TY - THES A1 - Reiß, Stefan T1 - Molekulare Analyse der humoralen Immunität beim Magenkarzinom T1 - Molecular analysis of the humoral immunity in gastric carcinoma N2 - Vor fast 100 Jahren postulierte Paul Ehrlich ein körpereigenes System, das in der Lage ist, Tumorentstehung zu erkennen und zu eliminieren. Die Weiterentwicklung dieser Hypothese führte in den Folgejahren zum Modell der „immunosurveillance“, einer angeborenen Wachfunktion des Immunsystems, welche im Regelfall die Entstehung von manifesten Tumoren verhindern kann. Neben zellulären Bestandteilen wie Makrophagen und natürlichen Killerzellen kommt dabei eine entscheidende Bedeutung den B-Lymphozyten mit ihrer Fähigkeit zur Produktion eines variablen Antikörperrepertoires zu. Diese angeborene, IgM-vermittelte, humorale Abwehrfunktion richtet sich insbesondere auch gegen glykopeptidische Oberflächenantigene maligner körpereigener Zellen. Allerdings scheint sich in seltenen Einzelfällen ein Tumorprozess durch Fluchtmechanismen dem Zugriff der Immunabwehr entziehen zu können. Die intensiven Wechselwirkungen von Immunsystem und Tumorwachstum sind Ziel weitreichender Forschung geworden, angetrieben von der Hoffnung, in naher Zukunft neue immunologische Therapieverfahren gegen maligne Tumoren aufbieten zu können. Bisher wenig untersucht ist allerdings die lokale Situation der humoralen Immunität innerhalb von Tumorgewebe. Vor diesem Hintergrund wurde in der vorliegenden Arbeit eine Sequenzanalyse des exprimierten Immunglobulin-Repertoires in situ, also aus gewebeständigen tumorinfiltrierenden B-Lymphozyten und solchen aus tumorfreiem Gewebe vorgenommen. Als Ausgangsmaterial diente Gewebe aus Magenkarzinomen und tumorfreier Magenschleimhaut des Magenantrums von acht Patienten mit fortgeschrittener Tumorerkrankung. Adenokarzinome des Magens stellen eine multifaktoriell bedingte, weltweit häufig auftretende Tumorentität mit besonders schlechter Prognose dar. In der Tat zeigen sich in den vorliegenden Ergebnissen signifikante Unterschiede zwischen Tumor und Antrum in den variablen Schwerkettengenen der gewebeständigen B-Lymphozyten. Diese betreffen sowohl die IgVH- Familienzugehörigkeit als auch die Mutationsraten und Mutationsmuster der einzelnen Sequenzen. Die entscheidenden Beobachtungen im Rahmen dieser Arbeit sind der in situ- Nachweis von naiven, nicht immunitätsgereiften Immunglobulinen der primären Immunantwort, insbesondere der mit Antitumoraktivität in Verbindung gebrachten IgVH3-Familie innerhalb des untersuchten Antrumgewebes sowie deren Fehlen innerhalb des Tumorprozesses. Der Nachweis affinitätsgereifter Immunglobuline innerhalb des Tumorprozesses legt eine zwar intensive, aber letztendlich ineffektive Auseinandersetzung des Immunsystems mit dem sich offenbar in diesem Stadium nicht mehr als ausreichend immunogenen erweisenden Tumorprozess nahe. Diese Ergebnisse heben die entscheidende Bedeutung der naiven Immunität für die Verhinderung von Tumoren (Immunüberwachung) hervor. Unklar sind allerdings nach wie vor die Escape-Mechanismen, die es einem Tumor erlauben, sich dieser primären Immunantwort zu entziehen. Weitere Forschungsarbeit im Bereich naiver Immunglobuline mit Antitumoraktivität, wie beispielsweise dem selektiv an Magenkarzinomzellen bindenden und Apoptose auslösenden Antikörper SC-1, könnte dazu beitragen, zukünftig völlig neue adjuvante immunologische Therapieverfahren in der Tumortherapie zu etablieren. N2 - Nearly 100 years ago Paul Ehrlich has postulated an endogenous system that is capable to recognize and to avoid the process of tumour genesis. In the following years further studies have led to the model of innate immunosurveillance, which explains the typical prevention of the development of manifest carcinoma. In addition to cellular components, such as macrophages and natural killer-cells, B-lymphocytes play an important role in this process by building a variable antibody repertoire. This innate, IgM-mediated, humoral immune resistance is in particular targeted on glycol-peptide cell surface antigens on malignant cells. Nevertheless, in rare cases tumours seem to evade from this influence of the immune system via escape mechanisms. The intensive interaction between the immune system and tumour growth has become an extensive field of research to develop new immunologic therapies for the treatment of malignant tumours in the near future. Little is known, however, about the local situation of humoral immunity within malignant tissue. A sequence analysis of expressed antibody repertoire in situ was done in this treatise by comparing tumour infiltrating B-lymphocytes to those being extracted from normal tissue. The material was taken from gastric carcinoma and tumour-free gastric mucosal tissue of the antrum of eight patients with advanced tumour stages. Adenocarcinoma of the stomach are a multifactorally caused, worldwide spread disease with an extraordinarily poor prognosis. Present data show indeed significant differences between tumour and antrum tissue concerning the immunoglobuline heavy chain variable regions of the B-lymphocytes extracted from tissue. Differences appear in both the allocation to IgVH-subfamilies and the mutation rate as well as the mutational pattern. In this study the most important observation is the in situ detection of innate non-maturated immunoglobulines of the primary immune response. In particular of the VH3-family, which is known to trigger anti-tumour activity, within the tumour-free antrum tissue and which is absent in the tumour process. The detection of affinity-maturated antibodies within the tumour tissue shows an intensive but eventually ineffective competition between the immune response and the tumour process that seems to be insufficiently immunogen in this stadium. These results point out the relevance of innate immunity in avoiding carcinoma (immunosurveillance). The escape mechanisms of a tumour from the primary immune response, however, remain still uncertain. Further research on naïve immunoglobulines with anti-tumour activity, for example on SC-1, which binds selectively on gastric carcinoma cells and causes apoptosis, might contribute to establish new adjuvant immunologic procedures in tumour therapy. KW - Magenkrebs KW - Humorale Immunität KW - Antikörper KW - Immunglobuline KW - gastric carcinoma KW - humoral immunity KW - antibody KW - immunoglobuline Y1 - 2007 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-26592 ER - TY - JOUR A1 - Rauch, Bernhard A1 - Salzwedel, Annett A1 - Bjarnason-Wehrens, Birna A1 - Albus, Christian A1 - Meng, Karin A1 - Schmid, Jean-Paul A1 - Benzer, Werner A1 - Hackbusch, Matthes A1 - Jensen, Katrin A1 - Schwaab, Bernhard A1 - Altenberger, Johann A1 - Benjamin, Nicola A1 - Bestehorn, Kurt A1 - Bongarth, Christa A1 - Dörr, Gesine A1 - Eichler, Sarah A1 - Einwang, Hans-Peter A1 - Falk, Johannes A1 - Glatz, Johannes A1 - Gielen, Stephan A1 - Grilli, Maurizio A1 - Grünig, Ekkehard A1 - Guha, Manju A1 - Hermann, Matthias A1 - Hoberg, Eike A1 - Höfer, Stefan A1 - Kaemmerer, Harald A1 - Ladwig, Karl-Heinz A1 - Mayer-Berger, Wolfgang A1 - Metzendorf, Maria-Inti A1 - Nebel, Roland A1 - Neidenbach, Rhoia Clara A1 - Niebauer, Josef A1 - Nixdorff, Uwe A1 - Oberhoffer, Renate A1 - Reibis, Rona A1 - Reiss, Nils A1 - Saure, Daniel A1 - Schlitt, Axel A1 - Völler, Heinz A1 - Känel, Roland von A1 - Weinbrenner, Susanne A1 - Westphal, Ronja T1 - Cardiac rehabilitation in German speaking countries of Europe — evidence-based guidelines from Germany, Austria and Switzerland LLKardReha-DACH — Part 1 JF - Journal of Clinical Medicine N2 - Background: Although cardiovascular rehabilitation (CR) is well accepted in general, CR-attendance and delivery still considerably vary between the European countries. Moreover, clinical and prognostic effects of CR are not well established for a variety of cardiovascular diseases. Methods: The guidelines address all aspects of CR including indications, contents and delivery. By processing the guidelines, every step was externally supervised and moderated by independent members of the “Association of the Scientific Medical Societies in Germany” (AWMF). Four meta-analyses were performed to evaluate the prognostic effect of CR after acute coronary syndrome (ACS), after coronary bypass grafting (CABG), in patients with severe chronic systolic heart failure (HFrEF), and to define the effect of psychological interventions during CR. All other indications for CR-delivery were based on a predefined semi-structured literature search and recommendations were established by a formal consenting process including all medical societies involved in guideline generation. Results: Multidisciplinary CR is associated with a significant reduction in all-cause mortality in patients after ACS and after CABG, whereas HFrEF-patients (left ventricular ejection fraction <40%) especially benefit in terms of exercise capacity and health-related quality of life. Patients with other cardiovascular diseases also benefit from CR-participation, but the scientific evidence is less clear. There is increasing evidence that the beneficial effect of CR strongly depends on “treatment intensity” including medical supervision, treatment of cardiovascular risk factors, information and education, and a minimum of individually adapted exercise volume. Additional psychologic interventions should be performed on the basis of individual needs. Conclusions: These guidelines reinforce the substantial benefit of CR in specific clinical indications, but also describe remaining deficits in CR-delivery in clinical practice as well as in CR-science with respect to methodology and presentation. KW - cardiac rehabilitation standards KW - scientific guidelines KW - secondary prevention KW - coronary artery disease KW - chronic heart failure KW - heart valve repair KW - ICD-CRT KW - ventricular assist device KW - heart transplantation KW - peripheral artery disease KW - pulmonary hypertension KW - myocarditis KW - adults with congenital heart disease Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239709 SN - 2077-0383 VL - 10 IS - 10 ER -