Die kontinuierliche Rezirkulation von Immunzellen durch periphere und sekundäre lymphatische Organe (SLOs) ist Bestandteil der Immunüberwachung und wichtig für die Aufrechterhaltung und Funktionsbereitschaft des Immunsystems. Der homöostatische Chemokinrezeptor CCR7 vermittelt dabei nicht nur die Rezirkulation von Lymphozyten durch SLOs, sondern scheint auch an der homöostatischen Rezirkulation von Lymphozyten durch nicht-lymphoide periphere Gewebe beteiligt zu sein. Im Rahmen dieser Arbeit wurde mithilfe von CCR7-defizienten Mäusen die funktionale Bedeutung von CCR7 für die homöostatische Rezirkulation von Lymphozyten durch das Peritoneum untersucht und nachgewiesen, dass CCR7 der dominante Chemokinrezeptor ist, der unter physiologischen Bedingungen die Transitzeit von Lymphozyten durch das Peritoneum festlegt. Die gestörte Rezirkulation von Lymphozyten begünstigte außerdem die Entstehung von tertiären lymphoiden Organen (TLOs) in der Magenschleimhaut von CCR7-defizienten Mäusen. Untersuchungen zur zellulären und molekularen Grundlage dieser und weiterer pathomorphologischer Veränderungen in der Magenschleimhaut von CCR7-defizienten Mäusen verdeutlichten die Funktion von CCR7 für die Etablierung von zentraler und peripherer Toleranz gegenüber gastrischen Antigenen. Fehlt CCR7, dann entwickelten Mäuse eine spontane Autoimmungastritis, welche durch gastritogene CD4+ T-Zellen verursacht wurde, deren Aktivierung auch unabhängig von Lymphknoten und TLOs erfolgte. Die Entstehung von TLOs wird auch bei einer durch Helicobacter pylori ausgelösten chronischen Gastritis beobachtet. Die Expression des homöostatischen Chemokinrezeptors CXCR5 und seines Liganden CXCL13 ist mit der Entwicklung dieser TLOs korreliert worden. Unter Verwendung eines Mausmodells für H. pylori-induzierte chronische Gastritis konnte gezeigt werden, dass CXCR5 die Ausbildung von TLOs vermittelt und eine Rolle für die Induktion von H. pylori-spezifischen T-Zell- sowie humoralen Immunantworten spielt. / Homeostatic recirculation of immune cells through peripheral and secondary lympoid organs (SLOs) is required for immune surveillance and the maintenance and functionality of the immune system. The homeostatic chemokine receptor CCR7 controls not only lymphoid cell trafficking to and within SLOs, but also seems to be involved in the homeostatic recirculation of lymphocytes through non-lymphoid peripheral tissues. Within the scope of this work we investigated the functional relevance of CCR7 for the homeostatic recirculation of lymphocytes through the peritoneal cavity and could show, that CCR7 is the dominant chemokine receptor which defines the transit time of lymphocytes in the peritoneal cavity under physiological conditions. Impaired recirculation of lymphocytes also promoted the development of tertiary lymphoid organs (TLOs) in the gastric mucosa of CCR7-deficient mice. Analysis of the cellular and molecular mechanisms underlying these and other pathomorphological alterations in the gastric mucosa of CCR7-deficient mice provided further evidence regarding the function of CCR7 for the establishment of central and peripheral tolerance towards gastric antigens. Mice that lack CCR7 spontaneously developed autoimmune gastritis, which was caused by gastritogenic CD4+ T-cells. Such autoreactive T cell responses were also initiated in the absence of lymph nodes and TLOs in CCR7/LT-alpha double-deficient mice. Development of TLOs is also observed during chronic gastritis induced by Helicobacter pylori. The expression of the homeostatic chemokine receptor CXCR5 and its ligand CXCL13 has been correlated with the development of these TLOs. Using a mouse model for H. pylori-induced chronic gastritis, we could show that CXCR5 is responsible for the development of TLOs and also plays a role for the induction of H. pylori-specific T and B cell responses.

Made available in DSpace on 2014-07-29T15:07:31Z (GMT). No. of bitstreams: 1 Daniel Barbosa.pdf: 1143657 bytes, checksum: d56a1f0787d16e510afed007895c5973 (MD5) Previous issue date: 2010-10-24 / Abdominal wall defects may occur in fairly all animal species, and frequently demand corrective surgical treatment including implants of meshes, such as polypropylene. However, this biomaterial is not free from complications, what stimulates constant researches for new biomaterials that present certain advantages. Due to its well known biocompatibility, poliHEMA hydrogel was the chosen biomaterial for experimental abdominal wall implant associated to polypropylene mesh. This essay compared tissue responses to the employment of polypropylene mesh alone (group PP) and polyHEMA Hydrogel film associated to polypropylene mesh (group PH) on the correction of induced abdominal wall defects on bitches. Twelve mongrel adult female dogs, weighting from 10 to 20 kg, were divided in two equal groups. The animals from group PP received the polypropylene mesh implant whilst those from group PH received polyHEMA hydrogel coated polypropylene mesh to replace the abdominal transverse muscle. Six animals from each group were submitted to surgical procedure to remove the meshes at 30 and 60 days of the postoperative period. Tissue repairing phenomena such as: chronic inflammatory reaction, giant cell presence (foreign body chronic granulomatous inflammatory reaction) and connective tissue proliferation were microscopically evaluated. It may be concluded that polyHEMA hydrogel as a coating agent on polypropylene mesh implanted onto abdominal wall of female dogs triggers greater deposition of type I collagen, than polypropylene mesh alone. / Os defeitos na parede abdominal estão presentes em praticamente todas as espécies animais e não raro demandam tratamento cirúrgico corretivo com implantação de telas como a de polipropileno. Contudo esse biomaterial não é livre de complicações, o que impulsiona a constante pesquisa na busca de novos biomateriais que apresentem vantagens. O hidrogel de poliHEMA por ser reconhecidamente biocompatível foi o biomaterial de escolha para a implantação experimental em associação à tela de polipropileno na parede abdominal. Este estudo comparou as respostas teciduais do uso da tela de polipropileno isolada (grupo PP) e o filme de hidrogel de poliHEMA associado à tela de polipropileno (grupo PH) quando utilizados na correção de defeitos criados na parede abdominal de cadelas. Foram utilizadas 12 cadelas sem raça definida, adultas, pesando entre 10 e 20 kg, divididas em dois grupos de seis. Os animais do grupo PP receberam o implante da tela de polipropileno e os animais do grupo PH receberam a tela de polipropileno revestida de hidrogel de poliHEMA em substituição ao músculo transverso do abdome. Seis animais de cada grupo foram submetidos ao procedimento cirúrgico para a retirada das telas aos 30 e 60 dias do pós-operatório. Foram avaliados microscopicamente os fenômenos de reparo tecidual como: reação inflamatória crônica, presença de células gigantes (reação inflamatória crônica granulomatosa tipo corpo estranho), e proliferação conjuntiva. Conclui-se que o hidrogel de poliHEMA como agente de revestimento da tela de polipropileno quando implantado na parede abdominal de cadelas desencadeia maior deposição de colágeno tipo I quando comparado a tela de polipropileno isolada.