into transgenic DEREG mice, where Tregs can be transiently but selectively depleted by injection of diphtheria toxin. The effect of Treg depletion on the outcome of HBV infection was characterized by detailed virological, immunological, and histopathological analysis. Numbers of Tregs increase in the liver rapidly after initiation of HBV replication. Initial depletion of Tregs revealed their complex regulatory function during acute infection. Tregs mitigated immunomediated liver damage by down-regulating the antiviral activity of effector T cells by limiting cytokine production and cytotoxicity, but did not influence development of HBV-specific CD8 T cells or development of memory T cells. Furthermore, Tregs controlled the recruitment of innate immune cells such as macrophages and dendritic cells to the infected liver. As a consequence, Tregs significantly delayed clearance of HBV from blood and infected hepatocytes. Conclusion: Tregs limit immunomediated liver damage early after an acute infection of the liver, thereby contributing to conservation of tissue integrity and organ function at the cost of prolonging virus clearance. (HEPATOLOGY 2012;56:873-883).     

Die Bedeutung des Hüftwerts für die Diagnose und Prognose deformierter Hüftgelenke

Zusammenfassung In einer vorausgegangenen Arbeit wurde der Hüftwert in die röntgenologische Diagnostik des Hüftgelenkes eingeführt. In der vorliegenden Veröffentlichung wurde seine Zuverlässigkeit mit anderen bisher verwandten Meßmethoden, wie dem ACM-Winkel von Idelberger u. Frank und dem CE-Winkel Wibergs, verglichen. Die Kombination verschiedener Meßverfahren in Form des Hüftwertes erwies sich dabei den einzelnen Verfahren als überlegen.Ferner wurden verschiedene Prognosen deformierter Hüftgelenke untersucht. So fanden wir z. B., daß bei Schmerzbeginn vor dem 25. Lebensjahr etwa 10 Jahre vergehen, ehe ein leicht deformiertes Hüftgelenk in ein schwer deformiertes übergeht; nach dem 25. Lebensjahr wird die entsprechende Zeitspanne kontinuierlich kürzer, nach dem 30. Lebensjahr beträgt sie schließlich 5 Jahre.Bei vielen leicht deformierten und gelegentlich auch bei schwer deformierten Gelenken tritt der erste Schmerz erst in späteren Lebensjahren auf, vielleicht auch überhaupt nicht. Es fand sich keine Korrelation zwischen dem Grad der Deformierung und dem Zeitpunkt des Schmerzbeginns. Daher sollte mit Korrektureingriffen bis zum Beginn von Schmerzen gewartet werden.

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The significanz of the Hüftwert (summerized hip factor) for the diagnosis and prognosis of a deformed hip joint

Summary The Hüftwert (summerized hip factor) in the roentgenological diagnosis of the hip joint was introduced in a previous paper. In the present publication the reliability of this summerized hip factor was compared with other current applied methods of measurement, such as the ACM-angle of Idelberger and Frank and the CE-angle of Wiberg. A combination of different methods of measurement in the form of a summerized hip factor has been proven superior to a single method of measurement.Furthermore, the different prognosis of a deformed hip joint was studied. We found for example that in cases with pain beginning before 25 years of age, approximately 10 years will pass, before a slightly deformed hip joint becomes severely deformed. After 25 years of age the time interval is only 5 years.In many slightly deformed and occasionaly also in severe deformed joints the first pain appears not until the later years of life. Pain may even not appear at all. A correlation between the degree of deformation and the point of time when pain begins, was not observed. For this reason operative treatment should not be given until the onset of pain.

     

Cross-competition of CD8+ T cells shapes the immunodominance hierarchy during boost vaccination

CD8+ T cell responses directed against multiple pathogen-derived epitopes are characterized by defined immunodominance hierarchy patterns. A possible explanation for this phenomenon is that CD8+ T cells of different specificities compete for access to epitopes on antigen-presenting cells, and that the outcome of this so-called cross-competition reflects the number of induced T cells. In our study using a vaccinia virus infection model, we found that T cell cross-competition is highly relevant during boost vaccination, thereby shaping the immunodominance hierarchy in the recall. We demonstrate that competition was of no importance during priming and was unaffected by the applied route of immunization. It strongly depended on the timing of viral antigen expression in infected APCs, and it was characterized by poor proliferation of T cells recognizing epitopes derived from late viral proteins. To our knowledge, this is the first demonstration of the functional importance of T cell cross-competition during a viral infection. Our findings provide a basis for novel strategies for how boost vaccination to defined antigens can be selectively improved. They give important new insights into the design of more efficient poxviral vectors for immunotherapy.     

Perioperative myocardial ischemia in patients with peripheral arterial occlusive diseases

Patients with peripheral vascular disease (PVD) often have coronary artery disease (CAD) which means an increased risk during anesthesia. The prevalence of CAD is nearly 50% among such patients. Owing to claudication, diagnostic stress tests can rarely be performed in PVD patients. In order to evaluate the frequency of transient perioperative myocardial ischemia, Holter monitoring was performed in 30 consecutive PVD patients with ASA II-III and AVK scale (Fontaine) II-IV who were undergoing femoropopliteal bypass surgery. Patients who had left bundle branch block and left ventricular hypertrophy or were taking digitalis medication were excluded from Holter monitoring. The ST-segment analysis of the frequency modulated recordings (n = 19) revealed episodes of myocardial ischemia in 26% of the patients. Most (75%) of the episodes occurred preoperatively, and 25%, during or after the anesthesia or during preparation for it. Risk factors for CAD were more often found in patients with ST segment alterations than in patients without ST segment deviations, even though the preoperative antianginal medication administered was comparable in the two subgroups. It is concluded that in a considerable subset of PVD patients silent myocardial ischemia occurs, which can be related to the different perioperative intervals by means of ST segment analyses of Holter recordings. The ST segment may allow a better insight into the cardiac state of PVD patients. Further studies are necessary in larger populations to test our suspicion.     

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