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1
Balu, Sucharitha. "Cloning and characterisation of chicken interleukin-12 and the interleukin-12 receptor." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419213.
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2
Werner, Christoph. "Von Interleukin-12 zur p40-Zytokinfamilie Interleukin-12-unabhängige Wirkungen von p40-Zytokinen in der Infekt- und Tumorabwehr /." [S.l.] : [s.n.], 2003. http://dol.uni-leipzig.de/pub/2003-34.
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3
Werner, Christoph. "Von Interleukin-12 zur p40-Zytokinfamilie: Interleukin-12-unabhängige Wirkungen von p40-Zytokinen in der Infekt- und Tumorabwehr." Doctoral thesis, Universitätsbibliothek Leipzig, 2004. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-37550.
Texte intégralRésumé :
Interleukin-12 (IL-12) ist ein zentrales Zytokin in der Entwicklung einer protektiven, zellulären Typ 1-Immunantwort. Es ist aus einer p40- und einer p35-Untereinheit aufgebaut. Es stimuliert NK- und T-Zellen zur Ausschüttung großer Mengen IFN-gamma und setzt so eine Typ 1-Immunantwort in Gang. Die p40-Untereinheit des IL-12 kommt auch in anderen biologisch wirksamen Verbindungen wie beispielsweise als Monomer, Homodimer oder als IL-23 (in Verbindung mit einer p19-Untereinheit) vor. Während das Homodimer in der vorliegenden Arbeit als reiner Antagonist zu IL-12 zu wirken scheint, wurden für IL-23 bereits zu IL-12 agonistische Wirkungen demonstriert. Im Mittelpunkt der vorliegenden Arbeit stand die Erarbeitung p40-abhängiger Wirkungen unter Ausschluß der Effekte von IL-12, d. h. möglicherweise IL-23-abhängiger Effekte. In den vorliegenden Untersuchungen wurde mit gendeletierten Mäusen gearbeitet, so dass IL-12 in diesen Systemen keine Rolle spielen kann sondern nur die p40-Proteine außer IL-12. Im Infektionsmodell mit Salmonella Enteritidis wurden p35-gendeletierte (p35-/--) und p40-/--Mäuse verwendet. Durch eine Induktion der p40-Expression waren Unterschiede auf die Wirkung der p40-Proteine zurückzuführen. Es zeigte sich, dass p40-Proteine durch die Induktion einer IFN-gamma Produktion eine Verbesserung der Abtötung intrazellulärer Pathogene bewirkten. Dadurch gelang in den p35-/--Mäusen die Eindämmung der systemischen Infektion besser und diese Mäuse überlebten länger als die p40-/--Mäuse. In Tumormodellen mit dem Lewis-Lungenkarzinom und dem Melanom B16 wurden p35/40-/--Mäuse, welche keine p40-Proteine bilden können, mit der für p40 kodierenden DNA gentherapiert. Durch diese lokale Gentherapie kam es zu einer Reduktion des Tumorwachstums. In immunhistologischen Untersuchungen war eine Rekrutierung von Makrophagen und eine Hemmung der Angiogenese im Tumorbereich sichtbar. Lokale und systemische Proteintherapien mit dem Homodimer oder IL-23 hatten keinen Effekt auf das Wachstum des Tumors, was auf die Existenz eines weiteren noch unbekannten heterodimeren p40-Proteins hindeutet. In vitro konnte gezeigt werden, dass IL-23 die IFN-gamma-Produktion durch Splenozyten induziert und dieser Effekt durch das Homodimer antagonisiert werden kann. Interessanterweise kann es in primären Milzzellkulturen auch IL-12 antagonisieren. Eine In-vitro-Infektion führte zu einer p40-abhängigen IFN-gamma-Produktion, die auch durch das Homodimer antagonisiert werden konnte. Während die Effekte der p40-Proteine im Infektionsmodell möglicherweise auf IL-23 zurückgeführt werden können und diese Effekte auch durch In-vitro-Untersuchungen gestützt werden, muss nach den Ergebnissen im Tumormodell auf die Existenz eines weiteren, bisher unbekannten p40-Proteines, p40-x, geschlossen werden<br>Interleukin-12 (IL-12) is a key cytokine in the development of a protective cellular Th1 immune response. It consists of a p40 and a p35 subunit. Following stimulation with IL-12, NK and T cells produce large amounts of IFN-gamma resulting in a type 1 immune response. The p40 subunit of IL-12 is also part of other biologically active proteins such as monomeric or homodimeric p40 or the heterodimeric IL-23 (in combination with a p19 subunit). While in this study the homodimeric p40 appears to antagonize IL-12, IL-23 was demonstrated to have agonistic effects. The aim of this study was to investigate p40-dependent effects which can be observed independently of IL-12, i.e. potential effects mediated by IL-23. For the experiments mutant mice were used so that IL-12 dependent mechanisms could not play a role but only p40-dependent proteins excluding IL-12. In a Salmonella Enteritidis infection model p35-gene deleted (p35-/-) and p40-/- mice were used. As the expression of p40 is induced by bacterial antigen, differences between the strains were caused by the p40 protein. During the infection p40 proteins induced IFN-gamma production thus improving the killing of intracellular pathogens. This resulted in a better control of the systemic infection and longer survival periods of the p35-/- mice as compared to p40-/- mice. For the experiments in the tumor model using the Lewis-Lung carcinoma and the Melanoma B16 as tumors, p35/40-/- mice which are unable to produce any p40 proteins, received gene therapy with DNA encoding for p40. This local gene therapy resulted in a reduced tumor growth. Immunohistochemical examination revealed an infiltration of the tumor tissue with macrophages and a reduced neoangiogenesis within the tumor. This effect could not be achieved by local administration of IL-23 or the p40-homodimer as a protein, indicating the existence of an as yet unknown heterodimeric p40 protein. In vitro experiments showed that IL-23 induces IFN-gamma production by splenocytes and this effect can be antagonized by the homodimer. Interestingly, IL-23 is also able to antagonize IL-12 in primary splenocyte cultures. In vitro infection with Salmonella resulted in an p40-dependent IFN-gamma production that could also be antagonized by the homodimer. The protective effects in the infection model might be caused by IL-23, which is supported by the in vitro results. On the other hand, in the tumor model IL-23 does not seem to be the player and it must be concluded that the protective effects are caused by an other as yet unknown p40-dependent protein p40-x
4
Walter, Claudia. "Bestimmung der Zytokine Interleukin-1ra, Interleukin-6, Interleukin-10 und Interleukin-12 im Vaginalsekret bei Frauen mit Bakterieller Vaginose." Diss., lmu, 2004. http://nbn-resolving.de/urn:nbn:de:bvb:19-28461.
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5
Chakir, Habiba. "Role of interleukin-12 and interleukin-18 in murine immune cell regulation." Thesis, University of Ottawa (Canada), 2003. http://hdl.handle.net/10393/28980.
Texte intégralRésumé :
Interleukin 12 plays a central role in NK cell activation and CD4 +T cell differentiation. IL-12 acts via a receptor composed of IL-12Rbeta1 and IL-12Rbeta2 subunits. IL-12Rbeta1 plays a primary role in ligand binding whereas IL-12Rbeta2 is responsible for signaling. IL-18 shares some functional activities of IL-12. However, there is a considerable amount of contradictory data in the literature regarding the requirements for IL-12 and IL-18 responsiveness.
This work examined the expression of IL-12Rbeta2 on murine NK and T cells and the requirements for acquisition of IL-12/IL-18 responsiveness. NK cells stimulated with IL-2+IL-12 or IL-2+IL-18 exhibited rapid upregulation of IFN-gamma expression followed by upregulation of IL-10 or IL-13 mRNA, respectively. NK cells from IL-12Rbeta2-deficient mice responded to IL-2+IL-18 independently of IL-12. Furthermore, flow cytometric analyses revealed that NK cells activated in vitro with IL-2 differentiate into two distinct cell subsets expressing different levels of IL-12Rbeta2.
Like NK cells, NK-T cells also responded to IL-2+IL-12 or IL-2+IL-18 without stimulation of the antigen-specific T cell receptor (TCR). Previously, it was thought that all T cells require activation via the TCR in order to respond to IL-12 or IL-18. Thus, responsiveness of conventional T cells to IL-2+IL-12 or IL-2+IL-18 in the absence of TCR ligation was assessed. Naive CD4+T cells from wild type or DO11.10/Rag2-/- OVA-specific TCR transgenic mice responded to IL-2+IL-12 or IL-2+IL-18 by expressing IFN-gamma and cells grown in IL-2+IL-12 exhibited signs of polarization towards a TH1 phenotype.
Transgenic BALB/c mice constitutively expressing the IL-12Rbeta2 chain were generated and the role of the IL-12Rbeta2 in TH2 phenotype development was analyzed using the TH1-dependent murine leishmaniasis model. Despite constitutive expression of the IL-12Rbeta2 chain, transgenic TH2 cells did not revert to TH1 when restimulated with IL-12 and mice remained susceptible to Leishmania. The role of IL-12Rbeta2 in TH1 cell development was also analyzed using the same model. Resistant C57BL/6 mice defective in IL-12Rbeta2 gene exhibited susceptibility to L. major infection and expressed a T H2 phenotype, consistent with a critical role for IL-12 in this model.
Thus understanding the expression of IL-12Rbeta2 in NK and CD4 +T cells and its regulation by cytokines may constitute an important element in studies in cancer and autoimmune disease therapy.
6
Swinburne, Sarah Jane. "A study of the molecular and biological characteristics of ovine interleukin-12." Title page, contents and summary only, 2000. http://web4.library.adelaide.edu.au/theses/09PH/09phs9777.pdf.
Texte intégralRésumé :
Bibliography: leaves 172-214. Interleukin-12 (IL-12) is a heterodimeric cytokine composed of two disulphide-linked subunits, p35 and p40, which form biologically active p70. IL-12 is able to induce IFN-y production from T and NK cells, and promote the proliferation of mitogen-activated T cells. It is thought that IL-12 may be an important cytokine in the initiation and progression of allograft destruction. This thesis describes the characterisation of ovine IL-12.
7
Rempel, Julia D. "Interleukin-12 and interleukin-10 regulation of antibody responses upon protein antigen immunization." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ41623.pdf.
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8
Athie, Morales Veronica. "Interleukin 12 signalling pathways in human T lymphocytes." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249566.
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9
Schardt, Victor. "Vergleichende Untersuchungen zur Hefepilzbesiedelung von Mundhöhle und Vagina und Bestimmung von Interleukin-4, Interleukin-10 und Interleukin-12." Diss., lmu, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-155152.
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10
Naseer, Tanveer 1971. "In vivo expression of interleukin-12 and interleukin-13 in the pathogenesis of asthma." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=23925.
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IL-12 and IL-13 are recently discovered cytokines which belong to Th1 and Th2 subtypes, respectively. To further support the hypothesis that Th2-type cytokines are involved in asthma, mRNA levels for IL-12 and IL-13 were measured in bronchial biopsies from asthmatics and normal controls as well as in moderately severe asthmatics before and after corticosteroid therapy using the technique of in situ hybridization. The number of IL-13 mRNA positive cells in asthmatics was significantly higher than that found in normal controls. However, there was a significant decrease in the number of IL-12 mRNA positive cells in asthmatic biopsies compared to normal controls. Following corticosteroid therapy, a significant decrease in IL-13 mRNA positive cells and an increase in the number of cells expressing IL-12 mRNA was detected. The results suggest an in vivo role of the cytokines in modulating allergic responses and support the role of Th2 type cytokines in asthma.
11
Dreisbach, Julia. "Klonierung, Expression und funktionelle Analyse von Hühner-Interleukin-12." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-33383.
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12
Azbil, Tatiana. "Nachweis von Candida-Spezies und Bestimmung der Zytokine Interleukin-1 beta, Interleukin-1ra, Interleukin-4, Interleukin-6, Interleukin-8, Interleukin-10 und Interleukin-12 im Vaginalsekret und im Serum bei Schwangeren in Relation zum Gestationsalter." Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-57576.
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13
Tso, Hoi-wan, and 曹凱韻. "Interleukin 12P40 genetic polymorphisms and tuberculosis in Chinese." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B29246933.
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14
Wagner, Frank. "Die Bedeutung von Interleukin-12p75 und Interleukin-12p40 für die Abwehr einer Infektion mit Cryptococcus neoformans im murinen Modell." Doctoral thesis, Universitätsbibliothek Leipzig, 2004. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-37485.
Texte intégralRésumé :
Um die Rolle von Interleukin-12p75 (IL-12p75) und Interleukin-12p40 (IL-12p40) in der Abwehr einer Kryptokokken-Infektion im Mausmodell zu untersuchen, wurden Mäuse auf 129Sv/Ev Stammhintergrund intraperitoneal und intranasal mit Cryptococcus neoformans (C. neoformans) infiziert. Dabei wurden die Unterschiede im Infektionsverlauf und in der Immunreaktion von Wildtyp-, IL-12p35-/- und IL-12p35/p40-/--Mäusen analysiert. Unterschiede zwischen den Wildtyp- und den IL-12p35-/--Mäusen lassen auf die Bedeutung von IL-12p75 schließen, wogegen Unterschiede zwischen IL-12p35-/-- und IL-12p35/p40-/--Mäusen auf die Rolle von IL-12p40 schließen lassen. Untersucht wurden sowohl die Erregerkonzentration in den Organen, Antigenspiegel im Blut, histologische Veränderungen und Serumantikörperkonzentrationen. Nach intraperitonealer Infektion war die Keimbelastung der Organe bei den Wildtyp-Mäusen geringer als bei beiden IL-12-/--Mausstämmen. Bei Wildtyp-Mäusen waren nicht nur weniger lebende Kryptokokken in den Organen zu finden, sondern auch weniger Kryptokokken Antigen im Serum als bei beiden IL-12-/--Mäusen nachweisbar. Das zeigt, dass IL-12p75 für die Kontrolle der intraperitonealen Infektion mit C. neoformans notwendig ist. IL-12p40 hatte ähnlich wie IL-12p75, wenn auch in etwas geringerem Masse, eine protektive Rolle bei der Erregerabwehr. Ohne IL-12p40 war eine Kontrolle der Infektion auf einem geringen Niveau der Keimbelastung nicht möglich. Besonders deutlich wurde dieses Phänomen beim Antigentiter bei den IL-12p35/p40-/--Mäusen. Durch das Fehlen von IL 12p40 wurde bei den IL-12p35/p40-/--Mäusen viel mehr Antigen über das Blut im Serum verteilt als bei den IL-12p35-/-- oder den Wildtyp-Mäusen. Die Wirtsreaktion bei einer Infektion mit C. neoformans geht mit der Bildung von Granulomen einher. Ohne IL-12p75 kam es zwar noch zur Bildung von Granulomen, diese zeigten aber eine veränderte zelluläre Zusammensetzung. Die IL-12p35/p40-/--Mäuse waren nicht zur Ausbildung von typischen Granulomen fähig. Bei ihnen kam es zu einer vermehrten Ansammlung von Kryptokokken fast ohne Entzündungszellen. IL-12p40 ist also für die Ausbildung einer zellulären Entzündungsreaktion notwendig. IL-12p40 ist auch für die Antikörperbildung gegen C. neoformans erforderlich. Die IL 12p35/p40-/--Mäuse waren kaum in der Lage, spezifische Antikörper gegen C. neoformans zu bilden. IL-12p75 ist für die Ausbildung einer Th1-Antwort notwendig. Infizierte Wildtyp-Mäuse produzierten doppelt soviel IgG2a, welches für ein Th1-Antwort typisch ist, wie die IL 12p35-/--Mäuse. Der intranasale Infektionsweg kommt der natürlichen aerogenen Infektion recht nahe. Deshalb wurde zusätzlich zur intraperitonealen Infektion - dieser Infektionsweg zur Untersuchung der Immunantwort gegen C. neoformans berücksichtigt. Auch bei intranasaler Infektion ist IL-12p75 für die Kontrolle der Keimbelastung der Organe notwendig. Interessanterweise war die Keimbelastung der Lunge bei den IL-12p35-/--Mäusen etwas höher als bei den IL-12p35/p40-/--Mäusen. Bei den Wildtypmäusen war die Dissemination der Kryptokokken aus der Lunge in die Milz und ins Gehirn gering. Ein Fehlen von IL-12p75 bewirkte allerdings eine Besiedlung besonders des Gehirns. Nach intranasaler Infektion kam es in der Lunge von Wildtyp-Mäusen zu atypischen Granulomen mit zentraler Einschmelzung von Gewebe und Kryptokokken. Diese Reaktion war bei den IL-12p35-/--Mäusen noch stärker ausgeprägt als bei den Wildtyp-Mäusen. Bei den IL-12p35/p40-/--Mäusen blieb eine Gewebsreaktion größerer Areale aus. Es waren nur eine Aktivierung des BALT zu sehen. IL-12p40 ist demnach auch nach intranasaler Infektion für eine zelluläre Entzündungsreaktion notwendig. Möglicherweise kann sich diese Eigenschaft von IL-12p40 bei intranasaler Infektion in einer immunpathologischen Reaktion äußern, die bei IL-12p35-/--Mäusen für eine massive Infiltration der Lunge mit Entzündungszellen verantwortlich ist. Der Gehalt an Kryptokokken-spezifischen Antikörpern war nach intranasaler Infektion fünf- bis zehnmal höher als nach intraperitonealer Infektion. Der intranasale Infektionsweg zeigte also eine wesentlich ausgeprägtere humorale Antwort. Der Typ der Immunantwort schien sich im Gegensatz zur intraperitonealen Infektion in Richtung Th2 (d. h. verstärkte Antikörperbildung) verschoben zu haben. Sowohl nach intraperitonealer wie auch nach intranasaler Infektion mit C. neoformans lassen sich die immunstimulatorischen Aktivitäten von IL-12p75 und von IL-12p40 nachweisen, auch wenn diese sich in Abhängigkeit vom Infektionsweg etwas unterschiedlich manifestieren<br>To analyse the role of interleukin-12p75 (IL-12p75) and interleukin-12p40 (IL-12p40) in the defence against Cryptococcus neoformans (C. neoformans) a murine infection model was established and studied. Mice of wild-tpye 129Sv/Ev background as well as IL-12p35-/- and IL-12p35/p40-/- 129Sv/Ev mice were infected intraperitoneally or intranasally with C. neoformans. The differences between the immune response of these genotypes were analysed. Comparing wild-type and IL-12p35-/--mice allows for conclusions related to the importance of IL-12p75, comparing IL-12p40-producing IL-12p35-/- mice with IL-12p35/p40-/- mice shows the importance of IL-12p40. Fungal organ burden, serum antigen levels, inflammatory cell responses, and antibody production were examined. The fungal organ load in wild-type mice was smaller than in both mutant IL-12-/--mice. In wild-type mice fewer cryptococci were found in organs and less cryptococcal antigen in serum than in IL-12p35-/- and IL-12p35/p40-/- mice. This underlines the importance of IL 12p75 for the control of the infection with C. neoformans. In addition, IL-12p40 was found to have a similar but weaker role as IL-12p75 in protection against C. neoformans. In the absence of IL-12p40 IL-12p35/p40-/- mice developed higher antigen titers than IL-12p35-/- and wild-type mice. The host response against infection with C. neoformans is associated with granuloma formation. Recruitment of inflammatory cells to granulomas was altered in the absence of IL 12p75. In addition, IL-12p40 contributed significantly to granuloma formation since IL 12p35/p40-/- mice developed no or only very poor granulomatous responses. Therefore, IL 12p40 is required for inflammatory cell responses. IL-12p40 was also found to be required for antibody production against C. neoformans. Infected IL-12p35/p40-/--mice had only very low levels of specific antibodies against C. neoformans. IL-12p75 is known to be essential for protective Th1 response against intracellular microorganisms. Th1 responses are commonly associated with the production of IgG2a. Infected wild-type mice produced 2-fold higher IgG2a levels than IL-12p35-/--mice. To adapt the infection model more to the natural infection mode the intraperitoneal infection route was changed to an intranasal route. Following intranasal infection IL-12p75 also proved to be necessary for control of the fungal organ load. Interestingly the organ load was higher in IL-12p35-/--mice than in IL-12p35/p40-/-mice which suggest a role of IL-12p40 in cell recruitment. Following intranasal application of cryptococci fungal dissemination to spleen and brain was reduced as compared to the intraperitoneal infection route. Without IL-12p75 dissemination of C. neoformans to the brain occured. This shows that IL-12p75 is involved in control of dissemination from lung to brain. The inflammatory response of IL-12p35-/--mice was stronger than the tissue response of wild-type mice. The massive tissue reactions of IL-12p35-/--mice caused big areas of diffuse cellular infiltration in their lungs. In IL-12p35/p40-/--mice inflammatory responses could be observed only in the peribronchial tissue. This shows that IL-12p40 is not only needed for a cellular inflammatory response following intraperitoneal but also following intranasal infection. Following intranasal infection IL-12p40 can induce immunopathological effects. Intranasal infection of mice with C. neoformans resulted in five to ten times higher antibody responses than intraperitoneal infection. This suggests that intranasal infection of mice results in a more Th2-biased humoral response. In summary, these experiments show that besides IL-12p75 also IL-12p40 contributes to cellular immunity against C. neoformans. The immunostimulatory properties of both, IL 12p75 and IL-12p40, can be observed after intraperitoneal and intranasal infection routes with similar but also distinct manifestations
15
Suri, Deepak. "Non-cytolytic control of hepatitis virus replication and the role of interleukin-12(IL-12)." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411248.
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D'Avila, Tiago Landim. "Administração de plasmídeos codificantes de IL-12 e IL-1 em cães e expressão de IL- 12 em células de inseto por baculovírus recombinante." reponame:Repositório Institucional da FIOCRUZ, 2011. https://www.arca.fiocruz.br/handle/icict/4317.
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Previous issue date: 2011<br>Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, Bahia, Brasil<br>A interleucina-12 (IL-12) é uma glicoproteína heterodímerica, codificada por dois
genes distintos co-expressados na mesma célula. IL-12 precisa ser glicosilada para
exibir atividade funcional. Essa glicoproteína promove a diferenciação de células T e
é capaz de estimular a proliferação de células T ativadas e células NK. Além disso,
IL-12 promove a produção IFN-γ por células NK e o aumento da atividade lítica de
células NK e linfócitos T CD+ citotóxicos. Várias das atividades de IL-12 são
desempenhadas ou são amplificadas pela associação com IL-2. Em nosso
laboratório, foi gerada uma construção plasmideal capaz de expressar IL-12 canina,
na forma de proteína de fusão de cadeia única (pcDNA3.1-scca-IL-12), e outra
construção plasmideal capaz de expressar IL-2 canina (pcDNA3.1-ca-IL-2) em
células de mamífero. Experimentos preliminares, a combinação de IL-12 e IL-2
expressas em sobrenadantes de células COS-7 mostrou-se capaz de promover
produção de IFN-γ em células mononucleares de sangue periférico (CMNSP) de
cães sadios. Visando a avaliação do potencial do uso de IL-12 e/ou IL-2 para o
desenvolvimento de vacina ou método imunoterapico, no presente trabalho, grupos
de cães sadios foram injetados três vezes, com intervalo de 2 dias entre cada duas
doses consecutivas, com plasmídeo pcDNA3.1-scca-IL-12 e/ou pcDNA3.1-ca-IL-2
por via muscular por eletroporação. Em seguida, os cães foram submetidos à
avaliação clinica, clinico-laboratorial (hemograma, determinação da concentração de
transaminases, proteínas, ureia e creatinina no soro) e ensaios foram realizados
para a detecção da expressão das proteínas recombinantes (sensibilização de
CMNSP para produção de IFN-γ e determinação da concentração de IL-2 no soro).
Não foram observadas diferenças nos parâmetros avaliados entre os grupos de
animais. Visando a produção de IL-12, células BTI-Tn-5B1-4 foram infectadas com
baculovírus recombinante contendo cDNA scca-IL-12 e capazes de adicionar uma
cauda de 6 histidinas na extremidade carboxila. Para isso, duas construções
diferentes em baculovírus foram elaboradas nosso laboratório, sendo uma delas no
presente trabalho. Células BTI-Tn-5B1-4 infectadas com as construções em
baculovírus apresentaram a proteína recombinante: a) parcialmente degradada e em
grande quantidade no sedimento celular e b) integra e em baixa quantidade no
sobrenadante da cultura; de acordo com os resultados de obtidos por SDS-PAGE e
Western blot.<br>Interleukin-12 (IL-12) is a heterodimeric glycoprotein, encoded by two distinct genes
co-expressed in the same cell. IL-12 needs to be glycosylated to display functional
activity. This glycoprotein promotes differentiation of T cells and is capable of
stimulating proliferation of activated T cells and NK cells. In addition, IL-12 promotes
IFN-γ production by NK cells and increased lytic activity of NK cells and cytotoxic Tlymphocyte
CD +. Several of the activities of IL-12 are held or amplified by the
association with IL-2. In our laboratory, a plasmideal construction was generated to
express canine IL-12 like single-chain fusion protein (pcDNA3.1-scca-IL-12), and
other construction to express canine IL-2 (pcDNA3.1-CA-IL-2) in mammalian cells.
Preliminary experiments, the combination of IL-12 and IL-2 supernatants expressed
in COS-7 cells was able to promote IFN-γ in peripheral blood mononuclear cells
(PBMC) of healthy dogs. To assess the potential of using IL-12 and/or IL-2 for the
development of vaccine or immunotherapy method, in this study, groups of healthy
dogs were injected three times with an interval of 2 days between each two
consecutive doses with plasmid pcDNA3.1-scca-IL-12 and/or pcDNA3.1-ca-IL-2
intramuscularly by electroporation. Then the dogs were submitted to clinical
evaluation, clinical and laboratory (blood count, determination of the concentration of
transaminases, proteins, urea and serum creatinine) and tests were performed to
detect the expression of recombinant proteins (PBMC sensitization to produce IFN-γ
concentration and determination of serum IL-2). No differences were observed in all
evaluated parameters between the groups of animals. Aiming the production of IL-12
cells, BTI-Tn-5B1-4 were infected with recombinant baculovirus containing cDNA
scca-IL-12 and capable of adding a tail of 6 histidines at the carboxyl end. For this,
two different constructs were prepared in our laboratory baculovirus, one of them in
this work. Cells BTI-Tn-5B1-4 infected with the constructs presented in the
recombinant baculovirus: a) partially degraded in large quantities in the sediment cell
and b) incorporates and in low quantities in the culture supernatant, according to the
results obtained by SDS-PAGE and Western blo
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Rietschoten, Johanna Goverta Ingeborg van. "Transcriptional regulation of the human interleukin-12 receptor ß2 gene." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2002. http://dare.uva.nl/document/66510.
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Fu, Hangfei. "Interleukin 35 inhibits ischemia-induced angiogenesis essentially through the key receptor subunit Interleukin 12 receptor beta 2." Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/546609.
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Biomedical Sciences<br>Ph.D.<br>Peripheral arterial disease (PAD) is a worldwide disease caused by atherosclerosis. It is a circulatory condition where narrowed blood vessels reduce blood flow to the peripheral such as legs. Although current gold standard treatment for advanced PAD patients is still based on surgical revascularization, there is no effective therapy for many patients that are not suitable for surgery. In addition, better recovery from surgical revascularization largely relies on angiogenesis in the adjacent ischemic tissue. Thus, novel pro-angiogenic therapies to improve post-ischemic neovascularization are urgently desired. However, current poor understanding of the roles of anti-inflammatory cytokines in angiogenesis prevents the development of these new therapies. We and others have reported that IL-35 is a newly identified inducible immunosuppressive heterodimeric cytokine in the IL-12 family. IL-35 is composed of p35 (IL-12A) and EBI3, and its receptors are comprised of homodimers or heterodimer of IL-12Rb2 and gp130 (IL-6ST). We have shown that IL-35 inhibits endothelial cell (EC) activation induced by lipopolysaccharide (LPS) or atherogenic lysophosphatidylcholine (LPC). At least partially through these new EC-dependent mechanisms, IL-35 inhibits inflammation in autoimmune diseases, infectious diseases, atherosclerosis, and tumors. Recent studies have indicated the role of IL-35 in angiogenesis in rheumatoid arthritis and different tumors. However, whether and how IL-35 regulates post-ischemic angiogenesis in peripheral artery disease are unrevealed. In our study, we used hindlimb ischemia (HLI) and Matrigel plug assay as in vivo angiogenesis models and wound healing assay as in vitro angiogenesis model to study the role and underlying mechanisms of IL-35-mediated angiogenesis. We made the following findings: 1) muscle in human and mouse has high angiogenic potential in physiological conditions; 2) angiogenic cytokines and chemokines including anti-inflammatory cytokines are predominantly regulated by inflammatory transcription factors; 3) IL-35 signaling is induced in ischemic muscle; 4) IL-12Rb2, but not IL-6ST, is the key receptor component of IL-35 signaling in ischemic muscle and hypoxic human microvascular endothelial cells (HMVECs); 5) hyperlipidemia (atherogenic factor) impairs angiogenesis in vivo and in vitro, which partially acts through the induction of IL-35; 6) IL-12Rb2 deficiency improves HLI-induced angiogenesis in both WT or apolipoprotein E (ApoE) -/- mice (an atherosclerosis model); 7) IL-35 injection inhibits HLI-induced angiogenesis in WT mice but not that in the IL-12Rb2 deficient mice; 8) IL-35 injection enlarges the avascular area in gastrocnemius muscle after HLI; 9) IL-35 obstructs fibroblast growth factor-2 (FGF2)-induced angiogenesis in Matrigel plug assay in vivo; 10) CD45-CD31+ ECs from the IL-35-injected ischemic muscle at day 14 of HLI have an abnormal extracellular matrix organization, activated integrin pathways (cell-matrix adhesions), disrupted vascular endothelial (VE)-cadherin-plakoglobin complex (cell-cell adhesions), and increased infiltration and migration of bone marrow-derived leukocytes; 11) IL-35 inhibits HMVEC migration in wound healing assay in vitro presumably through upregulation of anti-angiogenic proteins including pigment epithelium-derived factor (PEDF), serpin family B member 5 (SERPINB5, Maspin), and thrombospondin (THBS)-1. These results suggest that anti-inflammatory cytokine IL-35, signaling through the key receptor subunit IL-12Rb2, inhibits HLI-induced angiogenesis and delays tissue repair by dysregulating cell-cell and cell-matrix adhesions, which leads to the impaired vascular adhesion junction and maturation of blood vessels.<br>Temple University--Theses
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Gedge, Vicki L. "Natural killer cell responses to exercise : changes in cellular activation and/or distribution /." [St. Lucia, Qld.], 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16841.pdf.
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Renton, Louise Margaret. "Studies of some antiparasitic agents." Thesis, University of St Andrews, 1997. http://hdl.handle.net/10023/13992.
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Each year, between 300 and 500 million people develop malaria. Close to 3 million people die as a result. Due to resistance there are now few drugs left which are effective against malaria; one is a Chinese herbal remedy called qinghaosu (artemisinin). A section of this thesis represents an attempt to understand further the mode of action of this antimalarial agent. Several mechanisms involving iron have been proposed and the main categories reviewed (chapter 3). Techniques including ESR spectrometry, fluorescence and absorbance measurements were used to further probe the mode of action of qinghaosu. The findings of these studies provide support for a mechanism proposed by Wu et al., involving cleavage of the peroxy bridge in qinghaosu with the ferrous ion as opposed to antimalarial activity being due to the generation of high valent iron-oxo species. The ether derivative of qinghaosu, arteether has been studied using 2D NMR in order to provide further insight into the unusual structure of this compound (chapter 4). A comparison of the sp2 lactone functionality in qinghaosu with the sp3 ether group in arteether was performed. Evidence is presented for different conformations and chemical shift values. The immune system protects the human body from invasion by foreign substances or cells. A key part of this immune response comes from cellular components known as macrophages. The killing process of macrophages appears to involve nitric oxide. However, this natural defence mechanism is not very efficient as the body is susceptible to invasion by microbes. The term microbe includes both parasites and bacteria. The toxicity of nitric oxide (NO) and NO donor compounds has been investigated using the bacterium E. coli (chapter 5). In addition, studies have been performed using parasites. Malarial parasites (Plasmodia) are difficult to culture, therefore Leishmania parasites which cause the tropical disease leishmaniasis were used as a model (chapter 6). Evidence is presented for the toxic nature of NO donor compounds towards both parasites and bacteria. However, qinghaosu and its derivatives did not prove effective against Leishmania mexicana parasites in contrast with their reported antimalarial activity. The conclusions of this study suggest that qinghaosu possesses a toxicity mechanism selective for malarial parasites.
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Harker, Rosamond. "The role of interleukin-12 (IL-12) in respiratory syncytial virus disease in BALB/c mice." Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394681.
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Frellstedt, Linda. "Induction and characterization of endotoxin tolerance in equine peripheral blood mononuclear cells in vitro." Thesis, Virginia Tech, 2010. http://hdl.handle.net/10919/44307.
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Endotoxemia is responsible for severe illness in horses. Individuals can become unresponsive to the endotoxin molecule after an initial exposure; this phenomenon has been called developing a state of â endotoxin toleranceâ (ET). ET has been induced in horses in vivo; however, cytokine expression associated with ET has not been investigated. The purpose of this study was to develop and validate a method for inducing ET in equine peripheral blood mononuclear cells (PBMCs) in vitro, and to describe the cytokine profile which is associated with the ET. <p>
Blood was collected from 6 healthy horses and PBMCs were isolated. ET was induced by culturing cells with three concentrations of endotoxin given to induce ET, and evaluated after a second dose of endotoxin given to challenge the cells. The relative mRNA expression of IL-10 and IL-12 was measured by use of quantitative PCR. <p>
ET was induced in all cells (n=6) exposed to the 2-step endotoxin challenge. In PBMCs treated with 1.0 ng/ml of endotoxin followed by challenge with 10 ng/ml of endotoxin, the relative mRNA expression of IL-10 in tolerized cells was not different from positive control cells. In contrast, the relative mRNA expression of IL-12 in tolerized cells was decreased by 15-fold after the second endotoxin challenge compared with positive control cells. <p>
This experiment demonstrated a reliable method for the ex vivo induction of ET in equine PBMCs. A marked suppression of IL-12 production is associated with ET. The production of IL-10 was not altered in ET in our model.<br>Master of Science
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Bacon, Christopher M. "Lymphocyte regulation and JAK-STAT signal tranduction by interleukin-12 : comparison with interleukin-2 and other related cytokines." Thesis, University of Sheffield, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301669.
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Becker, Christoph. "Die Regulation des Interleukin-12-p40-Promotors in Monozyten und Makrophagen." [S.l.] : [s.n.], 2000. http://ArchiMeD.uni-mainz.de/pub/2001/0100/diss.pdf.
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Schardt, Victor [Verfasser], and Ernst Rainer [Akademischer Betreuer] Weissenbacher. "Vergleichende Untersuchungen zur Hefepilzbesiedelung von Mundhöhle und Vagina und Bestimmung von Interleukin-4, Interleukin-10 und Interleukin-12 / Victor Schardt. Betreuer: Ernst Rainer Weissenbacher." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1032862645/34.
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劉鐵夫 and Tiefu Liu. "The role of interleukin-12 in the pathogenesis of human systemic lupuserythematosus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1998. http://hub.hku.hk/bib/B31237459.
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Howes, A. F. "The regulation of interleukin-10 and interleukin-12 in macrophages : investigating the differential regulation of IL-10 and IL-12 in C57BL/6 and BALB/c mice." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1409974/.
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Pattern recognition receptors (PRR) detect microbial products and induce cytokines which shape the immunological response. Interleukin-12 (IL-12) is a proinflammatory cytokine important for the differentiation of T helper 1 (Th1) cells which produce IFN-γ to activate macrophages and eradicate intracellular pathogens. In contrast, interleukin-10 (IL-10) is an immunosuppressive cytokine that minimises immune-driven host pathology, but can also lead to defective pathogen clearance. The regulation of IL-10 and IL-12 is therefore of interest due to their central roles in the orchestration of an effective but regulated immune response. C57BL/6 and BALB/c mice differ significantly in their resistance to several pathogens. We observed that macrophages generated from these mice produce reciprocal levels of IL-10 and IL-12 in response to the bacterial ligands LPS and Pam3CSK4, which activate TLR4 and TLR2 respectively, and heat-killed Burkholderia pseudomallei, a Gram-negative bacterium which activates TLR2 and TLR4. We have investigated this differential cytokine production in order to further dissect the molecular mechanisms underlying the regulation of IL-10 and IL-12. Detailed analyses of protein production, signal transduction and transcriptional kinetics have identified a type I IFN dependent, but IL-27 independent mechanism for the differential production of IL-10 in LPS and heat-killed B.pseudomallei stimulated C57BL/6 and BALB/c macrophages. Microarray analysis of LPS stimulated C57BL/6 and BALB/c macrophages further revealed potential regulatory networks that may differ between these mouse strains. These findings highlight key pathways responsible for the regulation of IL-10 and IL-12, and may provide valuable information on factors contributing to the ability of C57BL/6 and BALB/c mice to clear bacterial infections.
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Costa, Sidnei Ferro. "Estimulação combinada de IL-12 e IL-15 promove a resposta imune celular em cães com leishmaniose via IFN-y /." Araçatuba, 2019. http://hdl.handle.net/11449/182241.
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Orientador: Valéria Marçal Felix de Lima<br>Resumo: A Leishmaniose Visceral (LV) é causada nas Américas, pelo protozoário intracelular obrigatório Leishmania infantum e os cães domésticos são os principais reservatórios urbanos do parasita e em áreas endêmicas, o aumento da LV em humanos tem sido associado ao aumento da infecção canina. Os atuais medicamentos disponíveis para a Leishmaniose Canina (CanL) não são completamente eficientes e meses após o tratamento a maioria dos cães apresentam recidiva, indicando a necessidade de buscar formas alternativas de tratamento. Na CanL, cães desenvolvem uma resposta imune celular (Th1) ineficiente para combater o parasita e a estimulação das vias de citocinas em células de defesa com proteínas recombinantes, tem o potencial de se tornar parte de métodos imunoterapêuticos eficazes. Neste estudo, as citocinas recombinantes caninas (IL-12, IL-2, IL-15 e IL-7) e o receptor solúvel de IL-10R1 (sIL-10R1), com atividade antagonista, foram avaliadas pela primeira vez em combinações (IL-12/IL- 2, IL-12/IL-15, IL-12/sIL-10R1, IL-15/IL-7) ou isoladamente (sIL-10R1) quanto à capacidade imunomodulatória em células mononucleares do sangue periférico (sigla em inglês PBMC) de cães com leishmaniose. Todas as combinações de proteínas recombinantes testadas mostraram melhorar a resposta linfoproliferativa. Além disso, as combinações de IL-12/IL-2 e IL-12/IL-15 promoveram a diminuição na expressão da proteína “Programed Cell Death 1” (PD-1) nos linfócitos. Estas mesmas combinações de citocinas e IL-12/sI... (Resumo completo, clicar acesso eletrônico abaixo)<br>Abstract: Visceral Leishmaniasis (LV) is caused in the Americas by the obligate intracellular protozoan Leishmania infantum and domestic dogs are the major urban reservoirs of the parasite and in endemic areas, and increase LV in humans has been associated with increased canine infection. The current medications available for Canine Leishmaniasis (CanL) are not completely effective and months after treatment most dogs present with relapse, indicating the necessity to looking for alternative forms of treatment. In CanL, dogs develop an ineffective cellular immune response (Th1) to combat the parasite. Then, the stimulation of cytokine pathways in defense cells with recombinant proteins, has the potential to become part of effective immunotherapeutic methods. In this study, the canine recombinant cytokines (IL-12, IL-2, IL-15 and IL-7) and the soluble receptor of IL-10R1 (sIL-10R1) with antagonistic activity, were evaluated for the first time in combinations IL-12/IL-2, IL-12/IL-15, IL12/sIL-10R1, IL-15/IL-7) or alone (sIL-10R1) for their immunomodulatory capacity in peripheral blood mononuclear cells (PBMC) from dogs with leishmaniasis. All combinations of recombinant proteins tested were shown to improve lymphoproliferative response. Further, combinations of IL-12/IL-2 and IL-12/IL-15 promoted decrease in programmed cell death protein 1 (PD-1) expression in lymphocytes. These same combinations of cytokines and IL-12/casIL-10R1 induced IFN-y production in PBMC. Furthermore, the combinat... (Complete abstract click electronic access below)<br>Mestre
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Entleutner, Markus Jörg Michael. "Die Rolle von Interleukin-12 und Interleukin-18 bei bakterieller Peritonitis in dem Mausmodell "Colon-Ascendens-Stent-Peritonitis" (CASP)." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=964490595.
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Rao, Vittal Sree Rama. "Significance of interleukin-10 and interleukin-12 levels in breast cancer patients and their possible role in tumour immunology." Thesis, University of Hull, 2006. http://hydra.hull.ac.uk/resources/hull:16056.
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Patients with cancer are thought to have significant impairment of the immune system. One of the manifestations is believed to be skewing of the cytokine profile in favour of the immunosuppressive Th2 cytokine family as opposed to the immunofacilitatory Th1 cytokine family. In this MD thesis, a prospective study was undertaken to determine whether this occurred in breast cancer patients. IL-IO (representing the Th2 cytokine family) and IL-12 (representing the Th1 cytokine family) levels in the serum, IL-12 production capability of peripheral blood mononuclear cells (PBMC) along with the levels of IL-to and IL-12 in the tumour microenvironment as detected by immunohistochemistry were determined in breast cancer patients and compared with levels in healthy volunteers. No difference in serum IL-to and IL-12 levels or IL-12 production capability of PBMC was noted between breast cancer patients and controls. Among the known prognostic factors (tumour size, grade, lymph node involvement and oestrogen receptor status), grade was found to be inversely related to serum IL-12 levels (by univariate and multivariate analysis; P=O.045). No significant association between these prognostic factors and IL-IO levels were noted. Immunohistochemistry revealed mild to intense staining for IL-IO in the tumour vicinity, but in the case of IL-12, the staining was inconclusive. The effect of therapy on the levels of IL-IO and IL-12 was also investigated. Following surgical excision, serum IL-IO levels and IL-12 production capability of PBMC did not show significant change. However, serum IL-12 levels were significantly elevated after surgery raising the possibility of a partial skewing of the immune response in favour of the Th1 cytokine profile (Wilcoxon signed ranks test, P=O.OOl). After completion of adjuvant therapy (chemotherapy and/or radiotherapy), serum IL-IO levels again did not show any significant change, but serum IL-12 levels showed a downward trend which may be due to the immunosuppressive effect of the adjuvant therapy (Wilcoxon signed ranks test, P=O.06). In conclusion, this study did not find any evidence of Th2 bias as a manifestation of immune suppression in breast cancer patients. The change in serum IL-12 levels following surgery and adjuvant therapy is interesting and may reflect a change in immune status following the therapeutic interventions. The significance of this must be elucidated by studies with long term follow-up before definite conclusions can be made.
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Bauer, Julia [Verfasser], та Tobias [Akademischer Betreuer] Weissenbacher. "Die Bestimmung der Zytokine Interleukin-23, Interleukin-17a, Interleukin-12, Interleukin-10, Interleukin-6, Tumor-Nekrose-Faktor-α und MIP-1β im Vaginalsekret und deren Bedeutung im Rahmen der Frühgeburtlichkeit / Julia Bauer ; Betreuer: Tobias Weissenbacher". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/1128074052/34.
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Klenk, Erin Ingersoll. "Endoplasmic Reticulum Stress and the Unfolded Protein Response Result in Synergistic Upregulation of Interleukin-23 and Interleukin-12 by LPS." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1250092843.
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Bechara, Rami. "Étude de la coopération entre les cellules dendritiques et les lymphocytes T dans les allergies aux produits chimiques et aux médicaments." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS474/document.
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Les allergies aux produits chimiques et aux médicaments constituent un problème majeur de santé publique. L’objectif de ce travail est de mieux comprendre l’interaction entre les cellules dendritiques (DC) et les lymphocytes T (LT) dans les allergies induites par les haptènes métalliques (nickel et cobalt) et les médicaments [benzylpénicilline (BP)]. En présence des signaux de danger, les DC acquièrent un phénotype dit « mature » et présentent l’antigène apprêté aux LT spécifiques de cet antigène. Les LT représentent les cellules effectrices responsables d’une manière directe ou non des symptômes observés lors des réactions allergiques. Dans un premier temps, nous montrons que le nickel est capable d’induire un ratio d’interleukines (IL) IL-23/IL-12p70 élevé dans les DC favorisant ainsi la polarisation Th17 qui est détectée chez la majorité des patients allergiques au nickel. Nous montrons aussi pour la première fois une production de l’IL-27 par les DC activées par le nickel. Nous avons ensuite montré l’implication du TLR4 et de la voie Jak-STAT dans la régulation des cytokines membres de la famille de l’IL-12. L’activation de la voie Jak-STAT est nécessaire pour la réponse Th1 en favorisant la production de l’IL-12p70 et en inhibant la production de l’IL-23 par les DC activées par du nickel. Par ailleurs, nous avons identifié et, pour la première fois, une activation du facteur de transcription NFIL-3, au sein des DC, par le nickel et le cobalt voire d’une manière plus intense avec ce dernier. D’autre part, nous avons mis en évidence l’existence d’un répertoire de LT naïfs CD4+ et CD8+, provenant de la population générale, spécifiques du nickel. L’activation de ces LT requiert les molécules du complexe majeur d’histocompatibilité (CMH) et ils présentent un faible taux de réactivité croisée avec le cobalt. Simultanément, nous avons mis en évidence la possibilité de détecter des LT naïfs CD8+ spécifiques de la BP. L’activation de ces LT dépend des molécules du CMH de classe I et du protéasome. D’une manière générale, notre travail contribue à une meilleure compréhension des mécanismes des réactions allergiques d’une part, en montrant la fine régulation des cytokines membres de la famille de l’IL-12 dans les DC et d’autre part en élucidant les mécanismes de l’immunisation contre les molécules allergisantes<br>Drug and chemical allergy is a major public health concern. The aim of this work is to understand the interaction between dendritic cells (DCs) and T-lymphocytes (LT) in allergic manifestations induced by metallic haptens (nickel and cobalt) and benzylpenicillin (BP). DCs capture the antigen, start maturation, migrate to the regional lymph node and activate hapten-specific T-cells. The latter will represent the effector cells responsible directly or not for the symptoms observed during allergic reactions. We showed that nickel induced a high ratio of interleukin (IL) IL-23 compared to IL-12p70 in DCs leading to Th17 polarization as seen in allergic patients. We also showed for the first time the production of IL-27 by nickel-activated DCs. Moreover, we showed the involvement of TLR4 and Jak-STAT pathways in IL-12 cytokine family regulation. The activation of the Jak-STAT pathway seems to maintain the IL-23/IL-12p70 balance by limiting IL-23 production and promoting Th1 polarization. Furthermore, we identified for the first time the activation of NFIL-3 in DC by nickel and cobalt, more intensely with the latter. In addition, nickel-recognizing CD4+ and CD8+ naïve T-cells repertoire was identified from the general population. These positive T-cells were shown to recognize nickel in the context of major histocompatibility complex (MHC) molecules. We also showed that a low frequency of nickel-recognizing CD4+ naïve T-cells cross-reacted with cobalt. Simultaneously, we showed the possibility of detecting a naïve CD8+ T-cells repertoire for BP. The activation of these specific T-cells requires MHC class I molecule and proteasome. In resume, our work contributes to a better understanding of allergic reactions, on one hand, by studying the fine regulation of the IL-12 cytokines family in DCs and on the other hand, by clarifying the mechanisms of immunization against drugs and chemicals
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Kelleher, William Peter. "The influence of interleukin-12 and Rauscher leukaemia virus on dendritic cell function." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.402485.
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Liu, Tiefu. "The role of interleukin-12 in the pathogenesis of human systemic lupus erythematosus /." Hong Kong : University of Hong Kong, 1998. http://sunzi.lib.hku.hk/hkuto/record.jsp?B20381505.
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Li, Lijin. "Immunopathology of Coccidioidal Granulomata and the Regulation of Interleukin-12 Signal Transduction in Human Coccidioidomycosis." Diss., The University of Arizona, 2005. http://hdl.handle.net/10150/193826.
Texte intégralRésumé :
Coccidioidomycosis is a growing problem in the United States. There is still an incomplete understanding of the immunological response associated with human coccidioido-mycosis, although previous studies have indicated that cell-mediated immunity (CMI) is critical in the control of this disease. We have examined necrotizing pulmonary coccidioidal granulomata using immunohistochemical staining for lymphocyte subsets and for the cytokines interleukin-10 (IL-10) and gamma interferon (IFN-?). Discrete perigranulomatous lymphocytic clusters were identified containing roughly equal numbers of T (CD3+) and B (CD20+) lymphocytes. While the number of cells expressing IL-10 was similar in the mantle and in the perigranulomatous clusters, there were significantly more cells expressing IFN-? in the mantle compared to the clusters (P = 0.037). Confocal microscopy revealed that CD4+ T lymphocytes and B lymphocytes are associated with IL-10 production. CD4+CD25+ T lymphocytes were also identified in the perigranulomatous clusters but were not associated with IL-10 production. This is the first report noting perigranulomatous lymphocyte clusters and IL-10 in association with human coccidioidal granulomata, suggesting a down-regulation of cellular immune response.IL-12 is critical in driving a T helper type 1 (Th1) immune response. To understand the mechanism associated with hyporesponsiveness to IL-12 stimulation seen in some anergic patients with disseminated coccidioidomycosis, IL-12 receptor expression and function were determined in PBMCs from immune and nonimmune healthy donors. By using a relative quantitative RT-PCR technique, we found that IL-12R?1 is constitutively expressed in PBMCs and is equally up-regulated by coccidioidal antigen preparation T27K in both immune and nonimmune donors. On the other hand, the IL-12R?2 expression level is increased by T27K only in PBMCs from immune but not nonimmune donors. In addition, the increased IL-12R?2 expression in immune PBMCs is correlated with Stat4 activation and the induction of IFN-? production by IL-12. These data suggest that the IL-12R?2 expression and signal transduction is functional in host immunity against Coccidioides infection. Subsequent research, which involved the stimulation of lymphocytes with autologous dendritic cells (DCs) pulsed with T27K, revealed that the up-regulation of IL-12R?2 expression and signal transduction is associated with the induction of IFN-? production by DCs pulsed with T27K.
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Alkayyal, Almohanad. "Exploiting the Antitumor Immune Response Using IL-12 Armed Oncolytic MG1 Virus In An Infected Cell Vaccine." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/35599.
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Despite improvements in chemotherapy and radical surgical debulking, peritoneal carcinomatosis (PC) remains among the most common causes of death for abdominal cancers. Immunotherapies have demonstrated efficacy in selected solid malignancies but their potential in PC is poorly explored. Here I report that intraperitoneal injection of an infected cell vaccine (ICV), consisting of autologous tumor cells infected ex-vivo with an oncolytic Maraba MG1 virus expressing interleukin-12 (IL-12), promotes the migration of activated natural killer (NK) cells to the peritoneal cavity in response to the secretion of interferon gamma-induced protein-10 (IP-10) from dendritic cells. This recruitment of cytotoxic, IFNγ-secreting NK cells is associated with a dramatic reduction in tumor burden and improved survival in a colon cancer model of PC. Even in mice with bulky PC (tumors >8 mm), a complete radiological response was demonstrated within 8-14 weeks, associated with 100% long-term survival. Importantly, these results were recapitulated in human lymphocytes exposed to human tumor cell lines infected with MG1-IL12. Finally, I demonstrate that MG1-IL12-ICV generates an effective CD4 and CD8 T cell response in mice following prophylactic immunization associated with the maturation of peritoneal dendritic cells and enrichment of tumor-specific peritoneal T cells. The research presented in this thesis suggests that an MG1-IL12-ICV is a promising therapy that could provide benefit to the thousands of patients diagnosed with PC each year.
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Schnabel, Christiane Liliane [Verfasser]. "Acute immune response of healthy horses to linear DNA encoding Interleukin 12 and Interleukin 18 complexed with SAINT-18 / Christiane Liliane Schnabel." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2015. http://d-nb.info/1073931110/34.
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O'Hara, Richard James. "Interleukin-12 a pivotal cytokine in cell mediated immunity : the role in colorectal cancer." Thesis, University of Hull, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395426.
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Holanda, Flávia Mendes da Cunha. "Estudo da associação entre paracoccidioidomicose e os polimorfismos dos genes IL12B (posição 3' UTR+1188 A/C), IL12RB1 ( posição 11014 A/G no éxon 7) e IFNG ( posição + 874 T/A)." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5134/tde-02052016-141504/.
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Introdução. A paracoccidioidomicose (PCM) é uma micose sistêmica crônica, endêmica na América Latina, principalmente Brasil, sendo a oitava causa de morte entre as doenças infecciosas crônicas recorrentes. A PCM infecção é caracterizada por uma resposta Th1, a forma aguda por um perfil misto da resposta Th2/Th9, enquanto na forma crônica caracteriza-se pelo perfil Th17/Th22. A ocorrência e gravidade da PCM humana podem também estar associadas a fatores genéticos como os polimorfismos dos genes de citocinas. Objetivos. 1. Descrever a frequência dos polimorfismos de (SNPs) IFNG +874 T/A, IL12B 3\' UTR +1188 A/C e IL12RB1 11014 A/G no éxon 7 em pacientes e controles; 2. Investigar a associação entre esses polimorfismos e as diferentes formas clínicas da micose; 3. Verificar se há associação entre esses polimorfismos e a secreção das citocinas IFN-y, IL-12p40 e IL-12p70. Materiais e Métodos. 143 pacientes com PCM foram incluídos (40 com a forma aguda, 100 com a forma crônica multifocal e 17 unifocal). Critérios de inclusão: ter doença ativa (DA) comprovada por exame micológico ou histopatológico positivo ou presença de anticorpos anti-Paracoccidioides brasiliensis (>= 1/32 por contraimunoeletroforese) ou ter doença curada/tratada (CT) quando comprovada anteriormente pelos critérios de DA e atualmente com títulos de anticorpos estáveis e <= 4 em dois períodos com intervalo >= 6 meses. Analisaram-se os SNPs IFNG pela técnica de PCR-ARMS (\"Polymerase Chain Reaction - Amplification Refractory Mutational System\"), IL12B e IL12RB1 por RFLP (\"PCR-Restriction Fragment Lenght Polymorphism\"). Para a dosagem de citocinas foram utilizadas as técnicas de ELISA (n=29) e CBA (\"Cytometric Bead Array\"; n= 18), sendo considerados estatisticamente significantes, os valores de p < 0,05 para os testes de x2 e o teste de Kruskal-Wallis, com pós-teste de Dunn. Resultados. O genótipo AA do SNP IL12RB1 foi mais frequente na forma crônica multifocal e o genótipo AG, na forma unifocal masculina (p= 0,048). À análise desta forma clínica entre ambos os sexos, o genótipo AG foi também mais frequente no sexo masculino (p= 0,009). Segundo a etnia, foi demonstrada diferença estatisticamente significante nas frequências dos genótipos e alelos dos SNPs IFNG e IL12RB1 (p < 0,05). Em relação às formas clínicas da PCM, houve similaridade nas frequências dos genótipos e alelos dos SNPs estudados. Quanto aos níveis das citocinas, para os SNPs IFNG, IL12B e IL12RB1, maiores níveis de secreção de citocinas, frente a PHA, foram registrados nos grupos CT e CO em relação ao DA, sugerindo relação com a evolução da doença e com a imunossupressão já descrita na doença ativa. Conclusão. Não houve associação entre os SNPs IFNG, IL12B e IL12RB1 e as diferentes formas da doença quando todos os pacientes foram analisados; no sexo masculino, sugere-se que o genótipo AA esteja associado à doença crônica mais disseminada (IL12RB1). Houve diferença significante entre as etnias nos SNPs IFNG e IL12RB1, sugerindo-se a ampliação do número de pacientes em determinadas etnias e na forma clínica unifocal para melhor compreensão dessas associações<br>Introduction. Paracoccidioidomycosis (PCM) is a systemic chronic mycosis, endemic in Latin America, mainly in Brazil where it is the eighth cause of death among chronic recurrent infectious diseases. PCM infection is characterized by the Th1 immune response, the acute form, by a mixed Th2/Th9 profile, while the chronic form is characterized by Th17/Th22 profile. The occurrence and severity of human PCM can also be associated with genetic factors such as polymorphisms on genes of cytokines. Objectives. 1. To describe the frequencies of the single nucleotide polymorphisms (SNPs) IFNG +874 T/A, IL12B 3\'UTR +1188 A/C and IL12RB1 11014 A/G on exon 7, on patients with PCM and non-PCM controls; 2. To investigate the association between those SNPs and the different clinical forms of PCM. 3. To verify the possible association between those SNPs and the secretion of the cytokines IFN-?, IL-12p40 and IL12p70. Materials and Methods. 143 patients with PCM were included (40 with acute form, 100 with multifocal chronic form and 17 unifocal). Inclusion criteria: active disease (DA) proved by fungal identification on direct microscopy/histopathology or culture, or presence of antibodies antiParacoccidioides brasiliensis ( >= 1/32 by counterimmunoelectrophoresis) or cured/treated disease (CT) when previously proved by criteria of DA and present stable antibodies titles =6 months in between. The SNP IFNG was analyzed by PCR-ARMS (Polymerase Chain Reaction - Amplification Refractory Mutational System) and the SNPs IL12B and IL12RB1 by PCR-RFLP (PCR-Restriction Fragment Length Polymorphism). The levels of cytokines were detected by ELISA (n= 29) and CBA (Cytometric Bead Array; n= 18) and values of p < 0.05 for ?2 test and Kruskal-Wallis\' test, with Dunn\'s post-test were considered statistically significant. Results. The AA genotype of SNP IL12RB1 was the most frequent in the multifocal chronic form while the AG was more frequent in men with the unifocal chronic form of PCM (p = 0.048). On this clinical form in the comparison between genres, the AG genotype was also more frequent in men (p= 0.009). On ethnicity, it was demonstrated statistical difference between the frequencies of genotypes and alleles of SNPs IFNG and IL12RB1 (p < 0.05). In the comparison between the clinical forms of PCM, the frequencies of genotypes and alleles of the evaluated SNPs were similar. On the levels of cytokines, for SNPs IFNG, IL12B and IL12RB1, increased levels of cytokines were observed with PHA on the CT and CO groups compared with DA, suggesting a connection with the evolution of the disease and the previously described immunosuppression during active disease. Conclusion. There was no association between the SNPs IFNG, IL12B and IL12RB1 and the different forms of PCM when all patients were analyzed; among men, it is suggested that the AA genotype of IL12RB1 is associated with a more disseminated chronic disease. There was a significant difference between the ethnicities on SNPs IFNG and IL12RB1, being the latter also associated with the chronic form in men. The increase in the number of patients in certain ethnic groups and in the unifocal clinical form of PCM might help the better understanding of these associations
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Müller, Stephanie Irene [Verfasser], Matthias J. [Akademischer Betreuer] Feige, Martin [Gutachter] Zacharias, Johannes [Gutachter] Buchner, and Matthias J. [Gutachter] Feige. "Folding and quality control of the interleukin 12 family cytokines interleukin 27 and interleukin 35 / Stephanie Irene Müller ; Gutachter: Martin Zacharias, Johannes Buchner, Matthias J. Feige ; Betreuer: Matthias J. Feige." München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1200547667/34.
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Brenner, Stephan. "Auswirkungen plazentarer Plasmodium falciparum-Infektionen primigravider Mütter auf die Ausbildungeiner Immunantwort bei Neugeborenen." [S.l. : s.n.], 2006.
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Nomura, Takamasa. "Essential role of interleukin-12(IL-12)and IL-18 for gamma interferon production induced by listeriolysin O in mouse spleen cells." Kyoto University, 2002. http://hdl.handle.net/2433/149709.
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Dodd, Christopher H. "Toll-like receptor stimulation can lead to differential production of IL-23 and IL-12." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2009r/dodd.pdf.
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Meier, Susanne [Verfasser], Matthias J. [Akademischer Betreuer] Feige, Johannes [Gutachter] Buchner, and Matthias J. [Gutachter] Feige. "Folding and quality control of the cytokines interleukin 12 and interleukin 23 / Susanne Meier ; Gutachter: Johannes Buchner, Matthias J. Feige ; Betreuer: Matthias J. Feige." München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1212178084/34.
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Gri, Giorgia. "The role of interferon gamma and other cytokines in the antitumour activity of interleukin 12." Thesis, Open University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251409.
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Furumoto, Katsuyoshi. "Spleen-derived dendritic cells engineered to enhance interleukin-12 production elicit therapeutic antitumor immune responses." Kyoto University, 2001. http://hdl.handle.net/2433/150175.
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Sam, Hakeem. "Mechanism(s) of interleukin-12-induced protection against early murine blood-stage P. chabaudi AS malaria." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0025/NQ50255.pdf.
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Sam, Hakeem. "Mechanism(s) of interleukin-12-induced protection against early murine blood-stage P. Chabaudi AS malaria." Thesis, McGill University, 1998. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35939.
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Previous studies suggest that IL-12, the potent Th1-inducing cytokine, IFN-gamma, TNF-alpha and nitric oxide (NO) contribute to resistance against blood-stage malaria. Early Th1 responses correlate with resistance, whereas predominantly Th2 responses are associated with susceptibility. In the present studies, the requirements for endogenous IL-12 and its role in host defense against blood-stage P. chabaudi AS malaria were investigated. Our results reveal, for the first time, significant differences in the kinetics of endogenous IL-12 p70 synthesis and splenic IL-12R beta1 and beta2 mRNA expression between resistant B6 and susceptible A/J mice that correlate with the polarization of Th responses observed in these hosts during early blood-stage malaria. The spleen was found to be the major source of systemic IL-12 in infected B6 hosts. In addition, significant differences were observed between acutely infected B6 and A/J hosts, on a per cell basis, in IL-12 p70 release by splenic macrophages in vitro. Importantly, these differences correlated with greater malaria parasite-induced IFN-gamma synthesis in vitro by spleen cells from infected B6 mice. Furthermore, systemic IL-12 production and Th1 responses were found to be unimpaired in P. chabaudi AS infected mice deficient in TNFR compared to wild type controls. However, LPS, but not PRBC, -induced NO synthesis by splenic macrophages, was significantly reduced in infected TNFR deficient hosts. Finally, compared to controls receiving chloroquine (CQ) alone, the mechanism(s) of combined low dose IL-12 and CQ therapy for malaria-infected A/J mice was found to involve increased splenocyte expression of IL-12R beta1 and beta2 and IFN-gamma mRNA, together with enhanced parasite antigen-induced synthesis of IFN-gamma by spleen cells in vitro. This novel IL-12 and CQ therapeutic strategy resulted in significantly reduced parasitemia, enhanced survival, and was effective against established blood-stage malaria. Taken together
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Louw, Renate. "A study of the molecular mechanism of progestin-induced regulation of IL-12 and IL-10 and implications for HIV pathogenesis." Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/79822.
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Thesis (PhD)--Stellenbosch University, 2013.<br>ENGLISH ABSTRACT: Medroxyprogesterone acetate (MPA) and norethisterone (NET) and its derivatives (norethisterone
enanthate (NET-EN); norethisterone acetate (NET-A)), designed to mimic the actions of the
endogenous hormone progesterone (Prog), are extensively used by women as contraceptives and in
hormone replacement therapy (HRT). A number of reports have indicated that these synthetic
progestins affect immune function in the female genital tract thereby increasing the risk of acquiring
sexual transmitted infections. Despite these findings, very little is known about their mechanism of
action at the cellular level, in particular their steroid receptor-mediated effects on cytokine gene
expression. In the first part of this thesis, the effect of Prog, MPA and NET-A on the expression of
the endogenous pro-inflammatory cytokine gene, interleukin (IL)-12p40, and anti-inflammatory
cytokine gene, IL-10, was investigated in a human ectocervical epithelial cell line, Ect1/E6E7.
Quantitative realtime PCR (qPCR) showed that all three ligands significantly upregulated the tumor
necrosis factor alpha (TNF )-induced IL-12p40 gene expression, while IL-10 gene expression was
downregulated. Moreover, by reducing the glucocorticoid receptor (GR) levels with siRNA, these
effects were shown to be mediated by the GR. A more detailed investigation into the molecular
mechanism of the progestogen-induced upregulation of IL-12p40 gene expression, using chromatin
immunoprecipitation (ChIP), siRNA, co-immunoprecipitation and re-ChIP analyses, showed that
the progestogen-bound GR is recruited to the CCAAT enhancer binding protein (C/EBP)-
regulatory element of the IL-12p40 promoter, most likely via an interaction with the transcription
factor C/EBP . Similar experiments for the progestogen-induced downregulation of IL-10 gene
expression showed that the progestogen-bound GR is recruited to the signal transducer and activator
of transcription (STAT)-3 regulatory element of the IL-10 promoter, most likely via an interaction
with the transcription factor STAT-3. The second part of this study elucidated the influence of the
HIV-1 accessory viral protein R (Vpr) on progestogen-induced regulation of IL-12p40, IL-12p35
and IL-10 in the Ect1/E6E7 cell line. Results showed that in these cells, the overexpression of Vpr
significantly modulated the effects of Prog, MPA and NET-A on the mRNA expression of IL-
12p40 and IL-10, while only the NET-A effect was modulated on IL-12p35. Moreover, reducing
the GR protein levels by siRNA suggested that the GR is required by Vpr to mediate its effects.
Taken together, these results show that Prog, MPA and NET-A promote the pro-inflammatory
milieu in the ectocervical environment, and that during HIV-1 infections, this milieu is modulated.
Furthermore, the results suggest that the use of MPA or NET in vivo may cause chronic
inflammation of the ectocervical environment, which may have important implications for
ectocervical immune function, and hence susceptibility to infections such as HIV-1.<br>AFRIKAANSE OPSOMMING: Medroksieprogesteroon asetaat (MPA), noretisteroon (NET) en derivate daarvan noretisteroon
enantaat (NET-EN); noretisteroon asetaat (NET-A), ontwerp om die funksies van die natuurlike
hormone progesteroon (Prog) na te boots, word wêreldwyd deur vroue as voorbehoedmiddels sowel
as vir hormoon vervangingsterapie (HVT) gebruik. Daar is verskeie aanduidings dat hierdie
sintetiese progestiene die immuunfunksie in die vroulike geslagskanaal kan beïnvloed en ook die
moontlike vatbaarheid van seksueel oordraagbare infeksies kan verhoog. Ten spyte hiervan, is baie
min bekend oor hulle meganisme van werking op ‘n molekulêre vlak, veral in die besonder hul
effek op sitokinien geenuitdrukking. Die effek van Prog, MPA en NET-A op die geenuitdrukking
van ’n endogene pro-inflammatoriese sitokinien, interleukin (IL)-12, en ’n anti-inflammatoriese
sitokinien, IL-10, asook die onderliggend meganisme van werking, in ’n menslike ektoservikale
sellyn, Ect1/E6E7, is in die eerste deel van hierdie studie ondersoek. Kwantitatiewe “realtime”
polimerisasie ketting reaksie (PKR) het getoon dat al drie die ligande die tumor nekrosis faktor alfa
(TNF- )-geïnduseerde IL-12p40 geenuitdrukking opreguleer en IL-10 geenuitdrukking onderdruk.
Verder is gevind dat induksie van IL-12p40 en inhibisie van IL-10 deur Prog, MPA en NET-A deur
die glukokortikoïed reseptor (GR) gedryf word, aangesien volledige opheffing van die effekte op
hierdie sitokinien gene waargeneem is wanneer die GR proteïen vlakke deur middel van kort
inmengende ribonukleïensuur (siRNS) verminder is. 'n Meer beskrywende ondersoek in die
molekulêre meganisme is uitgevoer deur gebruik te maak van chromatien immunopresipitasie
(ChIP), siRNS, mede-immunopresipitasie en her-ChIP analises. Hierdie resultate het voorgestel dat
die progestogeen (Prog en die sintetiese progestiene)-gebonde GR tot die CCAAT verbeterende
bindings protein (C/EBP)- regulatoriese element van die IL-12p40 promotor betrek word en dat
die transkripsie faktor C/EBP benodig word om transkripsie van die IL-12p40 geen te aktiveer.
Met betrekking tot IL-10, het die resultate voorgestel dat die progestogeen-gebonde GR tot die sein
transduksie en aktiveerder van transkripsie (STAT)-3 regulatoriese element van die IL-10 promotor
betrek word en dat die transkripsie faktor STAT-3 benodig word om transkripsie van die IL-10 geen
te onderdruk. Die tweede deel van die studie het die invloed van die MIV-1 aksesorale virale
proteïen R (Vpr) op sitokinien geenuitdrukking, spesifiek die progestogeen-geïnduseerde regulering
van IL-12p40, IL-10 en IL-12p35, in die Ect1/E6E7 sellyn ondersoek. Resultate het getoon dat
ooruitdrukking van Vpr in hierdie sellyn die effekte van Prog, MPA en NET-A op die mRNS
uitdrukking van IL-12p40 en IL-10, en slegs die NET-A effek op IL-12p35, aansienlik moduleer.
Vermindering van die GR proteïen vlakke deur middel van siRNS het getoon dat Vpr die GR
benodig om hierdie veranderinge mee te bring. In samevatting, die resultate van hierdie proefskrif
stel voor dat Prog, MPA en NET-A die pro-inflammatoriese milieu in die ektoservikale omgewing
bevorder, en dat hierdie milieu gedurende MIV-1 infeksies verander. Verder, die resultate van
hierdie studie impliseer dat die gebruik van MPA en NET in vivo nadelige lokale
immuunonderdrukkende effekte mag hê wat kan lei tot kroniese inflammasie van die ektoservikale
omgewing en ‘n moontlike verhoging in die vatbaarheid van infeksies soos MIV-1.