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1
Kleinschmidt, Martin. "Design modularer Immunotoxine unter Verwendung polyionischer Fusionspeptide." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=973422343.
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Heisler, Iring. "Bedeutung spaltbarer Peptidlinker für die Funktion rekombinanter Saporin-EGF-Immunotoxine." [S.l.] : [s.n.], 2003. http://www.diss.fu-berlin.de/2003/210/index.html.
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Posch, Maximilian. "Neue Ansätze zur zielgerichteten Behandlung solider Tumoren." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2002. http://dx.doi.org/10.18452/14828.
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Eingeschränkte Apoptose trägt zur Tumorentstehung und zur Entwicklung von Chemoresistenz bei, da die Apoptose normalerweise Zellen mit genetischen Schäden oder malignem Potential eliminiert. Dieser Prozess, der bereits für viele unterschiedlichen Tumorzellen nachgewiesen wurde, limitiert häufig die Behandelbarkeit maligner Erkrankungen und ist somit ein grosses Problem in der heutigen Krebsbehandlung. Es existieren unterschiedliche Ansätze die Auslöseschwelle für die Apoptose zu vermindern, um so Chemotherapie-resistente Tumorzellen zu eliminieren. Im ersten Teil dieser Arbeit wurde das anti-tumorale Potential des bispezifischen 4625 Antisense-Oligonukleotid in Kombination mit chemotherapeutischen Wirkstoffen in vitro und in vivo untersucht. Der zweite Teil beschreibt die Ergebnisse mit dem rekombinanten Ep-CAM spezifischen scFv Immunotoxin 4D5MOC-B-ETA in vitro und im Modell der Nacktmaus. Bcl-2 und Bcl-xL sind Inhibitoren der Apoptose, die von vielen malignen Tumorzellen überexprimiert werden. Das Herunterregulieren von Bcl-2 oder Bcl-xL erniedrigt die apoptotische Auslöseschwelle und Tumorzellen sterben durch programmierten Zelltod. Das 4625 Antisense Oligonukleotid richtet sich gegen eine Region hoher Homologie in der bcl-2/bcl-xL mRNA und hemmt simultan die Expression von Bcl-2 und Bcl-xL. Die durch das bispezifische 4625 Antisense gehemmte Expression von Bcl-2 und Bcl-xL in Tumorzellen unterschiedlicher Histologie zeigen die Ergebnisse der Immuno-Blots. Weiterhin führt 4625 zur dosisabhängigen Wachstumshemmung von Krebszellen bei Konzentrationen von 75-600 nM im MTT Assay. Für die Kombinationsbehandlung wurden Paclitaxel und 5-FU jeweils als Standardtherapie zur Behandlung von Brust- und kolorektalem Karzinom gewählt. Die ip. Applikation von 20mg/kg KG 4625 mit oder ohne Paclitaxel/5-FU führte zu einem verlangsamten Wachstum humaner Tumor Xenotransplantaten in Nacktmäusen, im Vergleich mit denen die mit dem Kontrolloligonukleotid 4626 mit oder ohne Chemotherapie behandelt wurden. Bcl-2 und Bcl-xL spielen unterschiedliche Rollen in der Tumorentwicklung und sind häufig heterogen in soliden Tumorgeweben exprimiert. Diese Daten zeigen, daß die moderne Antisense Technologie eine wirksame Methode zur Herunterregulierung zweier Hauptinhibitoren der Apoptose mit einem einzigen Oligonukleotid darstellt, wovon möglicherweise mehr Patienten mit malignen Erkrankungen in Zukunft profitieren könnten. Die Expression bestimmter Zelloberflächenmoleküle ist ein häufiger Prozess in vielen soliden Tumoren, was sie für eine zielgerichtete Antikörpertherapie angreifbar macht. Das epitheliale Glykoprotein-2 (Ep-CAM) wird reichlich von epithelialen Tumoren und Tumorzellinien exprimiert. Die antineoplastische Aktivität des Ep-CAM spezifischen 4D5MOC-B-ETA Immunotoxin wird im zweiten Teil dieser Arbeit beschrieben. In vitro hemmt 4D5MOC-B-ETA spezifisch die Proteinsynthese in Ep-CAM positiven Krebszellen unterschiedlichen histologischen Ursprungs ermittelt durch [H3]leucin Aufnahme und reduzierte die Überlebensrate dieser Zellen in Konzentrationen von 0.01 bis 1 pM. Ep-CAM negative Zellen wurden als negative Kontrolle genutzt und blieben durch das Immunotoxin in Konzentration bis zu 10.000 pM unversehrt, was dessen hochgradige Ep-CAM Spezifität beweist. Die tägliche Applikation von 0.01 mg 4D5MOC-B-ETA im Nacktmausmodell führte zu einem Schrumpfen der Tumor Xenotransplantate während der Behandlungszeit. Diese hohe Wirksamkeit des scFv Immunotoxin bedarf weiterer Beachtung in der zukünftigen Krebstherapie.Impaired apoptosis contributes to cancer development and resistance towards chemotherapy, since apoptosis normally eliminates cells with damaged DNA or increased malignant potential. The increased resistance towards cell death often limits therapeutic options in the clinic and is one major problemin current tumor therapy. Different approaches, which have been described so far intend to lower the apoptotic threshold in order to eliminate chemoresistant cancer cells. In the first part of this thesis the anti-tumor potential of the bispecific 4625 oligonucleotide was investigated in combination with chemotherapeutic drugs in vitro and in vivo. The second part describes the anti tumor activity of the recombinant Ep-CAM specific scFv immunotoxin 4D5MOC-B-ETA in vitro and in nude mice. Bcl-2 and Bcl-xL are inhibitors of apoptosis frequently overexpressed in malignant tumor cells. Downregulation of either Bcl-2 or Bcl-xL lowers the apoptotic threshold and tumor cells undergo apoptosis. The 4625 antisense oligonucleotide targets a region of high homology shared by the bcl-2/bcl-xL mRNAs and simultaneously downregulates Bcl-2 and Bcl-xL. The 4625 bispecific Antisense Oligonucleotide downregulates Bcl-2 and Bcl-xL expression in cancer cell lines of diverse histological origins assessed by immuno blotting. It further leads to proliferation inhibition of cancer cells at concentrations ranging from 75-600 nM in MTT assay in a dose-dependent manner. For combination experiments Paclitaxel and 5-FU were chosen as standard therapy for the treatment of breast and colorectal cancer, respectively. The ip. application of 20 mg/kg 4625 with or without Paclitaxel/5-FU led to a growth inhibition of established human carcinomas xenografts in nude mice, relative to those treated with the 4626 control oligonucleotide with or without chemotherapy. Bcl-2 and Bcl-xL play nonredundant roles in tumor growth and are often heterogeneously expressed in solid tumor tissues. This data suggests that state-of-the-art antisense technology offers a potent approach to inhibit the expression of the two major anti-apoptotic proteins Bcl-2 and Bcl-xL with one single oligonucleotide, which could make additional patients benefit from a treatment with this antisense compound. Expression of certain cell surface antigens is a common process in many solid tumors making them suitable for targeted antibody therapy. The epithelial glycoprotein-2 (Ep-CAM) is abundantly expressed on carcinomas and cancer cell lines. The anti tumor activity of the Ep-CAM specific 4D5MOC-B-ETA immunotoxin is described in the second part. In vitro 4D5MOC-B-ETA specifically inhibited protein synthesis in Ep-CAM positive cancer cells of diverse histological origin assessed by [H3]leucin incorporation and reduced cell viability with IC50 ranging from 0.01 to 1 pM. Ep-CAM negative cells were taken as control and were not harmed by the immunotoxin at concentrations up to 10.000 pM, which proves the 4D5MOC-B-ETA Ep-CAM specific potential. In athymic mice, the systemic application of 4D5MOC-B-ETA at a dose of 0.01 mg per day resulted in the regression of established tumor xenografts during the time of treatment. This highly potent anti-tumor activity of a recombinant scFv immunotxin deserves further attention for use in cancer therapy.
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Jaffrézou, Jean-Pierre. "Reversion de la resistance pleiotropique et activation des immunotoxines : participation du metabolisme sphingolipidique." Toulouse 3, 1991. http://www.theses.fr/1991TOU30115.
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L'existence de molecules susceptibles a la fois de reverser in vitro la resistance mdr et d'activer les immunotoxines souleve un double interet d'un point de vue a la fois mecanistique et pharmacologique. Ceci suggere donc que ces agents interviennent au niveau du transport et/ou de la degradation intracellulaire. Il est en effet possible que les perturbations du metabolisme lipidiques induite par ces agents, et plus specifiquement celle de la sphingomyeline, sont a l'origine de leur activite
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The, Dean Timothy Neal. "Immunotoxic effects of aldicarb /." This resource online, 1990. http://scholar.lib.vt.edu/theses/available/etd-03142009-040641/.
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Keller, Jutta. "Entwicklung molekularer Adapter zur Optimierung von Immunotoxinen." [S.l.] : [s.n.], 2002. http://www.diss.fu-berlin.de/2002/243/index.html.
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Casellas, Pierre. "Immunotoxines molécules informatiques programmées à vocation cytotoxique /." Grenoble 2 : ANRT, 1987. http://catalogue.bnf.fr/ark:/12148/cb37603672m.
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Dean, Timothy Neal. "The immunotoxic effects of aldicarb." Thesis, Virginia Tech, 1990. http://hdl.handle.net/10919/41612.
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Rostaing-Capaillon, Odile. "Optimisation de l'efficacité antitumorale des immunotoxines "in vivo"." Montpellier 2, 1990. http://www.theses.fr/1990MON20188.
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L'utilisation des immunotoxines in vivo rencontre de nombreuses difficultes dont les principales sont une faible localisation tumorale apres injection intraveineuses et une activite cytotoxique insuffisante. L'amelioration de la capacite de ciblage des immunotoxines a chaine a de ricine eeeeea ete realisee grace a l'utilisation de fragments d'anticorps f(ab)2 et fab qui reduisent la taillee de l'immunotoxine et facilitent son extravasation et grace a la deglycosylation de la chaine a qui ralentit considerablement la clairance plasmatique de l'immunotoxine. Toutefois, seule l'injection intratumorale permet d'obtenir une saturation des antigenes cibles. Des facteurs specifique et non-specifique sont responsables de l'inactivation du site de fixation de l'anticorps, ce qui limite la capacite de ciblage de l'immunotoxine circulante mais l'activite cytotoxique des immunotoxines associees aux cellules tumorales est preservee. L'efficacite cytotoxique des immunotoxines in vivo est liee au nombre de molecules fixees par cellule. Cependant, meme apres saturation des antigenes cibles, l'effet antitumoral reste limite. L'injection intratumorale du conjugue albumine-monensine permet alors d'eradiquer une large masse tumorale constituee d'au moins huit cent millions de cellules par souris, meme si la localisation tumorale de l'immunotoxine est reduite
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Rust, Aleksander. "Novel payloads for immunotoxin-based treatment of neuroblastoma." Thesis, University of Sheffield, 2016. http://etheses.whiterose.ac.uk/16990/.
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Neuroblastoma is the most common form of extracranial solid tumour in childhood and the second biggest cause of cancer-related deaths in infants. Despite intensive, multi-modal treatment of advanced stage disease, prognosis is poor and relapse is common. This means that alternative forms of treatment are urgently needed. Targeted toxins are cytotoxic enzymes fused to a targeting ligand or antibody that bind to a receptor or antigen highly expressed on the cancer cell surface. Upon binding, the toxin is internalised and its cytotoxic activity leads to cell death. All currently used toxins function via the inhibition of protein synthesis, making them highly potent in both healthy and transformed cells. Low-level expression of target receptor, or non-specific uptake into healthy cells has caused dose-limiting side effects in all targeted toxins tested to date which has severely restricted their use in cancer treatment. In this thesis, novel protein delivery techniques were used to investigate the use of two enzymes, Burkholderia lethal factor 1 (BLF1) and botulinum neurotoxin type C (BoNT/C) protease, as possible alternative payloads for targeted toxin therapy in the treatment of neuroblastoma. BLF1 inhibits translation initiation by inactivation of eIF4A, and BoNT/C protease disrupts important membrane recycling events by cleavage of SNARE proteins. Both of these cytotoxic mechanisms show a degree of selectivity towards neuroblastoma cells. Future targeted toxins based on these enzymes may therefore have higher specificity towards neuroblastoma cells than conventional enzymes, leading to an increased therapeutic window and decreased side effects.
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Cook, Jonathan Paul. "An investigation of cleavable linkers in ricin A chain-interleukin 2 fusion proteins." Thesis, University of Warwick, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282457.
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Alderton, Wendy Karen. "Studies on the interaction of triazine dyes with ricin A." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282001.
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Saujet, Laure. "Etude du réseau de régulation de la sporulation chez Clostridium difficile." Paris 7, 2013. http://www.theses.fr/2013PA077269.
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Clostridium difficile est un bacille à Gram positif anaérobie strict et sporulé, responsable de diarrhées post-antibiotiques. Peu de données existent sur les processus cellulaires induits à rentrée en phase stationnaire de manière concomitante à la synthèse des toxines et sur les réseaux de régulation contrôlant la phase stationnaire et la sporulation. Nous avons construit un mutant sigH afin de déterminer le rôle de SigH, qui est un facteur sigma alternatif permettant l'expression de gènes de phase de transition et de l'initiation de la sporulation chez B. Subtilis. Nous avons comparé les profils d'expression de la souche 630Aerm et du mutant sigH en début de phase stationnaire. Chez C. Difficile, SigH régule l'expression de nombreux gènes impliqués dans la motilité, la sporulation, la division cellulaire, la virulence et le métabolisme. Enfin, l'expression des gènes de toxines est régulée négativement par SigH. Nous nous sommes ensuite intéressés à la cascade de régulation de la sporulation chez C. Difficile, qui implique 4 facteurs sigma chez B. Subtilis : SigF, SigE, SigG et SigK. Nous avons comparé les profils d'expression ; des mutants sigF, sigE, sigG et sigK et de la souche 630Aerm. Nous avons ainsi défini les régulons de chacun de ces facteurs sigma et montré que chez C. Difficile, le régulon SigE n'est pas sous la dépendance stricte de SigF et que SigG n'est pas nécessaire à l'activité de SigK. Nous avons aussi analysé le réseau de régulation dans chaque compartimeht de la spore et étudié le rôle des régulateurs SpoIIID et SpoVT. Ce travail a mis en évidence une communication moins stricte entre les deux compartiments de la spore que chez B. SubtilisClostridium difficile is a Gram-positive anaerobic spore-forming bacteria which is responsible for post-antibiotic diarrhea. Few data exist on cellular processes induced at the onset of stationary phase concomitantly with the synthesis of toxins and regulatory networks controlling stationary phase and sporulation. We constructed a sigH mutant to determine the role of SigH, which is an alternative sigma factor involved in the transcription of phase transition and initiation of sporulation genes in B. Subtilis. We compared the expression profiles of 630Aerm strain and the sigH mutant after 10 h of growth. In C. Difficile, SigH regulates the expression of many genes involved in motility, sporulation, cell division, virulence and metabolism. Finally, the expression of toxin genes is negatively regulated by SigH. We then studied the regulatory cascade of sporulation in C. Difficile, involving four sigma factors in B. Subtilis: SigF, SigE, SigG and SigK. We compared the expression profiles of the sigF, sigE, sigG and sigK mutants and the 6300erm strain. We defined the regulons of these sigma factors and showed that in C. Difficile, the SigE regulon is not under the strict dependence of SigF and SigG is not necessary for the SigK activity. We also analyzed the regulatory network in each compartment of the spore and studied the rote of SpoIIID and SpoVT regulators. This work showed a less strict communication between the two compartments of the spore in C. Difficile compared to B. Subtilis
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Badesha, Jasvant Singh. "Potential immunotoxic hazards in the environment." Thesis, University of Bristol, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336892.
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Majed, shaymaa. "Developing BLF1 as a novel immunotoxin for cancer treatment." Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/18938/.
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One approach to enhancing the natural properties of antibodies is by conjugating them to toxins, especially where tumours have developed resistance to previous therapeutic regimes. Despite considerable research on immunotoxins, to date only diphtheria toxin has been approved for clinical use. One problem is that even with antibody targeting, there is a risk of damage to normal cells through inappropriate uptake of toxins. A novel small toxin, Burkholderia Lethal Factor 1 or BLF1, which we recently identified, is selective for rapidly dividing cells and is usually only active if it is deliberately introduced into the cytoplasm. These features give BLF1 significant advantages over previous toxins that have been investigated. BLF1 acts specifically to inhibit the initiation of translation mediated by intiation factor eIF4A. Rapidly dividing cells such as cancer cells are particularly dependent on eIF4A mediated translation. In this study, we further investigated the activity of BLF1 across different cellular models and the role of macropinocytosis in uptake of BLF1 by some cell types that are directly sensitive to the toxin. We demonstrated that high rates of macropinocytosis correlated strongly with direct sensitivity to BLF1 and that BLF1 is primarily active against rapidly dividing cells, consistent with the known role of elF4A. We also developed model systems for assessing the potential of BLF1 for development as an immunotoxin using antibodies directed against the tetraspanin proteins CD9 and CD63. CD63 in particular was selected as a model antigen because it is rapidly internalised on antibody binding, which is an important feature of immunotoxins. These non-covalently linked BLF1 immunoconjugates were useful for assessing antigen targeting and internalisation; however, it was not really possible to demonstrate significant specific effects on cell growth. This may have been due to inefficient uptake of the toxin, problems associated with intracellular trafficking (e.g. poor endosomal escape) or instability of the conjugates. This thesis also describes the successful production of chemically cross-linked BLF1/anti-CD63 and BLF1/anti-CD9 immunotoxins (IMT) that demonstrated targeting and significant effects on the growth of human cancer cell lines. Further investigations revealed that targeted BLF1 IMT could be co-administered with saponin, which may work synergistically to enhance their potency as a combinatorial therapy. Determination of intracellular trafficking of BLF1 IMT suggests that different internalization routing may be involved in the uptake of IMT for a specific cell type or targeting antigen.
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Malan, Cheryl. "The efficiency of drinking water treatment plants in removing immunotoxins." Thesis, University of the Western Cape, 2010. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_5762_1308732795.
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The aim of this study was to evaluate the effectiveness of water treatment processes of two drinking water plants to remove immunotoxins and steroid hormones. Raw and treated drinking water was screened for effects on inflammatory activity using the biomarker IL-6, humoral immunity using the biomarker IL-10 and cell mediated immunity using the biomarker IFN-&gamma
. In vitro human whole blood culture assays were used in order to elucidate potential immunotoxicity.
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Ravel, Sophie. "Mécanisme d'action des immunotoxines : étude de l'intériorisation et du transport intracellulaire." Montpellier 2, 1990. http://www.theses.fr/1990MON20186.
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Les immunotoxines a chaine a de ricine allient une haute specificite de reconnaissance a une puissante toxicite. Neanmoins, ces molecules ont une efficacite inferieure a ce qui est necessaire pour une therapeutique du cancer. En vue d'ameliorer cette efficacite, nous avons examine le mecanisme d'action de ces conjuges. L'entree de l'immunotoxine, indispensable a l'activite cytotoxique, ne semble pas constituer l'etape limitante dans le processus d'intoxication des cellules leucemiques. Apres interiorisation, la majeure partie des molecules d'immunotoxine reste intacte, sans rupture du pont disulfure reliant la chaine a a l'anticorps. Une etude de fractionnement cellulaire a montre que le conjugue n'atteint pas les lysosomes mais se localise plutot dans un compartiment endosomo-golgi a partir duquel la chaine a pourrait etre transferee aux ribosomes. Le chlorure d'ammonium et la monensine qui ameliorent considerablement l'efficacite du conjugue, n'accelerent pas sa cinetique d'interiorisation et ne modifient pas sa degradation, ni sa localisation intracellulaire. Ceci suggere que l'etape limitante se situe tardivement dans le transport du conjugue, probablement au niveau du passage de la chaine a au cytosol. Nous avons constate que l'internalisation et le transport intracellulaire de l'immunotoxine sont gouvernes par l'anticorps porteur et que l'interiorisation de l'anticorps anti-t65 dans les lymphocytes t du sang peripherique est un processus rapide et conduit a une degradation massive dont les monocytes sont en grande partie responsables
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Costa, Leonor Coutinho. "Mechanisms of immunotoxic effects of nanomaterial in fish." Master's thesis, Universidade de Aveiro, 2013. http://hdl.handle.net/10773/12616.
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Mestrado em Química - Química Analítica e QualidadeInformation and knowledge related to nanotechnology raise new challenges to the scientific community mainly in terms of human health risks and environmental implications associated to nanomaterials. In this perspective, the contamination of aquatic environments cannot be overlooked since it is an ultimate repository of the contaminants where this emerging appears as part of a cocktail of different classes of contaminants. Thus, the major task of this work was to connect gaps in current knowledge with a comprehensive sequence of biological responses toward environmentally relevant concentrations of engineered nanomaterials (IONM - silica coated iron oxide nanomaterial functionalized with dithiocarbamate group) and their interaction with other conventional anthropogenic contaminant (Hg - mercury), outlining the interaction with the innate immune system of fish. The research was divided into following steps: i) phagocytes macrophages were isolated from peritoneum (P-phagocytes), gill (G-phagocytes), head kidney (HK-phagocytes) and spleen (S-phagocytes) of European eel Anguilla anguilla L. in order to evaluate whether, and how can IONM and its co-exposure to Hg modulate phagocytes status and function; ii) determine the changes in phagocytes activation and their association to peroxidative damage (OBA - oxidative burst activity; LPO - lipid peroxidation); iii) to assess the impact of IONM on phagocytes enzymatic (CAT - catalase; GPX - glutathione peroxidase; GR - glutathione reductase; and GST - glutathione S-transferase) and non-enzymatic (NP-SH - non-protein thiols; and TGSH - total glutathione) antioxidants protection overtime. It was hypothesized that IONM can cause measurable changes in fish immune response and oxidative stress modulation. A period of exposure-dependency was exhibited by IONM alone and IONM+Hg joint exposures accrued impacts on A. anguilla phagocytes. IONM exposure alone lead to an acute response in terms of viability increase in P-phagocytes and modulated phagocytic activity in P-, and S-.phagocytes during 2 hours of exposure; whereas, IONM lead to a chronic immunotoxicity during 72 hours exposure only in S-phagocytes. However, IONM+Hg exposure lead to both acute and chronic response in terms of modulated phagocytic activity with no change in viability in P-, HK- and S-phagocytes only. Increase in the period of exposure to Hg disrupted phagocytic activity of P-, HK- and S-phagocytes, an increase in P- and decrease in HK- and S- phagocytes was perceptible at late hours of exposure. The occurrence of synergism between IONM and Hg was evidenced at 72 hours by significantly increasing trends of phagocytosis increase. A differential extent of OBA and LPO induction at the end of different period of exposure to IONM, Hg or IONM+Hg was also perceptible. The OBA induction and its concomitant association to LPO induction were observed only in gill after exposure to Hg (8 and 48 hours) and IONM+Hg (8 hours). At late hours of exposure, an induction was observed in G- phagocytes (OBA) after exposure to IONM+Hg suggesting that the concomitant exposure was unable to mitigate the Hg-accrued negative impacts. A. anguilla also displayed that the damage was accompanied with a differential modulation of enzymatic and non-enzymatic antioxidants in P, G-, HK- and S-phagocytes. Under IONM alone exposure, no LPO induction along the time was observed probably due to efficient induction of, GR and GST providing a better protection to IONM exposed phagocytes. However, antioxidants protection responses displayed hours of exposure dependency in G- and S-phagocytes where, an insufficiency of elevated CAT, GPX, GST, NP-SH and TGSH was clearly depicted for the maintenance of pro- and antioxidant balance optimum for scavenging ROS and protecting membrane lipids against IONM impact. As increased LPO was observed under IONM alone exposure condition, the joint action of IONM+Hg led to elevated damages to membrane-lipids at 4 and 8 hours (G-phagocytes), 2 hours (HK-phagocytes) and 24 hours (S-phagocytes) of exposure. These responses together, point towards the antioxidants defense failure for the protection of membrane lipids during those periods of exposure to IONM+Hg. However, it is important to underline here that during the late hours of exposure (72 hours), the results imply the positive effect of the concomitant exposure (IONM+Hg) which significantly mitigated the said negative impacts of Hg. Overall, the observations of this study open up new insight into the areas of evaluation of immune defense mechanisms in fish exposed to IONM and recommend that the interactions between IONM and other conventional anthropogenic contaminants should be considered while interpreting the fish immunotoxicity responses to IONM exposure in a multi-pollution state.
Informações e conhecimentos relacionados com a nanotecnologia colocam novos desafios à comunidade científica, principalmente em termos de riscos para a saúde humana e alterações ambientais. A contaminação dos ambientes aquáticos não pode ser ignorada, uma vez que é um repositório final dos contaminantes onde estes aparecem como parte de um conjunto complexo de diferentes tipos. O objetivo principal deste trabalho foi relacionar lacunas no conhecimento atual com uma sequência de respostas biológicas, para concentrações ambientalmente relevantes de nanomateriais (ONM - nanomateriais de óxidos de ferro revestidos com sílica e funcionalizados com grupos de ditiocarbamato) e avaliar a sua interação com outros contaminantes antropogénicos, nomeadamente mercúrio (Hg), na interação com o sistema imunitário de peixes. A investigação desenvolvida foi dividida nos seguintes passos: i) os macrófagos fagocitados foram isolados da cavidade peritoneal (P-fagócitos), das guelras (G-fagócitos), da “cabeça do rim” (HK-fagócitos) e do baço (S-fagócitos) da enguia europeia Anguilla anguilla L., a fim de avaliar como podem os ONM e a sua co-exposição com o mercúrio modular o estado das fagocitoses e a sua função; ii) avaliar as alterações na ativação das fagocitoses e a sua associação ao dano peroxidativo (OBA – atividade respiratória oxidativa; LPO - peroxidação lipídica); III) avaliar o impacto das ONMs ao longo do tempo nos antioxidantes, nomeadamente fagocioses enzimáticas (CAT - catalase; GPX - glutationa peroxidase; GR - glutationa redutase; e GST - Glutationa S-transferase) e não enzimáticas (NP-SH- proteína não-tiol; e TGSH - glutationa total). É apresentada a hipótese de que as ONMs podem causar mudanças na resposta imunológica de peixe e modular o stress oxidativo. Uma dependência do período de exposição foi observada para as ONMs isoladas e também uma sucessão de impactos sobre as fagocitoses da Anguilla Anguilla. A exposição isolada às ONMs parece poder induzir uma resposta aguda em termos de aumento de viabilidade em P-fagócitos e uma atividade fagocítica modulada em P e S-fagócitos após 2 horas de exposição; as ONMs podem induzir imunotoxicidade crónica durante uma exposição de 72 horas, apenas em S-fagócitos. A coexposição a ONM+Hg induziu uma resposta aguda e crónica em termos de atividade fagocítica modulada, com nenhuma mudança na viabilidade em P, HK e S-fagócitos. O aumento do período de exposição a Hg interrompeu a atividade fagocítica de P-, HK - e S-fagócitos. Porém, um aumento de P - e diminuição de HK - e S-fagócitos foi percetível nas 72 horas. A ocorrência de sinergismo entre as ONMs e o Hg foi evidenciado às 72 horas pela tendência do aumento significativo das fagocitoses. Diferença nas induções de OBA e LPO para diferentes períodos de exposição, às ONMs, Hg e ONMs+Hg foi também percetível. Uma indução de OBA paralela à resposta do LPO foi observada unicamente nas guelras por exposição ao Hg (8 e 48 horas) e ONMs+Hg (8 horas). Para períodos mais longos de exposição, foi observada uma indução nas G-fagócitos (OBA) depois da exposição a ONMs+Hg, sugerindo que a contaminação ONMs+Hg é capaz de mitigar os impactos negativos do Hg-acumulado ao longo do tempo. A. Anguilla evidenciou danos ao nível da modulação diferencial de antioxidantes enzimáticos e não enzimáticos em P, G, HK e S-fagócitos. Sob exposição simples às ONMs, não foi observada nenhuma indução do LPO ao longo do tempo, talvez devido à indução eficiente de GR e GST, proporcionando uma melhor proteção para os fagócitos expostos às ONMs. No entanto, as respostas de proteção dos antioxidantes exibiram dependência das horas de exposição em G - e S-fagócitos onde uma insuficiência elevada em CAT, GPX, GST, NP-SH e TGSH foi claramente observada para a manutenção do equilíbrio antioxidante e eliminação de ROS, protegendo os lipídios da membrana contra o impacto das ONMs. A ação conjunta das ONM+Hg conduziu a elevados danos nos lipídios da membrana às 4 e 8 horas (G-fagócitos), 2 horas (HK-fagócitos) e 24 horas (SP-fagócitos) de exposição. Estas respostas conjuntas, apontam para o fracasso da defesa dos antioxidantes na proteção dos lipídios da membrana durante os períodos de exposição com ONM+Hg. De salientar que para exposições de 72 horas, os resultados evidenciam efeitos positivos da exposição concomitante a ONM+Hg o que atenuou impactos negativos do Hg. As observações deste estudo dão novas ideias sobre a avaliação dos mecanismos de defesa imunotoxicológica em peixes expostos a ONMs e indicam que as interações entre ONMs e outros contaminantes antropogénicos devem ser consideradas na interpretação das respostas imunotóxicas de peixe expostos às ONMs em situações contaminação múltipla.
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Smith, Karen Lesley. "Immunotoxic biomarkers of anthropogenic impact in marine invertebrates." Thesis, University of Plymouth, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394702.
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Many chemicals enter the marine environment as a result of human activities where they are available to exert a range of effects upon biota. Research has previously focused on the effects of chemicals upon various biological functions of biota in situ. However the impact of chemicals with immunotoxic functions has received little attention. The current research focused on the immunotoxicity of environmental pollutants on marine invertebrates, primarily Mytilus edulis. The aim of the research was to determine to what extent immune function altered in M edulis following exposure to environmental contaminants and how these alterations could be measured and incorporated into environmental monitoring programmes. Exposure of M edulis to the immunotoxicants copper and tributyltin in the laboratory indicated that biochemical measures of immune function were too sensitive for experimental manipulations to be used as biomarkers of pollution-induced stress. However, cellular analysis of immune function, as measured by an adapted immunotoxicity assay in combination with a measure of cell viability, was responsive to pollution-induced stress in a concentration-dependant manner. Cellular immune activity appeared to be regulated by the cytokine IL-1 and involved the release of lytic factors from haemocyte populations. Field evaluation of the immunotoxicity assay in New Bedford Harbour, USA, indicated that environmental contaminants within the estuary had an immuntoxic effect upon in situ mussel populations. The measure of immunotoxicity in mussel populations in New Bedford Harbour was a more sensitive measure of environmental impact than routinely used biomarkers such as lysosomal neutral red, cardiac monitoring and condition index. The immunotoxicity assay is therefore proposed as a sensitive, low cost and reliable biomarker of effect in mussel populations both in the laboratory and the field.
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Mussai, Francis Jay. "Immunotherapy and immunomodulation for haematological malignancies." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:6120e659-0dab-4447-b4d6-75e235d3b2c8.
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HA22 is an immunotoxin composed of an anti-CD22 variable fragment linked to a 38 kDa truncated protein derived from Pseudomonas exotoxin A. The mechanisms of cytotoxicity and resistance of HA22 against Acute Lymphoblastic Leukaemia (ALL) and Burkitt’s lymphoma were studied. Using a bone marrow mesenchymal cell culture assay to support ALL cell viability, I? investigated the in vitro cytotoxicity of HA22 against ALL blasts from newly diagnosed and relapsed patients. There was interpatient variability in sensitivity to HA22. There was no significant difference in HA22 sensitivity between diagnosis and relapse samples but peripheral blood ALL blasts were more sensitive to HA22 than those from bone marrow. The mechanisms of resistance to HA22 were studied, using cell lines as a model. The number of CD22 sites/ cell and the rates of immunotoxin internalisation did not affect HA22 cytotoxicity. HA22 mutants with resistance to lysosomal degradation and enhanced targeting to the endoplasmic reticulum had improved cytotoxicity. The role of apoptosis pathways proteins in HA22-mediated cell death was studied. Their role is complex but raised levels of the anti-apoptotic pathway protein Bcl-2 were found in the most resistant NALM6 cell line. Penetration of HA22 into Burkitt’s lymphoma masses was studied using a flow cytometric based method. HA22 rapidly penetrated into the lymphoma masses, however a barrier to further uptake is present which could not be overcome by the addition of adriamycin or taxol in the murine xenograft model. The ability of Acute Myeloid Leukaemia (AML) blasts to create an immunosuppressive niche was investigated using a cell line model and primary patient samples. AML blasts suppress T cell proliferation through altered arginine metabolism, dependent on the enzymes arginase II and iNOS. Small molecule inhibitors to arginase and iNOS restored T cell proliferation in vitro. AML further enhances its immunosuppressive niche by transforming surrounding monocytes into an M2-immunosuppressive phenotype, in an arginase dependent manner. The immunomodulatory protein Serum Amyloid A (SAA) was secreted by AML blasts, and leads to AML chemotaxis, IL-1production, and release of S100A9 protein. Finally, invariant Natural Killer T cells (iNKT) were shown to be cytotoxic to some AML blasts, in the presence of Galactosylceramide, and thus able to restore T cell proliferation. The results provide a strong rationale for the clinical testing of these novel immunotherapeutic and immunomodulatory strategies in patients with haematological malignancies.
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Struhalla, Marc. "Veränderung der Substratspezifität von Ribonuclease T1 und Einsatz des Enzyms in Immunotoxinen." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968550835.
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Calvete, Joanne Amanda. "Pre-clinical studies with the novel colorectal cancer targeted immunotoxin, ICI D0490." Thesis, University of Newcastle Upon Tyne, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336268.
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Symeonides, Stefan Nicholas. "Investigation of Bacillus thuringiensis Cry δ-endotoxin fragments as potential immunotoxin components." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611144.
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Tranquet, Olivier. "Anticorps chimériques dirigés contre des séquences des domaines répétés des gliadines pour mimer la réactivité des IgE de patients allergiques au blé." Thesis, Nantes, 2020. http://www.theses.fr/2020NANT4070.
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Les symptômes des allergies IgE dépendantes résultent de l’activation des basophiles et de mastocytes. Cette activation est provoquée par l’agrégation à la surface de ces cellules d’anticorps de type IgE par les allergènes. Les allergènes impliqués dans les formes les plus sévères d’allergie au blé, l’anaphylaxie induite par l’effort et l’allergie au gluten désamidé, sont très particuliers dans la mesure où ils contiennent des épitopes identiques répétés plusieurs fois. Dans cette thèse, nous avons obtenu et caractérisé des IgE monoclonales chimériques souris/homme dirigées contre les domaines répétés des gliadines, allergènes impliqués dans ces phénotypes sévères d’allergie au blé. Grace à ces IgE chimériques monoclonales, nous avons exploré le rôle qu’avait ces répétitions sur le déclenchement des symptômes de l’allergie et leurs implications sur le répertoire IgE des patients. Ces IgE chimériques ont démontré leur capacité à mimer la réactivité des IgE des patients. Elles ont par ailleurs révélé que l’organisation spatiale très particulière des épitopes permet l’activation des basophiles avec des IgE d’une seule spécificité dans ces deux types d’allergies au blé. Il apparaît ainsi que le répertoire IgE des patients allergiques au blé peut être extrêmement restreint et tout de même provoquer des réactions sévèresThe symptoms of IgE-dependent allergies result from the activation of basophils and mast cells. This activation is induced by the aggregation by allergens of IgE-type antibodies on the surface of these cells. The allergens involved in the more severe forms of wheat allergy, exercise-induced anaphylaxis and allergy to deamidated gluten, are very special in that they contain identical epitopes repeated several times. In this thesis, we obtained and characterized chimeric mouse/human monoclonal IgE antibodies directed against the repeated domains of gliadins, allergens involved in these severe wheat allergy phenotypes. Using these chimeric monoclonal IgE, we explored the role of these repeats on the onset of allergy symptoms and their implications on the IgE repertoire of patients. These chimeric IgE antibodies have been shown to mimic the reactivity of patients' IgE. They also revealed that the very particular spatial organization of the epitopes allows activation of basophils with IgE of a single specificity in these two types of wheat allergies. It thus appears that the IgE repertoire of patients with wheat allergy can be extremely restricted and still cause severe reactions
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Caras, James William. "Emulation and induction of cytotoxic immunity : immunotoxin therapies for AIDS and novel antiviral vaccines /." Digital version accessible at:, 1999. http://wwwlib.umi.com/cr/utexas/main.
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Swan, Jillian Rosemary Murdoch. "Workplace exposure to airborne microorganisms and the mechanisms of immunotoxic response." Thesis, University of Sheffield, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339986.
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Gurkan, Cemal. "Expression of membrane-acting immunotoxins based on the Bacillus thuringiensis Cyt2Aa1 toxin in Pichia pastoris." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620668.
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Pora, Hélène. "Sialylation de glycoprotéines inhibitrices de la synthèse protéique en vue d'améliorer la pharmacocinétique des immunotoxines." Paris 11, 1988. http://www.theses.fr/1988PA112265.
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La sialylation enzymatique des glycoprotéines toxines est une des méthodes qui devrait permettre l'amélioration de la pharmacocinétique des immunotoxines, celles-ci n'étant plus reconnues au niveau du foie par l'intermédiaire de la chine oligosaccharidique de la toxine. La sialylation du glycopeptide: N-acétylglucosamine asparagine a montré que l'utilisation d'enzymes immobilisées et de glycosyltransférases spécifiques permettait d'obtenir des glycoconjugués sialylés à l'échelle semi-prépara ive. Pour sialyler la toxine: chaîne A de ricine deux étapes préalables sont nécessaires: déglycosylation et galactosylation. Après déglycosylation par des endoglycosidases spécifiques, la chaîne A a une demi-vie plasmatique augmentée. Les faibles rendements obtenus à cette étape et surtout à l'étape de galactosylation n'ont pas permis de sialyler la chaîne A. La trichokirine est une hémitoxine utilisée pour la construction des immunotoxines. Après une étape de galactosylation préalable, nous avons greffé un acide sialique par mole de trichikirine. La trichokirine sialylée conserve son activité biologique, et sa demi-vie plasmatique est augmentée.
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Caudrelier, Marie. "Mechanisms underlying the variability in response of Acute Myelogenous Leukemia cells to the immunotoxin AVE9633." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=40782.
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Acute myelogenous leukemia (AML) five year survival ranges between 20-30% despite the administration of the most intensive chemotherapy regimen, hence the need to develop new therapeutic strategies. Substantial inter-patient variation in sensitivity to AVE9633, a very promising anti-CD33 immunoconjugate, was observed. The goal of this project is to identify the mechanisms underlying resistance of AML cells to AVE9633. Using the AVE9633 sensitive AML cell line, HL60, and its resistant variant HL60/s, we found that both internalize the immunotoxin to a similar extent. The uncoupling of the antibody from the CD33 receptor is significantly lower in HL60/s. CD33 degradation was seen to be reduced in the resistant cell line while Suppressor Of Cytokine Signalling 3, SOCS3, playing a role in CD33 degradation, is only expressed in the sensitive cell line. In conclusion, antibody-receptor uncoupling and CD33 degradation defects were shown to be associated with resistance to AVE9633 in the HL60/s cell line. The identification of these mechanisms of resistance could provide means to screen-out patients most likely to benefit from treatment with AVE9633 and identify new approaches to treat patients refractory to current cancer treatments.La Leucémie Myéloïde Aigue (LMA) est associée à une survie après cinq ans qui varie entre 20 et 30% en dépit de l’administration des régimes de chimiothérapie les plus intensifs, d’où la nécessité de développer de nouvelles stratégies thérapeutiques. Une importante variation de sensibilité cellulaire à l’AVE9633, un immunoconjugué anti-CD33 très prometteur, a été observée entre les patients. Le but de ce projet est d’identifier les mécanismes responsables de la résistance des cellules de LMA à l’AVE9633. En employant la lignée LMA sensible à AVE9633, HL60, et sa variante résistante, HL60/s, nous avons découvert que les deux lignées internalisent autant d’immunotoxine. Le découplage de l’anticorps du récepteur est significativement moindre dans la lignée résistante HL60/s. La dégradation de CD33 est réduite chez HL60/s alors que la protéine « Suppressor Of Cytokine Signalling 3 », SOCS3, jouant un rôle dans la dégradation de CD33, est uniquement exprimée dans la lignée cellulaire sensible. En conclusion, nous avons démontré que le découplage anticorps-récepteur et la dégradation de CD33 sont associés à la résistance de la lignée HL60/s à l’AVE9633. L’identification de ces mécanismes de résistance devrait pouvoir nous offrir des moyens d’identifier les patients les plus susceptibles de bénéficier d’un traitement par AVE9633 et de découvrir de nouvelles façons de traiter les patients ne répondant point aux traitements actuels du cancer.
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Pora, Hélène. "Silalytion enzymatique de glycoprotéines inhibitrices de la synthèse protéique en vue d'améliorer la pharmacocinétique des immunotoxines." Grenoble 2 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb37617617n.
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Mercatelli, Daniele <1982>. "Ribosome-inactivating proteins and their immunotoxins for cancer therapy: insights into the mechanism of cell death." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6791/.
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Ribosome-inactivating proteins (RIPs) are a family of plant toxic enzymes that permanently damage ribosomes and possibly other cellular substrates, thus causing cell death involving different and still not completely understood pathways. The high cytotoxic activity showed by many RIPs makes them ideal candidates for the production of immunotoxins (ITs), chimeric proteins designed for the selective elimination of unwanted or malignant cells. Saporin-S6, a type 1 RIP extracted from Saponaria officinalis L. seeds, has been extensively employed to construct anticancer conjugates because of its high enzymatic activity, stability and resistance to conjugation procedures, resulting in the efficient killing of target cells.
Here we investigated the anticancer properties of two saporin-based ITs, anti-CD20 RTX/S6 and anti-CD22 OM124/S6, designed for the experimental treatment of B-cell NHLs. Both ITs showed high cytotoxicity towards CD20-positive B-cells, and their antitumor efficacy was enhanced synergistically by a combined treatment with proteasome inhibitors or fludarabine. Furthermore, the two ITs showed differencies in potency and ability to activate effector caspases, and a different behavior in the presence of the ROS scavenger catalase. Taken together, these results suggest that the different carriers employed to target saporin might influence saporin intracellular routing and saporin-induced cell death mechanisms.
We also investigated the early cellular response to stenodactylin, a recently discovered highly toxic type 2 RIP representing an interesting candidate for the design and production of a new IT for the experimental treatment of cancer.
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Howe, William M. "Effects of Excitotoxic and Immunotoxic Lesions of the Posterior Parietal Cortex on Attention." W&M ScholarWorks, 2006. https://scholarworks.wm.edu/etd/1539626521.
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Keenan, James John. "Immunotoxic Effects of Mixtures of Endosulfan and Permethrin Via Caspase Dependent Thymocyte Apoptosis." Thesis, Virginia Tech, 2003. http://hdl.handle.net/10919/31647.
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Altered immune responses have been observed following occupational, inadvertent, or therapeutic exposure to xenobiotics. Many pesticides are known to cause immunotoxicity. Exposure to mixtures of pesticides, either concurrently or sequentially, may result in potentiating this effect partly because one can effect the metabolism of the other. The objective of this study was to determine the effect of the insecticides endosulfan, permethrin and their mixtures on C57/BL6 male mice thymocytes in vitro and to ascertain the mechanism by which these effects take place. Permethrin, a broad-spectrum synthetic pyrethroid, is a widely used insecticide in agriculture and public health. Endosulfan is a highly toxic chlorinated hydrocarbon insecticide used worldwide. We examined the immunotoxic potential of these pesticides using a flow cytometric technique in combination with 7-Amino Actinomycin D (7AAD) to distinguish live, early apoptotic, and late apoptotic/necrotic cells. DNA ladder assay, a hallmark of apoptosis
, was also used to determine the occurrence of apoptosis. Both endosulfan and permethrin were found to cause significant apoptotic death of thymocytes in a dose- and time- dependent manner. Thus, permethrin at 50, 100 or 300 µM was found to cause 5.5, 11.5 and 26.1% increases in early apoptotic cell death relative to control, respectively. Endosulfan at 25, 50 or 250 µM was found to cause 11.9, 15.7 and 68.0% early apoptotic cell death, respectively. For the mixture study, concentrations of 100 µM permethrin and 50 µM endosulfan were selected and found to cause 27.1% apoptosis. Thus, these pesticides in mixture have an additive immunotoxic effect. Increases in late-apoptotic/necrotic cells were found at these concentrations for either pesticide when exposed for 12 hours. DNA ladder assay confirmed the presence of DNA fragments and therefore the presence of significant apoptotic cell death.
Apoptosis is a morphologically distinct form of cell death that can be mediated by a variety of pathological and physiological stimuli. Because permethrin and endosulfan were found to induce apoptosis in C57/BL6 mice thymocytes in vitro, the objective of the second half of this study was to elucidate the potential mechanism by which these pesticides regulate apoptosis in immune cells. Caspases are a family of cystine-dependent, aspartate-directed proteases that have an integral role in apoptotic cell death. Caspases, which are normally inactive in healthy cells, are activated during apoptosis and form an irreversible cascade. There are two subsets of caspases, initiator caspases (i.e. caspase 8 and 9) and effector caspases (i.e. caspases 3 and 6). Caspase 3, a downstream effector of apoptosis, is activated by many different pathways and is an apoptotic marker in cells. Caspase 8 is the apical caspase in the extrinsic pathway. Caspase 9 is the apical caspase in the intrinsic pathway, therefore we investigated mechanisms of pesticide induced apoptosis involving the thymocyte caspase system. Thymocytes from C57/BL6 mice were incubated with varying concentrations of pesticides for varying amounts of time. Active caspase 3 was then measured using EnzCheck Caspase 3 Assay Kit. Relative fluorescence for permethrin exposed cells after 12 hours incubation in the presence of pesticides at 150, 100, and 50 µM and 40 minutes in the presence of AFC-substrate was found to be 387, 386, and 297, respectively. Relative fluorescence for endosulfan exposed cells at 150, 100 and 50 µM was 188, 177, and 294. Caspase 3 activity increased as permethrin concentrations increased and decreased as endosulfan concentrations were increased. Then the extrinsic and intrinsic pathways of apoptosis were further investigated. Active caspase 8 was measured using the ApoAlert Caspase Fluorescent Assay Kit. Relative fluorescence for permethrin exposed cells after 7 hours incubation in the presence of pesticides at 100, 150, and 200 µM was found to be 35.5, 10.5, and 0, respectively. Relative fluorescence for endosulfan exposed cells after 7 hours incubation at 25, 50, 100 and 150 µM was found to be 32.8, 63.8, 69.5, and 55.5, respectively. A mixture study was then performed using endosulfan (50, 100, 150 µM) combined with permethrin (100 µM). All combinations were found to have more than an additive effect, therefore the extrinsic pathway seems to be involved. Caspase 9 activity was measured using Caspase 9/Mch6 Fluorometric Protease Assay Kit. Relative fluorescence for endosulfan exposed cells after 7 hours incubation at 25, 50, 100 and 150 µM was found to be 43, 73, 78.9, and 5.12, respectively. Relative Fluorescence for permethrin exposed cells at 100, 150 and 200 µM was found to be 34.5, 39, and 55.5, respectively. A mixture study was then performed using endosulfan (25, 50 µM) combined with permethrin (100 µM). Both combinations were found to have less than an additive effect. These results suggest that apoptosis caused by both endosulfan and permethrin exert their effects via the caspase pathway. The results also show that mixtures of pesticides have a less than additive effect on caspase 9 activation and more than an additive effect on caspase 8 activation, therefore the extrinsic pathway is predominantly involved in thymocyte apoptosis caused by mixtures of permethrin and endosulfan.Master of Science
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Vemireddi, Vimala. "Immunotoxic and Oxidative Effects of Endosulfan and Permethrin on Murine SPlenocytes, in vitro." Thesis, Virginia Tech, 2004. http://hdl.handle.net/10919/32983.
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Indiscriminate use of pesticides appears to alter immune response in non-target organisms such as humans and other animals. Thus, immune modulation is considered as one of the potential risks and consequences following exposure to these chemicals. Because of the widespread usage, exposure to mixtures of pesticides during the lifetime of individuals is unavoidable and can result in potentiation of the toxic effects. Because immune cells are more susceptible to toxic insults at a lower dose than most other cell types, the effects of pesticides and their mixtures on murine splenocytes were evaluated. C57BL/6 male mouse splenocytes, in vitro, were exposed to permethrin and endosulfan, individually and in-combination (25-200 µM). The immunotoxic potential of these pesticides was monitored using a flow cytometric technique in combination with 7-Amino Actinomycin D (7-AAD) staining. Endosulfan exposures (25-150 µM) resulted in time- and dose-dependent increase in apoptotic and necrotic cell death in murine splenocytes, in vitro. Permethrin exposure (50-200 µM) resulted in neither a time-dependent/dose-dependent loss of splenocyte viability nor induction of apoptosis in splenocytes. With mixtures of permethrin and endosulfan, depressed viability and enhanced early apoptosis and late apoptosis/necrosis were observed. Exposure to mixtures of 50 µM endosulfan with 50 or 100 µM permethrin increased late apoptosis/necrosis compared to exposure to either chemical alone. DNA fragmentation, a hall mark of apoptosis was observed by DNA ladder technique, confirming the occurrence of apoptosis. Morphological observation using cytospun slides was also carried out to further confirm the presence of apoptosis and necrosis. These findings suggest that the immunotoxicity of endosulfan both individually and in mixtures with permethrin is associated with the occurrence of apoptotic and necrotic processes.
Further, the ability of these pesticides to alter the oxidative status of the cells, via reactive oxygen species (ROS) generation and modulation of intracellular antioxidant enzymes levels, was investigated. We monitored the generation of ROS such as hydrogen peroxide (H2O2) with 2´, 7´- dichlorofluorescin diacetate (DCFH-DA) assay and superoxide anion (O2-) with hydroethidine (HE) assay in combination with flow cytometry. Spectrophotometric techniques were used to measure antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR) and glutathione peroxidase (GPX). Results of the analyses revealed that individual pesticides increased the production of H2O2 in a time and dose-dependent manner. Both time and dose-dependent increases in O2- production were caused by permethrin; whereas endosulfan exposure resulted in only a dose-dependent increase. However, exposure to mixtures of these pesticides had little or no effect on the generation of H2O2 and O2- radicals as compared to individual pesticides. The levels of SOD and GPX in pesticide-treated splenocytes were found to be not different from solvent control. An increase in GR and CAT levels in cells was noticed with permethrin (100 µM) exposure. These findings suggest that permethrin and endosulfan have the ability to affect the cellular oxidative status and can cause toxicity in immune cells, in vitro.
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Rowe, Alexander M. "The effects of the herbicide atrazine on mammalian immune function." Morgantown, W. Va. : [West Virginia University Libraries], 2007. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=5181.
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Thesis (Ph. D.)--West Virginia University, 2007.Title from document title page. Document formatted into pages; contains vi, 183 p. : ill. (some col.). Includes abstract. Includes bibliographical references.
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Yang, Liying. "Targeting Interleukin-4 Receptor α with Hybrid Peptide for Effective Cancer Therapy." Kyoto University, 2014. http://hdl.handle.net/2433/188669.
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Pirzer, Thomas [Verfasser], Harald [Akademischer Betreuer] Kolmar, and Henning D. [Akademischer Betreuer] Mootz. "Generation of anti-HER1/2 immunotoxins by protein ligation using split inteins / Thomas Pirzer ; Harald Kolmar, Henning D. Mootz." Darmstadt : Universitäts- und Landesbibliothek Darmstadt, 2018. http://d-nb.info/1166851060/34.
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Kelly, Alexander. "Immunotoxic effects of orally administered sodium tungstate in wild-type and pre-leukemic mouse models." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114605.
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Due to its various desirable properties, tungsten is extensively used in a variety of industrial, military, and residential applications. Despite this wide-spread use, little is known about the toxicological profile and possible health effects of tungsten exposure. High environmental tungsten levels were identified near the site of three childhood pre-B acute lymphoblastic leukemia (preB-ALL) clusters within the United States, however, a causal link between tungsten and leukemogenesis has not been established. The major site of tungsten deposition is bone, the site of B cell development. Thus, we hypothesized that an accumulation of tungsten within the bone would be exposing the developing immune system within the bone marrow to high levels of tungsten and possibly alter the growth and development of B lymphocytes. In addition, our laboratory has previously demonstrated that developing B lymphocytes are susceptible to tungsten-induced DNA damage and growth inhibition in vitro. To extend these results, we assessed whether oral tungsten exposure altered B-cell development and induced DNA damage in vivo. Tungsten concentration in bone was correlated with transient differences in percentages of developing B-cells and increased DNA damage in both whole marrow and isolated B-cells. These findings confirm an immunological effect of in vivo tungsten exposure. Based on these findings and literature review, we propose that tungsten could act as a tumor promoter, providing leukemic "hits" in multiple forms to developing B lymphocytes within the bone marrow. To test this possibility, we bred "pre-leukemic" mice harbouring the TEL-AML1 fusion oncogene, believed to be the initiating genetic lesion uniquely associated with childhood acute lymphoblastic leukemia, and orally exposed them to 15 mg/l tungsten. We hypothesized that oral exposure to sodium tungstate in animals expressing TEL-AML1 would be sufficient to result in the development of leukemia. Preliminary results indicate that splenomegaly, with a corresponding increase in Gr-1+ cells in both the spleen and the periphery, occurs as a result of the combination of TEL-AML1 expression and tungsten exposure. Furthermore, a noticeable difference in the bone marrow was observed in these animals by fluorescence activated cell sorting analysis. Collectively, these findings warrant further investigation into the possible role tungsten may have in cancer development and progression.En raison de ses diverses propriétés souhaitables, le tungstène est utilisé massivement dans une variété d'usages industrielles, militaires et résidentielles. Malgré cette utilisation répandue, peu est connu au niveau du profil toxicologique et des effets possibles sur la santé lors d'une exposition au tungstène. Trois différents endroits contenant un haut taux de tungstène dans l'environnement ainsi qu'un nombre anormal d'enfants atteints de pré B leucémie lymphoblastique aiguë (Pré B - LLA) ont été identifiés aux États-Unis. Toutefois, aucun lien de causalité entre le tungstène et la leucémogénese n'a été établi. L'endroit majeur d'accumulation du tungstène est au niveau osseux, ce qui correspond au même site de développement que les cellules B. Ainsi, nous avons émis l'hypothèse qu'une accumulation de tungstène au sein de l'os exposerait le système immunitaire, qui est en développement au sein de la moelle osseuse, à des niveaux élevés de tungstène pouvant éventuellement modifier la croissance et le développement des lymphocytes B. De plus, notre laboratoire a précédemment démontré que les lymphocytes B en développement sont sensibles, in vitro, aux dommages à l'ADN et à l'inhibition de la croissance causés par le tungstène. Afin de pousser nos recherches davantage, nous avons tenté de savoir si l'exposition orale au tungstène modifierait le développement des cellules B et induirait des dommages à l'ADN de façon in vivo. La concentration de tungstène dans l'os était en corrélation avec les changements du pourcentage de cellules B en développement, ainsi qu'avec l'augmentation des dommages à l'ADN dans les cellules de la moelle et dans les cellules B isolées. Ces résultats confirment un effet immunologique de l'exposition in vivo au tungstène. En se basant sur ces conclusions ainsi que sur la littérature, nous proposons que le tungstène pourrait agir comme un promoteur de tumeur, en fournissant des "hits" leucémiques sous de multiples formes aux des lymphocytes B en développement dans la moelle osseuse. Pour vérifier cette possibilité, nous avons élevé des souris "Pré-leucémique" ayant l'oncogène de fusion TEL-AML1, que l'on croit être la lésion génétique associée à la leucémie lymphoblastique aiguë chez les enfants, et nous les avons exposés à 15 mg/l de tungstène par voie orale. Nous avons émis l'hypothèse que l'exposition au tungstate de sodium par voie orale chez les animaux exprimant TEL-AML1, serait suffisante pour entrainer le développement de la leucémie. Les résultats préliminaires indiquent que la splénomégalie ainsi qu'une augmentation correspondante des cellules Gr-1+ de la rate et de la périphérie se produisent à la suite d'une combinaison de deux facteurs : l'existence du TEL-AML1 et une exposition au tungstène. De plus, une différence éminente a été observée dans la moelle osseuse de ces animaux, à l'aide de cytométrie en flux (triage de sous-population). En somme, ces résultats justifient la poursuite d'enquêtes approfondies sur le rôle possible du tungstène dans la progression et dans le développement du cancer.
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Van, Grevenynghe Julien. "Effets des hydrocarbures aromatiques polycycliques sur les cellules hématopoïétiques : contribution à leur potentiel carcinogène et immunotoxique." Rennes 1, 2005. http://www.theses.fr/2005REN1B063.
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Les hydrocarbures aromatiques polycycliques (HAPs) constituent une des principales familles de contaminants toxiques, retrouvés en milieu professionnel mais aussi de façon ubiquiste dans l'environnement. L'exposition à de nombreux HAPs peut conduire à des effets toxiques majeurs bien documentés par des études expérimentales chez l'animal et des enquêtes épidémiologiques chez l'Homme. Ainsi ces HAPs peuvent être de puissants cancérogènes au niveau de différents tissus, notamment les poumons, le foie, l'estomac, l'intestin, la peau et le système hématopoïétique. L'exposition à ces composés peut se traduire également la survenue de pathologiees cardiovasculaires et par une altération de la fonction de reproduction. De plus les HAPs sont connus pour posséder des propriétés immunosuppresives importantes, qui pourrait contribuer indirectement à leur action carcinogène et ceci par un possible échappement des cellules néoplasiques. Les connaissances concernant ces composés chez l(Homme restent toutefois relativement restreintes et incomplètes. Notre projet de recherche a donc visé à étudier les effets délétères de HAPs sur les cellules hématopoïétiques humaines, ayant entre autre, un rôle important dans les phénomènes de défense de l'organisme. Ainsi nous avons pu démontrer que la lignée monocytaire/macrophagique constitue une cible importante des HAPs. Le système immunitaire a par ailleurs la particularité de se renouveler en permanence en formant à partir de cellules souches hématopoïétiques, positivement marquées par les antigènes CD34+, de nouvelles cellules effectrices impliquées dans les diverses facettes de la réponse immunitaire. Le fait que nous ayons démontré que ces cellules progénitrices sont également touchées par un traitement aux HAPs, renforce encore le puissant potentiel immunotoxique de ces composés chez l'homme, et ceci par une atteinte du système immunitaire sur plusieurs fronts. De plus l'ensemble de ces atteintes immunotoxiques dépend en partie de la formation de métabolites toxiques, ayant entre autre la particularité de fixer et endommager les composants intracellulaires.
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Peterson, William E. "Immunolesioning of identified motoneuron pools by the intramuscular injection of the immunotoxins, 192-IgG-saporin and OX7-saporin, in rats." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2002. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/MQ62820.pdf.
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Field, Sarah Alice. "Internalisation and trafficking characteristics of CD7 and CD38 on a human T-ALL cell line in relation to immunotoxin potency." Thesis, University of Southampton, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252378.
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Chiron, Marielle. "Sensibilité individuelle des cellules leucémiques fraîches vis à vis des immunotoxines : contribution à l'approche pharmacologique de la purge de moelle osseuse." Toulouse 3, 1990. http://www.theses.fr/1990TOU30222.
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La greffe medullaire chez des patients leucemiques permet de reparer la toxicite hematologique due a une chimioradiotherapie supralethale. Dans le traitement ex vivo de moelle osseuse autologue, les immunotoxines (its) a chaine a de ricine presentent un potentiel prometteur dans la perspective de l'elimination des cellules leucemiques contaminantes. En effet, elles sont concues pour tuer selectivement les cellules tumorales et combinent une haute specificite de reconnaissance due a l'anticorps a une puissante activite cytotoxique due a la toxine. Les variations de sensibilite individuelle des cellules leucemiques fraiches ont ete analysees vis-a-vis de deux types d'its a chaine a de ricine (it anti-cd5 et it anti hla-dr) afin d'evaluer leur potentiel dans la purge de moelle osseuse ex vivo. Dans cette etude, l'it anti cd5 (fab t101-rta) apparait comme un agent de purge a la fois fortement cytotoxique et hautement specifique pour les hemopathies lymphoides cd5 positives compte-tenu de son effet cytoreducteur important sur un echantillonage de cellules fraiches leucemiques et d'une toxicite nulle sur les progeniteurs hematopoietiques. L'it anti hla-dr apparait comme un excellent agent de purge pour les hemopathies lymphoides b en depit d'un certain degre de toxicite sur les progeniteurs hematopoietiques. Dans la purge des hemopathies myeloides, l'it anti hla-dr permet d'obtenir un index therapeutique superieur a celui de trois agents de la purge chimique (melphalan, etoposide et mafosfamide)
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Schlüter-Vorberg, Lisa [Verfasser], Jörg [Gutachter] Oehlmann, and Thomas A. [Gutachter] Ternes. "Emerging contaminants and their (immunotoxic) effects on aquatic organisms / Lisa Schlüter-Vorberg ; Gutachter: Jörg Oehlmann, Thomas A. Ternes." Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2019. http://d-nb.info/1178725960/34.
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Zambaux, Marie-France. "Amélioration de la biodisponibilité de protéines de la coagulation par formation de conjugués covalents solubles et de nanoparticules : application à la protéine C." Nancy 1, 1998. http://www.theses.fr/1998NAN11011.
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De nombreuses biomolécules possèdent une faible durée de demi-vie, ce qui est le cas de certaines protéines de la coagulation telles que le facteur VII et la protéine C. Pour tenter de remédier à cet inconvénient, deux approches sont possibles : la formation d'un conjugué covalent macromoléculaire soluble et l'encapsulation dans des nanoparticules furtives. Formation de conjugués : Une étude de faisabilité a été réalisée sur deux protéines modèles (l'hémoglobine et l'albumine) en milieu dilué avec des dextranes fonctionnalisés. Il n'a cependant pas été possible de transposer de manière satisfaisante les résultats obtenus aux différentes protéines de la coagulation (facteur VIII, facteur IX et protéine C). Le rôle des fonctions carboxylates et amines de ces protéines a cependant pu être souligné. Encapsulation : Des copolymères amphiphiles biodégradables constitués d'un bloc hydrophobe d'acide poly(lactique) (PLA) et d'un bloc hydrophile de monométhoxypolyéthylène (MPOE) ont été synthétisés dans le but de préparer des nanoparticules biodégradables furtives de protéine C par la technique de la double émulsion. Les conditions expérimentales permettant de préserver les caractéristiques de la protéine C encapsulée et d'optimiser son rendement d'encapsulation ont été déterminées sur des nanoparticules non furtives (PLA). Le caractère furtif de ces nanoparticules de copolymère MPOE-PLA vierges a été mis en évidence in vitro par l'étude de la consommation du complément et de la phagocytose. Puis, les conditions opératoires permettant l'obtention de nanoparticules furtives de protéine C possédant une charge satisfaisante en protéine C active, un diamètre proche de 200 nm et sa libération progressive ont ensuite été optimisées. Enfin, l'approche du comportement d'une telle suspension de nanoparticules furtives de protéine C in vivo chez le cobaye a permis de clairement mettre en évidence leur caractère furtif ainsi que la libération progressive de la protéine C encapsuléeA lot of biologically active molecules such as coagulation proteins i. E. Factor VIII and protein C have a short half-life in blood. Their half-life i. E. Their biodisponibility could be increased by means of either the formation of soluble covalent conjugates with a macromolecule or their encapsulation within stealth nanoparticles. Conjugate formation : A study was carried out on model proteins (hemoglobin and albumin) in low-concentration medium with derivatized dextrans but unfortunately, it couId not be applied to coagulation proteins (factor VlII, factor IX and protein C). However, the role of their carboxylate and amino groups could be underlined. Encapsulation : Biodegradable amphiphitic copolymers made of a poly(lactic acid) (PLA) hydrophobic block and of a monomethoxypolyethylene (MPEO) hydrophilic one were synthesized in order to prepare stealth biodegradable nanoparticles of protein C by a double emulsion method. Experimental conditions allowing the preservation of encapsulated protein C characteristics and the optimization of its encapsulation efficiency were determined for non stealth nanoparticles (PLA). The stealth character of blank MPEO-PLA nanoparticles were highlighted in vitro by studying complement consumption and phagocytosis. Afterwards, processing conditions allowing stealth nanoparticles of protein C with a satisfactory active protein C loading, a mean diameter of 200 nm and its progressive release were optimized. Finally, the in vivo behavior of such protein C nanoparticles was studied in guinea pig. Their stealth character and a progressive release of encapsulated protein C were brought to light
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Bryson, Christine Jane. "Delineating the apoptotic mechanisms of an anti-CD19 immunotoxin used in combination with the anti-CD20 antibody rituximab against human B-lymphoma cells." Thesis, University of Southampton, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404189.
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Lourenço, Emerson Luiz Botelho. "Efeitos dos tratamentos crônicos com produtos de biotransformação do benzeno sobre a mobilização de leucóticos polimorfonucleares na vigência de resposta inflamatória." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/9/9141/tde-18012018-110320/.
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Apesar da ampla demonstração do potencial tóxico do benzeno ao sistema imune, os mecanismos envolvidos nos seus diferentes efeitos não estão totalmente esclarecidos. Desta forma, o presente trabalho avaliou a mobilização e função de leucócitos polimorfonucleares (PMN) na vigência de resposta inflamatória aguda em ratos expostos a metabólitos do benzeno. Ratos Wistar, machos foram tratados por período de tempo prolongado (50 mg/kg; i. p.; 1 uma vez ao dia, 13 ou 16 doses diárias com intervalos de 2 dias a cada 5 doses) com hidroquinona (HQ), fenol (FE) ou veículo. As respostas inflamatória inata ou adquirida foram induzidas 24 hs após a última dose dos tratamentos. Para avaliar a intensidade de intoxicação, um método analítico foi padronizado para a extração de HQ e FE da urina dos animais por microextração em fase sólida, para subseqüente análise por cromatografia gasosa acoplada a espectrometria de massa. Os dados da validação mostraram que a técnica analítica é adequada, e a análise das amostras demonstrou o aumento na concentração urinária de HQ, FE e catecol (CAT) em urina dos ratos expostos, confirmando assim a exposição ao FE ou a HQ. A avaliação da resposta inflamatória inata demonstrou que o tratamento com HQ acarretou aumento acentuado no influxo de PMN para a cavidade inflamada. A análise do leucograma mostrou que o tratamento com HQ promoveu neutrofilia, que pode ser decorrente da mobilização destas células da medula, uma vez que número menor de células segmentadas na última etapa de maturação foi encontrado nestes animais. No entanto, durante a vigência de resposta inflamatória, a neutrofilia esperada para este processo não foi detectada nestes animais. Espécies reativas de nitrogênio podem participar dos efeitos aqui detectados em animais tratados com HQ, já que valores aumentados de óxido nítrico (NO) foram mensurados no sangue após o tratamento e no exsudato inflamatório. Diferentemente da exposição à HQ, a administração de FE não alterou a migração de PMN para o foco de lesão na vigência de reposta inflamatória aguda inata. Apesar do tratamento com FE ter acarretado linfocitopenia, a produção das células brancas no compartimento medular e a leucocitose em resposta ao processo inflamatório foram equivalentes ao encontrado em animais controles. No que concerne à resposta inflamatória alérgica, ambos os tratamentos inibiram o influxo de leucócitos para o lavado bronco-alveolar (LBA) e para o tecido pulmonar. A investigação dos mecanismos envolvidos que a exposição à HQ interfere com a síntese de imunoglobulina E e, eventualmente, com a desgranulação de mastócitos. Por outro lado, a exposição ao PHE não alterou estes parâmetros. Em conjunto, os dados aqui apresentados sugerem que os tratamentos com HQ ou FE provocam efeitos distintos na gênese de respostas inflamatórias de diferentes origens quanto à migração leucocitária, e que os mecanismos envolvidos com a imunotoxicidade induzida pelo benzeno é altamente complexa.Despite toxicity of benzene has been fully demonstrated, the mechanisms involved on its immunotoxicity are not fully comprehended. Then, the present work studied the mobilization and functions of polymorphonuclear cells (PMN) during acute inflammatory reactions in rats exposed to benzene metabolites. Male Wistar rats were treated with hydroquinone (HQ) or phenol (Phe) for prolonged period of time (50 mg/Kg; i.p.; once a day, 13 or 16 doses, 2 days intervals after each 5 doses). Innate or acquired inflammatory reactions were carried out 24 hours after the last dose of treatments. Animals treated with vehicle were employed as control. In order to determine the intensity of intoxications, an extraction method was developed in urine using a solid phase micro-extraction fiber. The subsequent analysis was performed on gas chromatography coupled to mass spectrometry. Data from validation showed the adequacy of methodology and demonstrated the presence of HQ, PHE and CAT in urine from exposed rats, corroborating the exposition to PHE or HQ. The evaluation of innate inflammatory reaction showed that HQ exposition promoted increment on the number of PMN cells to inflamed area. The leucogram demonstrated that treatment evoked neutrophilia, probably due to mobilizations of segmented cells in the last phase of maturation from bone marrow. However, during the inflammatory process, the characteristic neutrophilia was not detected. Nitrogen reactive species may participate of the intoxication, since elevated values of nitric oxide (NO) were found in blood after intoxication and in inflammatory exudates. Differentially from HQ exposition, administrations of PHE did not alter the migration of PMN into inflammatory focus. Despite the treatment promoted reductions on number of lymphocytes, the production of white cells on bone marrow and the neutrophilia during and inflammatory process were equivalent to those found in control animals. Regarding acquired inflammation, both treatments significantly inhibited the influx of leukocytes to bronchoalveolar fluid. This pattern of response did not reflect the accumulation of PMN cells on pulmonary tissue, since the myeloperoxidase activity was not higher when compared to control rats. The investigations of the mechanisms involved in the inhibited leukocyte recruitment, showed that HQ treatment probably impairs the immunoglobulin E synthesis and mast cell degranulation. On the other hand, FE exposition did not present these effects. Together, data herein suggest that HQ or PHE treatments promete singular effects on PMN recruitment during inflammatory reactions elicited by different agents, and the complexity of mechanisms responsible for the immunotoxicity induced by benzene.
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Haynes, Elizabeth M. "Mechanism of lipopolyamine-induced immunotozin sensitization in cancer cells." Honors in the Major Thesis, University of Central Florida, 2010. http://digital.library.ucf.edu/cdm/ref/collection/ETH/id/1417.
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This item is only available in print in the UCF Libraries. If this is your Honors Thesis, you can help us make it available online for use by researchers around the world by following the instructions on the distribution consent form at http://library.ucf.edu/Systems/DigitalInitiatives/DigitalCollections/InternetDistributionConsentAgreementForm.pdf You may also contact the project coordinator, Kerri Bottorff, at kerri.bottorff@ucf.edu for more information.Bachelors
Burnett School of Biomedical Sciences
Molecular Biology and Microbiology
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Kujbida, Paula da Silva. "Microcistinas produzidas pela cianobactérica Microcystis panniformis e alguns efeitos sobre funções de neutrófilos humanos." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/9/9141/tde-25052017-150102/.
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A proliferação acelerada de cianobactérias do gênero Microcystis em mananciais e reservatórios tem causado sérios danos ecológicos e à saúde pública, e é um problema que desafia as instituições responsáveis pelo fornecimento de água para a população. Essas cianobactérias produzem microcistinas (MC), heptapeptídeos cíclicos hepatotóxicos e que podem causar câncer. Neste trabalho, isolamos (CLAE preparativa) e identificamos (ESI-EM/EM) as microcistinas MC-LR e [ASp3]-MC-LR produzidas pela cianobactéria Microcystis panniformis. As concentrações dessas substâncias foram determinadas por CLAE e variaram de 0,25 a 2,75 (MC-LR) e 0,08 a 0,75 ([ASp3]-MC-LR) fmol. Célula-1. Analisamos as concentrações destes compostos em tempos diferentes durante o ciclo claro:escuro (C:E) e foi encontrado que a quantidade de MC por célula é pelo menos três vezes mais alta durante a fase clara do que a fase escura. Isto pode ser associado ao relógio biológico, pois as cianobactérias expressam um robusto ritmo circadiano no controle do mecanismo de tempo que é independente do ciclo de divisão celular. O mesmo ocorreu no ciclo claro:claro (C:C). Também estudamos os efeitos da MC-LR e [ASp3]-MC-LR sobre as funções de neutrófilos humanos in vitro. Essas substâncias têm capacidade quimiotáxica, uma vez que observamos um aumento de migração de neutrófilos, além de ativarem a formação de espécies reativas de oxigênio (ERO) e a fagocitose. Já a atividade microbicida é ativada somente pela MC-LR. Nossos resultados indicam que concentrações menores do que o limite máximo de exposição a MC-LR (1 µg.L-1), sugerido pela OMS, exercem efeito sobre funções de neutrófilos humanos in vitro, podendo contribuir com a toxicidade dessas MC.Cyanobacterial blooms of the genus Microcystis in water reservoirs have caused serious ecological and public health concern due to their ability to produce toxins. Microcystis and some other cyanobacerial species biosynthesize microcystins (MC). These cyanotoxins are hepatotoxic cyclic heptapeptides which can induce tumor promotion. In this study, MC-LR and [Asp3]-MC-LR were isolated (by preparative HPLC) and identified (by ESI-MS/MS) in the strain Microcystis panniformis BCCUSP100. Their levels were determined by HPLC and ranged from 0.25-2.75 and 0.08-0.75 fmols. cell-1 , respectively. The levels of MC-LR and [Asp3]-MC-LR were analyzed at different times during the light:dark (L:D) and light:light (L:L) cycles. It was found that the levels of MC per cell were at least three-fold as high during the day-phase than during the night-phase (L:D experiment). This may be associated to the biological clock since prokaryotic cyanobacteria express robust circadian (daily) rhythms under the control of a timing mechanism that is independent of the cell division cycle. Our findings also showed the same pattern under L:L cycle. The effects of MC-LR and [Asp3]-MC-LR in some human neutrophil functions were also studied by in vitro assays. We observed that MC have chemotactic capacity as well as can generate reactive oxygen species and increase phagocytosis activity. The killing activity was activated only by MC-LR. Our results indicated that lower concentrations of MC-LR than the one recommended by World Health Organization (1 µg.L-1) may affect human neutrophil functions in vitro. These findings can contribute to the elucidation of MC toxicity as well as its effects in human neutrophils.
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Waismam, Kaline. "Investigação dos efeitos de toxinas isoladas das cerdas da lagarta Lonomia obliqua sobe leucócitos, célula endotelial e rede microcirculatória." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/9/9141/tde-06092017-171829/.
Full textAbstract:
LOPAP (Lonomia obliqua prothrombin activator protease) é uma serino protease isolada das cerdas da Lagarta Lonomia obliqua que induz efeitos sobre a coagulação sanguínea, semelhantes ao extrato de cerdas bruto. Recentemente, foi obtido um peptídeo do LOPAP, P4, que parece possuir efeitos similares à proteína. No sentido de complementar os dados sobre estas toxinas, este estudo investigou os efeitos do LOPAP ou do P4 sobre interações leucócito-endotélio in vivo; expressão de moléculas de adesão, síntese de mediadores inflamatórios, apoptose e necrose de leucócitos e célula endotelial, além de suas possíveis ações sobre a formação de novos vasos. Aplicação tópica de 30µg/mL ou 300µg/mL (10µL) de LOPAP ou de P4 na rede microvascular do mesentério de ratos Wistar machos não alterou o diâmetro de vênulas pós-capilares, as interações dos leucócitos ao endotélio, nem a reatividade microvascular frente à acetilcolina ou noradrenalina. Somente a concentração de 1000µg/mL aumentou o número de leucócitos aderidos à parede vascular, simultaneamente a estases intermitentes nos vasos da microcirculação. Ensaios de citometria de fluxo mostraram que a incubação de LOPAP ou P4 (300µg/mL) não modificou a expressão de L-selectina e β2-integrina em neutrófilos circulantes obtidos de ratos Wistar. Por outro lado, incubações do LOPAP ou do P4 com célula endotelial (cultura primária obtida do músculo cremaster de ratos Wistar; 300µg/mL) induziram a expressão da molécula ICAM-1 , e somente o P4 promoveu a expressão de VCAM-1. Diferentemente, nenhuma das toxinas alterou a expressão de PECAM-1. Ensaios imuinoenzimáticos realizados em sobrenadantes de neutrófilos e de célula endotelial incubadas com LOPAP ou P4 (300µg/mL) mostraram que as toxinas não alteraram a secreção de interleucina-6 (IL-6), interleucina-10 (IL-10), fator de necrose tumoral-α (TNF-α) por neutrófilos; as toxinas não induziram a secreção de TNF-α pela célula endotelial, mas aumentaram a secreção de IL-6 e IL-10. A concentração de óxido nítrico (NO), quantificado pela reação de Griess, estava aumentada nos sobrenadantes dos dois tipos celulares incubados com LOPAP ou P4. A incubação de LOPAP ou P4 com neutrófilos ou célula endotelial não alterou a viabilidade celular, mas preveniu a apoptose da célula endotelial ou neutrófilo provocada pela carência de soro bovino fetal. A incubação simultânea com L-NAME (1 mM) reduziu a proteção conferida pelo LOPAP ou pelo P4. A investigação dos efeitos das toxinas sobre a formação da rede microcirculatória foi realizada em camundongos Swiss, machos, utilizando o modelo da câmara dorsal por microscopia intravital. A aplicação tópica do LOPAP ou P4 (30µg/mL, 300µg/mL; 10µL; 3 doses a cada 96 horas) no leito microvascular dorsal reduziu significantemente o número de vasos na rede microcirculatória em condições basais. Adicionalmente, o tratamento com P4 inibiu a formação de novos vasos provocada pela aplicação tópica de suplemento de fatores de crescimento vascular. O tratamento de célula endotelial de microcirculação de camundongos imortalizadas (tENd) com LOPAP ou P4 (300µg/mL) reduziu a capacidade de migração destas células. Em conjunto, os dados obtidos até o momento mostram que o LOPAP e o P4 não induziram as interações leucócito-endotélio in vivo e que a secreção de mediadores por neutrófilos e célula endotelial, como o NO, podem estar envolvidos com suas atividades anti-apoptótica. Ademais, o LOPAP e o P4 inibem o crescimento de novos vasos, e um dos possíveis mecanismos pode ser a interferência nos mecanismos de migração da célula endotelial.LOPAP (Lonomia obliqua prothrombin activator protease) is a serine protease isolated from the crude extract of Lonomia obliqua caterpillar, which induces effects on blood coagulation comparable to the extract. Recently it was obtained a peptide fragment from LOPAP, P4, with similar activities with the protein. This study aimed to complete data about these toxins, LOPAP and P4, on in vivo leukocyte-endothelial interactions; adhesion molecule expressions, synthesis of inflammatory mediators, necrosis and apoptosis of neutrophils and endothelial cells, besides possible actions on angiogenesis. Topical applications of 30μg/mL or 300µg/mL (10µL) of LOPAP or P4 on microvascular network of mesentery of Male Wistar rats did not affect the diameter of postcapillary venules, leukocyte-endothelial interactions, either vascular reactivity to acetylcholine or norepinephrine. Only topical application of 1000µg/mL (10 µL) promoted increment on the number of leukocytes adhered to vessel wall, simultaneously to intermittent blood stasis in the microvascular network. Flow cytometry assays showed that incubations with LOPAP or P4 (300µg/mL) did not modify the expression of L-selectin or β2-integrin in neutrophils from Male Wistar rats. On the other hand, incubations of LOPAP or P4 with primary cultured endothelial cells evoked expressions of ICAM-1, and only incubation with P4 promoted expression of VCAM-1. Differently, the treatments did not affect PECAM-1 expression in endothelial cells. Immunoenzimatic assays carried out in supernatants of neutrophils and endothelial cells incubated with LOPAP or P4 (300µg/mL) showed that both toxins did not alter the basal secretion of interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α) by neutrophils; both toxins did not promote secretion of TNF-α by endothelial cells, however they enhanced the secretion of IL-6 and IL-10. Concentrations of nitric oxide (NO), quantified by Griess reaction, were enhanced in the supernatant of neutrophils or endothelial cells incubated with LOPAP or P4. LOPAP or P4 treatments did not alter the viability of neutrophils or endothelial cells, but prevented the apoptosis of both type cell caused by fetal bovine serum deprivation. Simultaneous incubation with L-NAME (1 mM) and LOPAP or P4 reduced the protection on apoptosis exerted by the toxins. The action of toxins on formation of microcirculatory network was investigated in Male Swiss mice. Topical application of LOPAP or P4 (30µg/mL, 300µg/mL; 10µL; 3 times each 96 hours) in the microvascular network significantly reduced the number of vessels in basal conditions. Additionally, treatment with P4 inhibited the new vessel formation provoked by topical application of vascular growth factor supplement. Immortalized endothelial cells of mice (tEnd) incubated with toxins presented lower migration than cells incubated with saline. Together, data herein obtained showed that LOPAP and P4 did not evoke in vivo leukocyte-endothelial interactions and secretions of chemical mediators by neutrophils and endothelial cells, as NO, seem to be related to anti-apoptotic activities. Additionally LOPAP or P4 inhibit the microcirculatory network formation, by interfering, at least in part, by altering the migration of endothelial cells.