Thesis (Ph.D.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed on Feb. 2, 2010). Includes bibliographical references.

Die vorliegende publikationsbasierte Dissertationsschrift erörtert auf der Basis experimenteller Untersuchungen im Tiermodell die Auswirkungen von Stress auf die Zytokinproduktion und depressionsähnliches Verhalten. Außerdem wird getestet, ob die Blockade des Zytokins Tumornekrosefaktor-α (TNF‑α) eine Möglichkeit zur antidepressiven Intervention darstellt. Einleitend werden die Zusammenhänge von Stress, Zytokinen und Depression referiert sowie das hypothetische Modell erläutert, das den publizierten Untersuchungen zugrunde liegt. Es wird hypothetisiert, dass Stress zur Erhöhung der Produktion proinflammatorischer Zytokine führt und dass die vermehrte Zytokinproduktion depressive Verhaltensweisen hervorruft. Aus dieser Annahme leitet sich die Möglichkeit ab, durch Blockade der Wirkung des proinflammatorischen Zytokins TNF‑α antidepressive Effekte zu erzielen. In den beiden Arbeiten „The impact of social isolation on immunological parameters in rats“ (Archives of Toxicology) und „Stress-induced cytokine changes in rats“ (European Cytokine Network) wurde der Einfluss von sozialer Isolation, chronischem, milden und akutem Stress auf die Zytokinproduktion untersucht. In diesen Untersuchungen führten die verschiedenen Stressarten zu einer Modulation der Produktion proinflammatorischer Zytokine. Die dritte Publikation „Antidepressant effects of TNF‑α blockade in an animal model of depression“ (Journal of Psychiatric Research) berichtet von einem Experiment, in dem untersucht wurde, ob der TNF‑α-Inhibitor Etanercept antidepressive Effekte aufweist. Tatsächlich zeigte sich unter Etanercept ein Rückgang des depressionsähnlichen Verhaltens im forced swim test (FST) analog zu Verhaltensänderungen durch das in Tierversuchen als Standard-Antidepressivum geltende Imipramin. Die Autoren schlussfolgern, dass das Zytokinsystem durch Stress moduliert wird und so in die pathophysiologische Entwicklung einer Depression involviert sein könnte. Zytokininhibitoren könnten eine neue Klasse der Antidepressiva bei Therapieresistenz werden, wenn sich die Ergebnisse dieser Tierversuche in Studien an Probanden und an Patienten replizieren lassen.

No description available.

No description available.

Overwhelming evidence for senescence, the within-individual decline in performance at advanced age, has now been documented in the natural populations of many taxa. As such, the focus of senescence research is shifting from simply documenting its existence, towards understanding the fundamental mechanisms underpinning it and determining which environmental factors give rise to the considerable variation in senescence rates observed in nature. In this thesis I use a wild population of European badgers (Meles meles) to investigate three important traits implicated in, or arising as a direct product of, senescence; immune cell telomere length, pro-inflammatory cytokine response and body mass declines in late life. My work reveals rare longitudinal evidence for the existence of senescence in immune traits in a wild mammal. First, I show that within-individual declines in immune cell telomere length occur with increasing age (Chapter 2). Second, after demonstrating that immune cell telomere length displays repeatable between-individual differences in adulthood, I show that the environmental conditions experienced in early-life contribute to such between-individual variation. Individuals that experienced harsh early-life environmental conditions had shorter immune cell telomere lengths than those that experienced favourable conditions (Chapter 3). Third, I show that within-individual declines in a second immune trait, pro-inflammatory cytokine response, also occur with age (Chapter 4). However, the declines in immune cell telomere length and pro-inflammatory cytokine response occur independently of one another (Chapter 4). Finally I take advantage of a 37 year longitudinal dataset to reveal that sex differences in body mass senescence arise as a consequence of the scale of intra-sexual competition experienced in early adulthood (Chapter 5). Taken together this work provides novel evidence suggesting that age-related declines in immunocompetence can contribute to whole organism senescence in the wild. Furthermore, evidence that early life environmental and social conditions can markedly influence senescence rates has important implications for our understanding of the drivers of variation in senescence rates observed within natural populations.

Diese Arbeit beschreibt Ergebnisse einer in-vitro Untersuchung der Antipsychotika Chlorpromazin, Haloperidol, Clozapin, N-Desmethylclozapin und Quetiapin bezüglich ihrer Wirkung auf die Zytokinproduktion. Dafür wurde Vollblut von gesunden Probandinnen invitro mit dem Immunmodulator Toxic-Shock-Syndrome-Toxin-1 (TSST-1) stimuliert. Dabei wurden die Konzentrationen der Zytokine Interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-17 und Tumornekrosefaktor-α (TNF-α) im unstimulierten Blut und im stimulierten Blut, jeweils mit und ohne Zusatz der Antipsychotika gemessen. Es zeigte sich, dass TSST-1 eine signifikante Stimulation der Produktion aller getesteten Zytokine bewirkte und dass es über diese Stimulation mit TSST-1 hinaus zu einer Erhöhung von IL-17 unter allen getesteten Antipsychotika kam. Aufgrund dieser Ergebnisse ist es denkbar, dass Antipsychotika, in Ergänzung zu ihrer Wirkung an Dopaminrezeptoren, auch über diese immunologische Eigenschaft Wirkungen und Nebenwirkungen entfalten können. Weiterhin könnte die IL-17-Produktion ein Biomarker in der Behandlung mit Antipsychotika sein, der wiederum zur individuellen Vorhersage von Wirkungen und Nebenwirkungen beitragen könnte.

Prolonged exercise has been associated with depressed immune function, and hence an increased risk of infection. However, several nutritional supplements may reduce or overcome this problem. Thus, the aims of this thesis were to investigate the effects of some nutritional supplements on athletes immune function. In study 1 (Chapter 3), effects of several vaccine stimulant dose on whole blood culture cytokine production was carried out to determine effective vaccine stimulant dose; which was found to be between a dilution of 4000 (dose 4) and 1000 (dose 6) of the original vaccine. This finding was used for the other studies (Chapter 4 and 5). In addition, the relationship between data obtained from Evidence Investigator analyser and enzyme linked-immuno-sorbent assay (ELISA) for IL-10 was analysed and the results show a positive strong correlation between them. In study 2 (Chapter 4), in vitro effects of various immunomodulatory nutritional compounds on antigen-stimulated whole blood culture cytokine production was investigated and it was found that caffeine and quercetin showed tendency towards decrease cytokine production as the doses were increased. On the other hand, an upward trend was evident with kaloba, where high dose of kaloba seemed to increase the cytokine production. Since kaloba appeared to act as an immunostimulant in vitro, its effects on the immune response to prolonged exercise were examined in study 3 (Chapter 5). However, 7 days kaloba supplementation (20 mg of the root extract) did not alter athletes immune response although prolonged moderate intensity exercise significantly decreased S-IgA secretion rate and concentration post-exercise with the values returning to baseline by 1 h post-exercise. A 14-strain probiotic supplement effects on salivary antimicrobial proteins at rest and in response to an acute bout of prolonged exercise was investigated in study 4 (Chapter 6). Unfortunately, 30 days supplementation of the 14-strain probiotic appeared not enough to induce any significant effects on salivary antimicrobial proteins. Lastly, in study 5 (Chapter 7), the effects of a Lactobacillus probiotic on healthy people, who tend to have a higher than normal incidence of infection due to exercise stress-induced immune impairment was studied. In summary, this 16-week intervention study on 267 athletes found that regular ingestion of the probiotic reduced the extent to which training was negatively affected in endurance athletes when infection was present, and increased both S-IgA concentration and secretion rate over time. But it did not appear to reduce URTI incidence or the duration and severity of URTI episodes. Two major confounding factors, namely the unexpectedly low incidence of URTI during the winter period and the lower baseline S-IgA in the probiotic group may have prevented potential beneficial effects of probiotic supplementation from being identified.

Uterine inflammation after breeding is considered necessary for the clearance of excess semen and debris from the uterus. A subpopulation of mares fails to clear the inflammation in a timely fashion, and develops a persistent breeding induced endometritis (PBIE). Experiments were preformed to evaluate correlations of PBIE to endometrial quality and age. Mares of advanced age and poor endometrial quality had a higher incidence of PBIE. In addition, mares fluctuated in susceptibility to PBIE from one season to the next. The uterine inflammatory gene expression in susceptible and resistant mares within the first 24 hours after breeding was investigated. The peak endometrial cytokine gene expression occurred 6 hours after insemination, and susceptible mares were found to have a reduced response of the inflammatory modulating cytokines during this time. Intrauterine accumulation of the inflammatory byproduct nitric oxide (NO) was investigated in resistant and susceptible mares within the first 24 hours after breeding. Susceptible mares had an increase in NO accumulation over time, whereas NO accumulation in resistant mares remained relatively constant. The effects of immunomodulators on uterine inflammatory response and nitric oxide accumulation in susceptible mares was investigated. Immunomodulators decreased expression of the pro-inflammatory cytokine interleukin-1β and nitric oxide accumulation. In conclusion, endometrial quality and age are indicators of susceptibility to PBIE, and susceptibly can change from year to year. Six hours after breeding is a critical time for the development of PBIE, and susceptible and resistant mares have differential endometrial inflammatory gene expression, with susceptible mares appearing to have a defect in the inflammatory modulating immune response. Finally, treatment with immune modulators alters the IL1β gene expression and intrauterine nitric oxide accumulation, which may help to explain how they act to reduce inflammation during PBIE.

Les dommages cellulaires consécutifs à l'EME induits par une intoxication par le soman sont accompagnés par une réaction neuro-inflammatoire dont les conséquences sur le les lésions cérébrales restent mal connues. Les antagonistes du récepteur glutamatergique NMDA, comme la kétamine (KET), ont prouvé leur efficacité antiépileptique et neuroprotectrice même pendant la période réfractaire au traitement par benzodiazépines, au-delà de 10 à 20 min après le début des crises. La KET semble posséder également une action anti-inflammatoire périphérique. Pour compléter les données existantes, nous avons évalué l'impact de l'intoxication sur la réponse inflammatoire au moyen de différentes approches (RT-qPCR, dosages protéiques multiplex, histologie) dans le cortex et l'hippocampe de souris intoxiquées par le soman. Afin d'étudier l'efficacité de la KET sur la neuro-inflammation induite, nous avons mesuré, 48 h après l'intoxication, les effets de deux combinaisons de KET associée au sulfate d'atropine (SA) administrées à partir de 30 min ou 60 min après l'intoxication sur l'évolution de la masse corporelle, les dommages cérébraux, l'activation gliale et les taux des ARNm et des protéines de cytokines pro-inflammatoires, de chimiokines et de molécules d'adhésion. Après intoxication par le soman, nous avons mis en évidence une importante activation gliale et une augmentation des ARNm et des protéines de la plupart des médiateurs de l'inflammation étudiés. Les deux protocoles KET/SA ont montré une importante efficacité neuroprotectrice sans totalement supprimer la gliose mais en limitant la production des paramètres inflammatoires étudiés. En conclusion, nos résultats indiquent que de multiples voies inflammatoires sont activées après l'intoxication par le soman. L'utilisation d'une combinaison KET/SA est neuroprotectrice et limite la réponse inflammatoire même lorsque le début du traitement est retardé une heure après l'intoxication.

<p>Background: The reasons why some individuals become IgE-sensitised and allergic are largely unknown, though genetic- and early life environmental factors seem to be of importance.</p><p>Objective: The overall aim of this thesis was to investigate the relationship between IgE-sensitisation and allergic disease, viral infections, genetic markers and early life cytokines.</p><p>Results: IgE-sensitised children were found to have reduced numbers of IL-12 producing cord blood mononuclear cells (CBMC), whereas children diagnosed with eczema were found to have reduced numbers of IFN-γ producing CBMC. When dividing the children into early onset of IgE-sensitisation and late onset of IgE-sensitisation we found that the children with an early onset had low numbers of PHA-induced IL-4, IL-12 and IFN-γ secreting CBMC. At the age of two there was a general exacerbation of cytokine responses in the IgE-sensitised children, and the results were similar for the children with early onset IgE-sensitisation. Children with a late onset IgE-sensitisation were more similar to the non-sensitised children, but with a specific increase in the response to cat allergen (IL-4 and IFN-γ). The mothers of IgE-sensitised children, were just as their children, found to have an exaggerated cytokine response as compared to mothers of non-sensitised children. Maternal responses correlated well to the responses seen in the child, though the samples were taken two years after delivery.</p><p>Cytomegalovirus (CMV) infection in early life was associated to reduced numbers of IL-4, and increased numbers of IFN-γ producing cells at the age of two. No association between CMV seropositivity and IgE-sensitisation was seen. Epstein-Barr virus (EBV) infection, on the other hand, was inversely correlated with IgE –sensitisation, whereas no statistically significant association to cytokine production could be seen.</p><p>We also showed that the IL12B 1188 C-allele was associated to having a positive skin prick test at the age of two. The rare alleles of the three SNPs investigated (IL12B 1188C, IL12RB1132C and IRF1 1688A) were all associated to low IL-12 production at birth.</p><p>Conclusions: Our results indicate that allergic diseases are complex traits, and that both the genetic and the cytokine background differ between the different allergic diseases. We can also conclude that the time of onset seem to play a role when investigating IgE-sensitisation, and that perhaps early and late onset IgE-sensitisation have partly different causes. CMV and EBV infection early in life are associated to a protective cytokine profile and to protection from IgE-sensitisation, respectively, again indicating the heterogeneity and the complexity of allergic diseases.</p>