Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Bibliography: leaves 169-205. This thesis suggests that the testicular macrophage exhibits characteristics similar to that of a suppressor macrophage phenotype. The inhibition of lymphocyte proliferation by the testicular macrophage, its unique cytokine profile, high basal production of GM-CSF and prostaglandins, and the refractoriness to LPS all suggests a role that contributes to the immune privilege that is afforded the testis. However, these aspects of testicular macrophage immuno-biology also support a role in local cell-cell communication and regulation of the normal physiology of the testis, and macrophages may be directly involved in Leydig cell steriogenesis.

La microsporidie Encephalitozoon intestinalis est la cause de diarrhées fréquemment associées à d'autres manifestations, chez les sujets immunodéprimés infectés par le VIH. La muqueuse intestinale constitue la première barrière physiologique et immunologique s'opposant à l'entrée du parasite dans l'organisme. Pourtant, la majorité des connaissances concernant l'immunobiologie des microsporidies résulte d'études effectuées chez la souris infectée par la voie intra-péritonéale. L'immunité protectrice vis-à-vis des microsporidies a largement été associée à la réponse immune cellulaire et à la production de cytokines de type Th1, et plus particulièrement d'IFN-g. Cependant, le ou les mécanismes par lequel l'IFN-g intervient dans le contrôle des microsporidioses reste encore mal caractérisé. Nous avons donc étudié et comparé la réponse immune cellulaire chez les souris sauvages et chez les souris déficientes pour le récepteur à l'IFN-g (GRKO), après infection orale avec E. intestinalis. Dans un premier temps, nous avons observé chez les souris sauvages infectées, capable de contrôler et d'éradiquer le parasite, 1) la mise en place d'une réponse immune cellulaire de type Th1 au niveau de la muqueuse intestinale, des ganglions mésentériques et de la rate ; 2) la production au niveau du duodenum de chimiokines connues pour attirer les lymphocytes T et les macrophages ; et 3) une augmentation du nombre de lymphocytes intraépithéliaux intestinaux, capables d'exercer une activité cytotoxique contre des macrophages infectés par le parasite. Chez les souris GRKO infectées, nous avons montré 1) une altération du profil d'expression des chimiokines au niveau de la muqueuse intestinale ; 2) un défaut d'expression des cytokines Th1 et une expression plus précoce et/ou plus importante des cytokines Th2 au niveau de tous les compartiments étudiés ; et 3) une réponse splénique T CD8+ cytotoxique moins efficace. L'ensemble de ces résultats nous permet de mieux cerner le rôle de l'IFN-g dans l'immunité anti-microsporidienne.

<p>Immune complexes (ICs) are produced during normal immune responses and facilitate clearance of foreign antigens. ICs not efficiently cleared from the circulation can cause tissue damage. This might happen if ICs are formed with autoantibodies and autoantigens. Well described effects of ICs are neutralization of antigen, classical complement activation or FcR-mediated phagocytosis, whereas cytokine inducing effects of ICs in human clinical settings are less well described. I have investigated cytokine-inducing properties <i>in vitro</i> of ICs from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and cryoglobulinemia in association with lymphoproliferative diseases. </p><p>Cryoglobulin (CG)-induced cytokine production varied with changes in temperature and ionic strength in parallel to CG precipitation. IgG CG-induced cytokine production was also mediated via FcγIIa on monocytes. Blockade of the complement system, resembling the <i>in vivo</i> situation of complement consumption in CG-associated diseases, increased IgG CG induced IL-10 and decreased TNF-α production. This represents hitherto not described mechanisms for CG-associated inflammation.</p><p>ICs from SLE patients induced IL-10 and IL-6 production from PBMC cultures via FcγRIIa. Occurrence of anti-SSA autoantibodies and signs of <i>in vivo</i> complement activation contributed to increased levels of circulating ICs in SLE patients, corresponding to increased amounts of IC-induced IL-10 <i>in vitro</i>. This represents a possible vicious cycle that might perpetuate antibody dependent pathology in SLE, and put anti-SSA in a new pathological context.</p><p>RF-associated ICs from RA joints and ICs formed with antibodies against collagen type II from RA serum induced pro-inflammatory cytokine production from monocytes via FcγRIIa, showing how specific autoantibodies might induce or perpetuate joint inflammation in RA. </p><p>I have described how ICs can induce significant amounts of pathophysiologically important monocyte-derived cytokines in three major IC-dependent diseases. Blockade of FcγRIIa and suppression of monocytes/macrophages might be a means of reducing pathogenic IC-induced cytokine production in these diseases. </p>

<p>Type 1 diabetes (T1D) is due to a selective loss of the insulin producing β-cells. However, the process responsible for this loss is still unknown. There is accumulating evidence that enteroviruses (EVs) are involved in T1D. In addition to direct virus-induced cytolysis, EVs could facilitate β-cell destruction by inducing inflammatory cytokines. Induction of such genes has previously been shown in EV-infected islets <i>in vitro</i>. Modulation of inflammatory mediators expressed in the islets could be a possible strategy to reduce β-cell destruction.</p><p>In the first paper we screened uninfected isolated human islets for genes with the potential to induce or modulate an immune response. We found that several of the genes expressed in the islets encode proteins with a powerful biological activity, such as IL-1β, IL-8, MIP-2α, MCP-1 and MIF. This indicates that the islets themselves can express several triggers of inflammation, and if expressed <i>in vivo</i> these mediators would probably contribute to β-cell destruction.</p><p>The vitamin B3 derivate, nicotinamide (NA), has been shown to modulate expression of factors important for coagulation and inflammatory responses. Addition of NA into isolated islet cultures resulted in a reduced expression of the pro-inflammatory chemokine MCP-1 and the coagulation activator tissue factor, suggesting that NA may have implications for both inflammatory responses and the pro-coagulant activity of islets.</p><p>We successfully isolated EVs from three newly diagnosed T1D patients. All isolates showed tropism for human islets and β-cells <i>in vitro</i> and clearly affected islet function. We also found that EV infection induced islet secretion of the chemokines IP-10 and MCP-1and that this induction could be blocked or reduced by addition of NA to the culture medium. Interestingly, NA also reduced viral replication and virus-induced islet destruction.</p><p>To conclude, this thesis provides new information about expression and modulation of inflammatory mediators in infected and uninfected human islets that could trigger inflammatory reactions leading to β-cell destruction. Moreover, it further strengthens the causal relationship between EV and T1D.</p>

Chronic nerve recording and stimulation can be performed by means of nerve cuff electrodes in both animals and humans. These extraneural electrodes have been used not only for fundamental research but also for rehabilitation purposes as part of a neuroprosthetic device. They have therefore contributed to our knowledge of the nervous system and also allowed partial motor and sensory rehabilitation. However, the performance of existing nerve cuff electrodes remains limited and their designs must be improved. The main drawbacks of cuff electrodes are their poor selectivity and the morphological modifications they induce to surrounding tissue. Their selectivity is mainly dependant on the number of contacts which is limited by the hand-made manufacturing process. The morphological modifications are determined by the tissue-electrode interactions. A new spiral cuff nerve electrode is proposed to improve the selectivity and lessen the tissue reaction. The manufacture of this new electrode, based on photolithographic metal deposition technology, should allow for an increased number of contacts. Additionally, this electrode has self-sizing properties that potentially lowers the implant-induced tissue reaction. The present work aims to study the interactions between the electrode and implanted tissue in an attempt to better characterise the tissue reaction and to further control it. Firstly, the interactions between connective tissue and the laser-irradiated-platinum-metallised silicone rubber are assessed both with in vitro and in vivo methods. The cytocompatibility and biocompatibility of silicone is not altered by the platinum deposition process, suggesting that this new biomaterial can be used to manufacture cuff electrodes that can safely be implanted for chronic studies. The mechanical biocompatibility of spiral cuff nerve electrodes is then investigated by morphological, immunohistochemical and western-blots analyses. The peri-operative, acute and chronic events that are related to the implantation are studied. The results show that the commonly described fibrotic reaction surrounding the implant is preceded by an important early epineurial inflammation. Additionally, cytokines involved in this tissue reaction are identified and include the pro-inflammatory cytokine TNF-alpha and pro-fibrotic cytokine TGF-beta1. In continuation of the biocompatibility testing, cytokine neutralisation through monoclonal antibodies is proposed as a way to control some of the cuff electrode-induced tissue modifications. Immunohistochemistry and morphometry are used to demonstrate the feasibility of such a control. Results show that a single systemic injection of TNF-alpha neutralising antibodies is sufficient to reduce the early inflammatory reaction occurring in the epineurial compartment but not the subsequent fibrosis. The success of an implanted neuroprosthesis is fully dependant upon the interaction between the electrode and the surrounding tissue. This study suggests that, when trying to improve the design of an electrode, one should also consider the modulation of the tissue reaction as a convenient way to enhance the implanted electrode's long-term performance. / L'enregistrement et la stimulation chroniques de nerfs peuvent être réalisés au moyen d'électrodes neurales à manchon, aussi bien chez l'animal que chez l'homme. Ces électrodes extra-neurales ont été utilisées non seulement dans le cadre de recherches fondamentales mais aussi à des fins de réhabilitation au sein d'un dispositif neuro-prosthétique. Elles ont ainsi contribué à notre connaissance du système nerveux et ont parfois permis une restauration sensorielle et motrice partielle. Les performances des électrodes existantes demeurent cependant limitées et leur design doit être amélioré. Les principales faiblesses de ces électrodes à manchon sont leur sélectivité, insuffisante, et les modifications morphologiques qu'elles induisent au sein des tissus implantés. La sélectivité des électrodes dépend principalement du nombre de contacts que limite un procédé de fabrication manuel. Les modifications morphologiques sont, quant à elles, déterminées par les interactions entre les tissus et l'électrode. Une nouvelle électrode neurale, dite à manchon spiral, est proposée qui devrait accroître la sélectivité et réduire la réaction tissulaire. La fabrication de cette nouvelle électrode, basée sur la technologie de déposition photolithographique de métaux, devrait permettre d'augmenter le nombre de contacts. De plus, en raison de son aptitude à s'adapter au diamètre du nerf, cette électrode devrait potentiellement limiter la réaction tissulaire induite par l'implant. Le but de ce travail est d'étudier les interactions entre l'électrode et les tissus implantés afin de mieux caractériser la réaction tissulaire et, ultérieurement, la contrôler. Dans un premier temps, les interactions entre les tissus conjonctifs et le silicone après son irradiation au laser et sa métallisation sont testées au moyen de méthodes in vitro et in vivo. La cyto-compatibilité et la biocompatibilité du silicone ne sont pas altérées pas le procédé de dépôt du platine. Ceci suggère que ce nouveau biomatériau convient à la manufacture d'électrodes à manchon qui pourront être implantées chroniquement de façon sûre. Dans un second temps, la biocompatibilité mécanique des électrodes à manchon spiral est examinée au moyen d'analyses morphologiques, immunohistochimiques et de western-blots. Les événements péri-opératoires, aigus et chroniques liés à l'implantation sont étudiés. Les résultats montrent qu'une importante réaction inflammatoire précoce précède la réaction fibrotique autour de l'électrode, classiquement décrite après une implantation. De plus, une partie des cytokines impliquée dans la réaction tissulaire est identifiée: la cytokine pro-inflammatoire TNF-alpha et la cytokine pro-fibrotique TGF-beta1. Dans la continuité des études de biocompatibilité, la neutralisation de cytokine au moyen d'anticorps monoclonaux est proposé comme moyen de contrôle de modifications tissulaires induite par l'électrode à manchon. L'immunohistochimie et la morphométrie sont utilisées pour démontrer la possibilité d'un tel contrôle. Le résultats montrent qu'une seule injection systémique d'anticorps anti-TNF-alpha est suffisante pour réduire la réaction inflammatoire précoce dans le compartiment épineurial mais pas la fibrose subséquente. Le succès d'une neuroprothèse implantable dépend entièrement des interactions entre l'électrode et les tissus environnants. Cette étude suggère que, lors des tentatives d'amélioration du design des électrodes, la modulation de la réaction tissulaire devrait être considérée comme un moyen aisé d'augmenter les performances à long terme des électrodes implantées.

Thesis (M.S.)- -University of Puerto Rico, Mayagüez Campus, 2005. / Tables. Printout. Includes bibliographical references (leave 72)

The concept of sickness behavior offers a framework to view both the neurovegetative and psychological symptoms that accompany illness as a common entity that results from increased inflammatory activation. Despite the prevalence of sickness behavior in medical populations, to our knowledge this study provides the first attempt to develop a standardized measure to assess sickness behavior using standard self-report questionnaires commonly used with cancer patients. The set of items included in the measure match theoretical conceptualizations of sickness behavior and target symptoms that comprise anhedonia, depressed mood, cognitive dysfunction, social disinterest, fatigue, low libido, poor appetite, somnolence, sensitivity to pain, and malaise. The measure showed high internal consistency, adequate test-retest reliability, and good convergent validity with both psychological and biological correlates. A confirmatory factor analysis also determined that a two-factor, rather than a single-factor measurement model, encompassing a physical and a psychological sickness symptom dimension, accounted for sickness behavior. Future psychometric work is still needed to further validate this new practical assessment tool. Descriptive analyses revealed relatively low levels of sickness behavior symptoms in the sample as a whole with both physical and psychological sickness behavior symptoms exhibiting a significant linear decrease over time. As expected, both physical and psychological sickness behavior symptoms showed associations with two pro-inflammatory cytokine markers, IL6 and TNF-alpha and a neuroendocrine marker, cortisol. Longitudinal associations suggest that higher levels of the pro-inflammatory cytokine TNF-alpha may impact the progressive decline of physical sickness symptoms over time with symptoms taking longer to disappear. Because cortisol was associated with more rather than less physical sickness symptoms, results raise the question of whether the anti-inflammatory neuroendocrine activity may be dysregulated in breast cancer survivors. The mechanistic basis for these associations requires further examination. In this study it was also evaluated whether a cognitive behavioral stress management intervention and relaxation training intervention could reduce sickness symptoms over time. Breast cancer survivors were assessed at baseline and then randomly assigned to a 10-week cognitive behavioral stress management intervention (N = 70) or a 1-day control condition (N = 55). Psychosocial measures, urine, and blood were obtained from participants at 3 months, 6 months, and 12 months post-intervention to assess relevant behavioral, endocrine and immune variables. Relative to the control group, the experimental group showed marginally more prevalence of physical sickness behavior symptoms in the short term (post-intervention, 3-months; p = .08) and a steadier decline of symptoms in the long-term (15-month follow-up period). The adaptive nature of sickness behavior as a motivational strategy that helps restore homeostatic balance in the long run may be one possible interpretation of these results. Whether these intervention effects on sickness behavior were mediated by changes in pro-inflammatory cytokines or cortisol was examined but not supported by these data and needs to be further examined in future studies.

Thesis (M.S.)--University of Delaware, 2006. / Principal faculty advisor: Mary C. Farach-Carson, Dept. of Biological Sciences. Includes bibliographical references.

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.