Orientador: Paulo Sérgio Cerri / Resumo: A periodontite (DP) é uma doença imunoinflamatória que promove o recrutamento de células específicas que liberam mediadores, dentre eles interleucina-1 (IL-1), fator de necrose tumoral-alfa (TNF-α) e metaloproteinases da matriz (MMPs). Há evidências de que a diacereína, uma medicação anti-IL-1, reduz a produção de MMPs e TNF-α. O objetivo do presente estudo foi avaliar se a diacereína acelera a regressão da inflamação e reduz a perda óssea na DP induzida. No total, foram utilizados 66 ratos Holtzman distribuídos, aleatoriamente, nos diferentes grupos. Em 42 ratos, a DP foi induzida com inserção de uma ligadura no 1º molar superior direito por 7 dias. Após a indução, 12 animais foram sacrificados: 6 animais do grupo GP (grupo periodontite) e 6 animais do grupo controle (GC), usado como parâmetro da DP induzida. No 7º dia de indução da DP, a ligadura colocada em 36 ratos foi removida e iniciou-se o tratamento com 100 mg/kg de massa corpórea de diacereína (GPD) ou solução fisiológica (GPS) por gavagem durante 7, 15 e 30 dias. Após 24 horas da administração da última dose, 6 animais de cada grupo (GPD, GPS e GC) foram sacrificados. Após eutanásia, fragmentos de maxila com molares do lado direito foram removidos e logo imersos em solução de formaldeído 4%. Em seguida, os espécimes foram descalcificados em EDTA 7% e processados para inclusão em parafina. De cada fragmento, 5 cortes sagitais semi-seriados foram corados com hematoxilina e eosina (HE) para análises morfológica e quant... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Adult neurogenesis, is a lifelong process by which relatively few cells are added into two restricted regions of the brain. Integration of the cells into the existing neuronal circulatory, with the unique properties involved in the maturation of these cells, is possibly critical to the acquisition and retrieval of new memories. With the chronological aging of the organism a process of cellular senescence occurs throughout the body; a portion of which is independent of primary alterations to the stem cells; instead, it appears to be dependent on the environment where the cells reside, and is in part regulated by inflammation. Microglia, the resident immune cells in the brain, are neuroprotective but chronic activation of the microglia, such as the chronic activation that occurs with advanced age, can promote neurotoxic inflammation. However, it not clear if the aged-related increase in neuroinflammation is at least partly responsible for the aged related decrease in neurogenesis. To address the involvement in neuroinflammation in regulating neurogenesis we used 3 different potential therapeutically relevant manipulations. The first was a targeted approach directed at disrupting the synthesis of Interleukin-1beta (IL-1B), which is a proinflammatory cytokine that is consistently found elevated in the aged brain. The second was a cell therapy approach in which human umbilical cord blood cells were injected into the systemic circulation. The final approach was directed at a chemokine system, fractalkine/CX3CR1, which has been shown as an important paracrine signal, from neurons that regulates the activation state of microglia. While the three approaches used to manipulate, aging-rodent model system were different, a consistent finding was reached in all three studies. In the aged brain, microglia which are the predominate produces of IL-1B, negatively regulate neurogenesis. When IL-1B is decreased or microglia activation is decreased, neurogenesis can be partially restored in the aged brain. The results of these studies, demonstrate a key role for microglia in regulating the neurogenic neiche, which are amendable to therapeutic manipulations.

In dieser Arbeit wurde die Auswirkung von IL-1β sowie der Inhibierung von Il-1β bzw. seines Rezeptors auf die regulatorischen T-Helfer-Zellen (Tregs) gesunder Probandinnen, JIA- und RA-Patientinnen untersucht. Der größte Einfluss von IL-1β zeigte sich bei den untersuchten Zellen der gesunden Probandinnen. Unter IL-1β Stimulation wurde der Treg-spezifische Transkriptionsfaktor FoxP3 signifikant vermindert von den regulatorischen T-Helfer-Zellen, den induzierten regulatorischen T-Helfer Zellen und den Nicht-Tregs der gesunden Probandinnen exprimiert. Ebenfalls zeigte sich ein nicht-signifikanter Trend für eine gesteigerte IL-17 Produktion unter IL-1β Stimulation bei den Tregs der gesunden Probandinnen, der JIA- und der RA-Patientinnen und bei den Nicht-Tregs der gesunden Probandinnen. Dies war bei der IL-1β Inhibierung bzw. der Inhibierung des IL-1 Rezeptors nicht zu beobachten. / In this work, the influence of IL-1β or the inhibition of IL-1β or its receptor on regulatory T helper cells (Tregs) of healthy donors, JIA- or RA-patients was analysed. The biggest effect of IL-1β was observed in cells of healthy donors. After stimulation with IL-1β, expression of the Treg-specific transcription factor FoxP3 was significantly reduced in regulatory T cells, induced regulatory T cells and non-regulatory T cells of healthy donors. Also, a non-significant trend towards increased IL-17 production was found in Tregs of healthy donors, JIA- and RA-patients after IL-1β stimulation. This was not observed after inhibition of IL-1β or the IL-1β receptor.

Die individuelle Hautempfindlichkeit stellt einen bedeutsamen Risikofaktor für die Entwicklung von berufsbedingten Hauterkrankungen dar. Zur Beurteilung der Hautempfindlichkeit hat sich in der Berufsdermatologie der Alkaliresistenztest als Standardverfahren etabliert. Er wird heute in vielen methodischen Varianten durchgeführt, was eine einheitliche Beurteilung und Begutachtung von Versicherten mit Berufsdermatosen wesentlich erschwert. Außerdem fehlt trotz bestehender Standardisierungs- und Qualitätskriterien eine allgemeingültige Standardisierung der Hautirritabilitätsdiagnostik im Sinne einer Leitlinie. Das Ziel der vorliegenden Arbeit war zum einen, die aktuelle Hautempfindlichkeitsdiagnostik bundesweit zu vereinheitlichen, zum anderen, neue Testverfahren zu entwickeln, die nicht nur schneller durchzuführen sind, sondern auch mit weniger Belastungen für die Patienten einhergehen. Der Schnelle Modifizierte Alkali-Resistenz-Test (SMART) und der Differenzielle IrritationsTest (DIT) wurden im Rahmen einer Multicenter-Studie hinsichtlich der Praktikabilität im Einsatz bei den berufsdermatologischen Routineuntersuchungen evaluiert. Die Studie zeigte, dass weder klinische noch hautphysiologische Testergebnisse von den erfassten Umgebungsfaktoren wesentlich beeinflusst werden. Auf der Grundlage der vorliegenden Ergebnisse können der SMART und der DIT sowohl zur Identifizierung vermehrter konstitutioneller Risiken als auch zur Objektivierung einer resultierenden subklinischen Minderbelastbarkeit der Haut der Hände nach früherem, abgeheiltem Berufsekzem eingesetzt werden. In der zweiten Studie wurden immunologische Ursachen individueller Hautempfindlichkeit mittels der Abrissmethode untersucht. Auf der Basis der Ergebnisse dieser Studie lässt sich schlussfolgern, dass es noch nicht möglich ist, anhand eines Tesafilmabrisses eine Aussage zur individuellen Hautempfindlichkeit zu erhalten. Hierzu erscheinen weitere Forschungsprojekte mit größeren Stichproben erforderlich.

Exposure to traumatic events can lead to many varied psychological and physiological difficulties, including an increased risk for chronic physical health problems and chronic pain disorders, which are thought to be mediated through the three major biological systems involved in the human stress response. The objective of the present study was to examine the relationships between psychological symptoms and proinflammatory immune markers, Interleukin-1β (IL-1β) and Interleukin-6 (IL-6), which are thought to be related to many of the physical health problems associated with posttraumatic psychopathology. Female participants (N=12) were recruited from a trauma specialty clinic and participated in approximately one research session per month for up to one year of psychotherapy. Five participants had at least three data points and were further examined for longitudinal correlations. Baseline measurements of urinary IL-1β were associated with self-report measures of trait anxiety and dissociative symptoms. One participant, who completed nine research sessions over nearly 12 months, showed improvements in depressive symptoms, state and trait anxiety, and dissociative symptoms that seemed to correspond with decreases in IL-6. IL-1β did not seem to be related to any of her symptom measures. A second participant, with five data points over almost four months, showed less marked change in symptomatology, but her IL-6 levels seemed to correspond with depressive and dissociative symptoms, and her IL-1β levels seemed to be associated with trends in state anxiety and dissociative symptoms. Three other participants had between three and four data points, and the trends obtained were inadequate to determine whether any true relationship existed among the longitudinal variables. These results provide preliminary evidence that it may be possible to reduce chronic pro-inflammatory dysregulation through psychotherapy-facilitated symptom reduction.

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