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Baker, Richard James. "Human immune responses to alloantigens." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248200.
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Benham, Adam Maurice. "Indirect T cell allorecognition of donor MHC class I alloantigens." Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261866.
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Figueira, Eduardo Aleixo. "Avaliação clínica, histológica e imunológica de enxertos ósseos alógenos fresco-congelados utilizados como técnica na preservação de rebordo alveolar pós-extração." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/25/25146/tde-13122011-103726/.
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O osso alógeno fresco-congelado (FFBA, do inglês fresh-frozen bone allograft) é uma alternativa para os procedimentos cirúrgicos de enxerto ósseo, principalmente na preparação do rebordo alveolar para a instalação de implantes osseointegráveis. No entanto, existem alguns paradigmas que envolvem a relação entre resposta do sistema imunológico à aloantígenos presentes no enxerto e o seu comportamento clínico. Procurando entender essa relação, o FFBA foi avaliado como enxerto para preservar o rebordo alveolar pós-extração. Os resultados mostraram que embora tenha ocorrido uma redução estatisticamente significante na altura, espessura e volume do rebordo entre a avaliação inicial e final, essa redução não foi clinicamente significante, permitindo a instalação de implantes osseointegráveis. Em adição, as análises histológicas sugerem um bom comportamento do enxerto, com ausência de reação do tipo corpo estranho e formação de novo osso em todos os sítios analisados. Ao analisar o comportamento da resposta imune, os resultados mostraram que a injeção intradérmica de aloantígenos presentes no FFBA, não induziu uma reação de hipersensibilidade tardia nos pacientes após 4 meses do enxerto. Além disso, os monócitos do sangue periférico (PBMCs) dos pacientes não proliferaram frente aos aloantígenos in vitro. No entanto, os dados também demonstraram que os aloantígenos aumentam a produção de IL-2 e IFN-, mas não alteram a produção de IL-4 e IL-10, por PBMCs dos pacientes. Ao avaliar a relação entre a produção dessas citocinas e o comportamento clínico do enxerto, os dados mostram que existe uma correlação estatisticamente significante entre a produção de IL-2 in vitro e a redução (em %) da altura do rebordo alveolar, embora essa redução não tenha sido clinicamente significante. De fato, a presença de aloantígenos no FFBA não é suficiente para sua contraindicação como material de enxertia.<br>The fresh-frozen bone allograft (FFBA) is an alternative to surgical procedures of bone grafts, mainly in the preservation of alveolar ridge prior the installation of osseointegrated implants. However there are paradigms that surround the relation between immune response to alloantigens present inside the graft and the clinical response of the graft. An attempt to understand this relationship, the FFBA was evaluated as a graft to preserve the alveolar ridge post-extraction. The results show a statistically significant reduction in height, thickness and volume of the ridge between the initial and final examination, however this reduction was not clinically significant. The ridge preservation allowed implant installation and osseointegration. In addition, histologic analysis suggests a good performance of the graft with no foreign body reaction and formation of new bone at all sites. In analyzing the behavior immune response, the results showed that stimulation with alloantigens present in bone allograft induced no delayed hypersensitivity reaction in vivo. Additionally, periphery blood mononuclear cells (PBMC) from patients no proliferate in response to alloantigens in vitro. However, the data also demonstrated that the alloantigens increase IL-2 and IFN- production, but no IL-4 and IL-10 production, by PBMCs from patients. When evaluate the relation between the cytokines production and clinical parameters, the results demonstrate that there statistically significant correlation between IL-2 production in vitro and ridge height changes (%), although this clinical parameter is not clinically significant. In fact, the alloantigens in FFBA are not sufficient for its contraindications as grafting material.
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Goodacre, J. A. "A study of the frequency of mouse cells which present alloantigens and ovalbumin to T lymphocytes." Thesis, University of Newcastle Upon Tyne, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233305.
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Leber, Anne. "Untersuchungen zur Generierung, Migration und Funktion von Regulatorischen T-Zellen in der Schwangerschaft." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2011. http://dx.doi.org/10.18452/16394.
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Ein wichtiges Merkmal der normalen Schwangerschaft ist die Toleranz des mütterlichen Immunsystems gegenüber den fremden fetalen Antigenen. Regulatorische T-Zellen (Treg-Zellen) steigen während der frühen Schwangerschaft an und leisten einen entscheidenden Beitrag zur fetalen Toleranz. Allerdings sind die genauen Mechanismen ihres Anstieges und ihrer Wirkungsweise noch weitgehend ungeklärt. Erste Untersuchungen zeigten, dass die Anzahl an Treg-Zellen in der empfänglichen Phase des Estruszyklus in der Maus am höchsten war. Es kann vermutet werden, dass die erhöhte Anzahl an Treg-Zellen zum Zeitpunkt der Insemination eine frühe Erkennung von väterlichen Antigenen begünstigt und somit zur Vorbereitung des mütterlichen Immunsystems auf die Implantation des Embryos beiträgt. Weiterhin konnte nachgewiesen werden, dass Alloantigene im Ejakulat den frühen Anstieg der Treg-Zellen in der Schwangerschaft bedingen und dass das in der Samenblasenflüssigkeit enthaltene Zytokin TGF-beta die Expansion der Treg-Zellen unterstützt. Diese Ergebnisse befürworten eine Alloantigen-vermittelte Expansion der Treg-Zellen während der frühen Schwangerschaft, die darüber hinaus durch TGF-beta begünstigt wird. Im Rahmen dieser Arbeit konnte ebenfalls belegt werden, dass das Schwangerschaftshormon hCG einen entscheidenden Einfluss auf die Treg-Zellen im Verlauf der Schwangerschaft ausübt. Untersuchungen unter Verwendung von menschlichem Probenmaterial konnten deutlich zeigen, dass hCG die Migration von Treg-Zellen zu Trophoblasten vermittelt und zur Konvertierung von konventionellen T-Zellen in Treg-Zellen beiträgt. Darüber hinaus konnten Versuche im Mausabortmodell zeigen, dass die Applikation von hCG die Expansion und Funktion der Treg-Zellen entscheidend beeinflusst, wodurch das Auftreten von Aborten in Abortweibchen verhindert werden konnte. HCG vermittelt demnach die Generierung, Migration und Funktion der Treg-Zellen und trägt entscheidend zum erfolgreichen Verlauf der Schwangerschaft bei.<br>Normal pregnancy is characterized by the generation of maternal immune tolerance towards the foreign fetal antigens. Regulatory T cells (Treg cells) have been shown to increase in number during early pregnancy stages and to be essential for the establishment of fetal tolerance. However, the mechanisms and factors supporting their increase and function are not well defined. First investigations showed that Treg cells accumulated in the sexually receptive phase of the murine estrous cycle. Thus, it can be assumed that the accumulation of Treg cells around the time of insemination favours early recognition of paternal antigens and thereby prepares the maternal immune system for the implantation of the blastocyst into the maternal endometrium. Experiments investigating the increase of Treg cells during early pregnancy suggest that alloantigens present in the ejaculate mediated early Treg cell augmentation. Moreover TGF-beta, which represents a major component in the seminal fluid, provoked the proliferation of Treg cells. These results suggest that the early expansion of Treg cells is alloantigen-mediated and that seminal fluid-derived TGF-beta is involved in this expansion. Additionally it has been shown that the pregnancy hormone human Chorionic Gonadotropin (hCG) has an important impact on Treg cells during pregnancy. By using human samples it has been proven that hCG mediates the migration of Treg cells to trophoblast cells and supports the conversion of naïve T cells into Treg cells directly at the fetal-maternal interface. In mice, the application of hCG resulted in an increase in the number and function of Treg cells and thereby prevented abortion in a mouse abortion-prone model. Thus, hCG mediates the generation, migration and function of Treg cells and contributes to a successful pregnancy outcome.
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Opiela, Shannon Jacqueline. "Neonatal T Cell Responses are Highly Plastic: I. Neonates Generate Robust T Cell Responses against Alloantigens II. Functional Capabilities of Neonatal RTE are more Diverse than Adult RTE." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/139.
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Neonatal immune responses are typically deficient against a wide variety of antigens, including alloantigens, vaccine antigens, and infectious agents. These responses are characterized by Th2-skewed cytokine production, and deficient Th1 and cytotoxic responses. However, these deficient responses can be boosted to adult levels by the use of strong, Th1 promoting agents. This demonstrates that neonates are capable of developing mature immune responses under specific conditions. Using two different murine models, we have found that neonates develop robust Th and cytotoxic responses, which under some antigenic conditions significantly exceed those of adults. First, using a model of early life exposure to noninherited maternal antigens (NIMA), we found that murine neonates develop robust in vivo cytotoxic responses to low doses of alloantigens. Importantly, primary in vivo cytotoxic responses to alloantigen developed during the neonatal period, and persisted into adulthood. Neonates developed similar memory cytotoxic responses to donor spleen cells, bone marrow, and stem cell-enriched (Lin-) bone marrow cells, suggesting that the exposure dose is more important than the type of transplanted donor cell for the development of cytotoxicity. NIMA-exposed neonates also developed vigorous primary and memory allospecific Th1/Th2 responses which exceeded the responses of adults. These findings suggest that early exposure to low levels of NIMA may lead to long term immunological priming of all arms of T cell adaptive immunity. Second, we characterized the phenotype and function of neonatal recent thymic emigrants (RTE). RTE are the predominant cell type in murine neonates, and are present at higher frequencies within the neonatal CD4+ compartment than in adults. Our data demonstrate that RTE from murine neonates and adults are phenotypically and functionally distinct. In particular, although the magnitude of RTE cytokine responses from both age groups is dependent on the conditions of activation, neonatal RTE consistently exhibited higher levels of effector cytokine production than adult RTE. In particular, activation of neonatal RTE in the presence of IL-7 lead to greatly increased IFNgamma production, while adult responses were not altered. Overall, neonatal RTE responses were more plastic than those of adult RTE, as both Th1 and Th2 responses were altered in neonates using various activation conditions, while only Th2 responses were consistently changed in adults. Finally, in contrast to adult RTE, neonatal RTE proliferated in response to IL-7 stimulation at very early timepoints. This was associated with faster kinetics of IL-7Ralpha downregulation and higher levels of pSTAT5 in neonatal RTE. These quantitative and qualitative differences in neonatal RTE populations may largely explain the diverse responses that are elicited in neonates in response to different antigens, especially under those conditions in which Th1 responses are enhanced (i.e., exposure to NIMA alloantigens). Taken together, these data demonstrate that neonatal T cell responses are actually highly plastic, instead of intrinsically deficient. Furthermore, if given optimal stimulation conditions, neonatal responses can actually exceed those produced by adults.
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Pereira, Fabiana de Souza. "Frequência dos antigenos e anticorpos neutrofílicos humanos (HNA) em doadores e receptores de transplante alogênico de célula tronco hematopoiética (TCTH) e sua correlação com doença enxerto contra hospedeiro (DECH) aguda." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/139761.
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Background e objetivo. A reconstituição celular hematopoiética com o transplante de células tronco hematopoiéticas (TCTH) alogênicas é um método de tratamento estabelecido para uma variedade de doenças hematológicas, oncológicas e imunológicas. Entretanto, TCTH está associado a considerável morbimortalidade devido a fatores como recidiva da doença de base, grau de compatibilidade HLA, tipo de regime de condicionamento e infecções durante o período de neutropenia. Este estudo investigou a associação entre o aloantígenoneutrofílico humano (HNA) e o dia de pega, a ocorrência de DECH aguda e TRM em pacientes que foram submetidos a transplante de células tronco hematopoiéticas alogênico. Tipo de estudo e local. Estudo de coorte prospectivo realizado no Hospital de Clínicas de Porto Alegre. Métodos. Avaliamos 27 pacientes transplantados entre maio de 2013 e abril de 2014 e seus respectivos doadores. A tipagem HNA foi realizada, nas amostras dos doadores, por PCR-SSP e os anticorpos anti-HNA foram detectados nos pacientes utilizando o kit LABSCREEN MULTI (LSMUTR – One Lambda). Resultados. A idade variou entre 1 a 63 anos, com uma média de 20,4 ± 17,5 anos. Dezenove pacientes eram pediátricos (<21 anos) com média de idade de 10,05 ± 6,4 anos e entre os pacientes adultos a média foi 42,2 ± 12,6 anos. Houve um discreto predomínio do sexo masculino 16 (59,3%). As leucemias agudas foram frequentes em 19 (70,4%) dos pacientes, outras doenças oncohematológicas malignas (Linfoma Hodgkin e Linfoma não Hodgkin) estiveram em 3 (11,1%) e as não malignas (síndrome mielodisplásica, osteopetrose, hemoglobinúria paroxicística noturna, aplasia e doença granulomatosa) estiveram em 6 (22,2%) dos casos. A maioria dos pacientes 19 (70,4%), apresentavam a doença há menos de 12 meses na época do transplante e 24 (88,9%) deles foram totalmente compatível com seus doadores quanto ao sistema HLA. O regime de condicionamento mieloablativo foi utilizado em 16 (59,2%) dos pacientes e a profilaxia padrão para DECH (ciclosporina e metotrexate) foi utilizada em 15 (55,5%) dos pacientes. O dia de pega teve uma mediana de 19 e mínimo e máximo de 15 e 30, respectivamente. Quatro pacientes (14,8%) tiveram óbito antes da pega. Aproximadamente 63% (17 pacientes) apresentaram DECH aguda (em todos os estágios) e a taxa de mortalidade (TRM) foi de aproximadamente 44% dos casos (12 pacientes). Os pacientes que receberam TCTH de um doador aparentado tiveram TRM de aproximadamente 41% (7 pacientes) e os que receberam de um doador não aparentado foi de aproximadamente 45% (5 pacientes). A frequência dos antígenos HNA detectados nos doadores foi de 46,4% HNA-1a, 89,3% HNA-1b, 3,6% HNA-1c, 96,4% HNA-3a, 32,1% HNA-3b, 96,4% HNA-4a, 21,4% HNA-4b, 85,7% HNA-5a e 71,4% HNA-5b. A frequência dos anticorpos anti-HNA1a, anti-HNA1b, anti-HNA1c e anti-HNA2 no D0 foram respectivamente 46,4%, 42,9%, 42,9% e 53,6%. A associação entre a tipagem HNA dos doadores e anticorpos anti-HNAdos receptores com dia da pega, DECH aguda e TRM não mostrou correlação estatisticamente significativa. Conclusão. A frequência de HNA encontradanos doadores está de acordo com o descrito pela literatura. Contudo, a frequência dos anticorpos anti-HNAs foi bastante alta na população do estudo, embora a maioria apresentasse doença há menos de 12 meses até o transplante. Apesar de não encontrarmos uma correlação, novos estudos são necessários para melhor avaliar o papel do HNA no desfecho do TCTH.<br>Background and purpose. Hematopoietic cellular reconstruction with allogeneic hematopoietic stem cell transplantation (HSCT) is an established method of treatment for a variety of hematological, oncologic and immunologic diseases. However, HSCT is associated with considerable morbidity and mortality due to recurrence of underlying disease, incomplete HLA compatibility, type of conditioning regimen and infection during the unavoidable period of neutropenia. This study investigates a surrogate cause of morbidity: compatibility of Human Neutrophil Antigens (HNA) between donors and receivers and its association with day of engraftment, incidence of acute graft versus host disease (GVHD) and total rate of mortality (TRM) in patients who underwent allogeneic HSCT. Type of study and location. Prospective cohort study carried out at the Hospital de Clínicas de Porto Alegre (HCPA), Brazil. Methods. We have studied 27 patients who underwent HSCT between May, 2013 and April, 2014, and their respective donors. HNA typing in the donors was performed by PCR-SSP (One Lambda) and anti-HNA antibodies in receivers were detected using the LABSCREEN MULTI kit (LSMUTR-One Lambda). Results. The age ranged from 1 to 63 years, with an average of 20.4 ± 17.5 years. Nineteen were pediatric patients (<21 years) with an average age of 10.05 ± 6.4 years, and among adult patients the average was 42.2 ± 12.6 years. There was a discreet male prevalence, 16 (59,3%). The acute leukemias were frequent in 19 (70,3%) of patients, other malignant onco-hematological diseases (Hodgkin Lymphoma and non-Hodgkin's Lymphoma) in 3 (11,1%) and non-malignant (myelodysplastic syndrome, osteopetrosis, paroxysmal nocturnal hemoglobinuria, aplasia and granulomatous disease) in 6 (22,2%). Nineteen (70,3%) of the patients, had the disease for less than 12 months at the time of the transplant and 24 (88,9%) were fully HLA compatible with their donors. Myeloablative conditioning regimen was used in 16 (59,3%) of the patients and the standard prophylaxis for GVHD (cyclosporine and methotrexate) was used in 15 (55,5%) of the patients. The day of engraftment had a median of 19 and minimum and maximum of 15 and 30, respectively. Four patients (14,8%) died before the engraftment. Approximately 17 patients (63%) showed acute GVHD (in all stages) and the total rate of mortality (TRM) was approximately 44% of the cases (12 patients). Patients who received HSCT from a related donor had TRM of approximately 41% (7 patients) and those who have received an unrelated donor was approximately 45% (5 patients). The frequency of HNA antigens detected in donors was 46,4% HNA-1a, 89,3% HNA-1b, 3,6% HNA-1c, 96,4% HNA-3a, 32,1% HNA-3b, 96,4% HNA-4a, 21,4% HNA-4b, 85,7% HNA-5a and 71,4% HNA-5b. The frequency of antibodies anti-HNA1a, anti-HNA1b, anti-HNA1c and anti-HNA2 at D0 were respectively 46,4%, 42,9%, 42,9% and 53,6%. The association between the HNA donor typing and anti-HNA antibodies of receivers with day of the engraftment, acute GVHD and TRM showed no statistically significant correlation. Conclusion. The HNA frequency found in our donors was close to the described in the literature. The frequency of anti-HNAs antibodies, however, was quite high in our study population; although the majority presented the disease for less than 12 months before the transplant. The association between HNA donor typing and anti-HNA antibodies of patients with day of engraftment, acute GVHD incidence and TRM showed no statistically significant correlation. As the number of cases was small, further studies with higher numbers and with antigen/antibodies assayed in both sides of transplantation pairs, are needed to better assess the role of the HNAs on the outcome of HSCT.
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Fluck, Nicholas C. "Immunological events resulting from intrathymic delivery of alloantigen." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312492.
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Hoff, Uwe. "Bedeutung der Alloantigen-unabhängigen Faktoren in der Frühphase nach tierexperimenteller Nierentransplantation." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=974978132.
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Seltrecht, Nadja [Verfasser]. "Alloantigen-spezifische regulatorische T-Zellen zur Toleranzinduktion nach Organtransplantation / Nadja Seltrecht." Hannover : Technische Informationsbibliothek und Universitätsbibliothek Hannover (TIB), 2012. http://d-nb.info/1022810782/34.
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Hoff, Uwe. "Bedeutung der Alloantigen-unabhängigen Faktoren in der Frühphase nach tierexperimenteller Nierentransplantation." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2005. http://dx.doi.org/10.18452/15249.
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Die Schädigung des Organs durch Ischämie-Reperfusion (IR) im Rahmen der kadaverischen Organtransplantation hat bedeutenden Anteil an der Pathogenese verzögert einsetzender Organfunktion und Auswirkungen auf das Langzeitüberleben des Transplantats. In der vorliegenden Studie sollte der Einfluss unspezifischer Schädigung durch IR verglichen mit spezifischen Alloantigen-abhängigen Mechanismen während der Frühphase nach der Transplantation sowie die Auswirkungen prolongierter Aufbewahrung auf Schädigung und Immunogenität des Organs ermittelt werden. Nach vorausgegangener vierstündiger kalter Ischämiezeit wurden Organe aus syngen (Lew/Lew) und allogen (F344/Lew) transplantierten Ratten an 8 aufeinander folgenden Zeitpunkten innerhalb der ersten 10 Tage zu funktionellen, immunhistochemischen und morphologischen Veränderungen untersucht. In weiteren Gruppen wurden syngen transplantierte Organe 24 Stunden nach der Transplantation untersucht, die zuvor ansteigenden kalten Ischämiezeiten zwischen 2 und 48 Stunden ausgesetzt wurden. Im zeitlichen Verlauf zeigten sich bis 7 Tage nach der Transplantation keine wesentlichen Unterschiede zu Nierenfunktion, Morphologie, Zellinfiltration und Expression von Adhesionsmolekülen zwischen allogenen und isogenen Gruppen. Die zunächst eintretende Verschlechterung der Nierenfunktion war begleitet von einem Einstrom neutrophiler und monozytärer Zellen und morphologischen Veränderungen im Sinne von akuter Tubulusnekrose (ATN). Unter zunehmender Infiltration von Monozyten/Makrophagen kam es funktionell und morphologisch zur Regeneration. Neutrophile traten vornehmlich über Interaktion von ICAM-1/LFA-1 und Monozyten/Makrophagen über VCAM-1/VLA-4 aus dem Gefäßsystem aus. Gabe von Cyclosporin A führte zu signifikanter Reduktion ED-1-positiver Makrophagen nach 10 Tagen, ohne jedoch den Anteil des aktivierten Makrophagensubtyps ED-2 zu beeinflussen. Ansteigende kalte Aufbewahrung des Organs führte zu größerer vaskulärer Schädigung, die sich durch abnehmende Intensität und lückenhaftere Verteilung von PECAM-1 auf dem Endothel äußerte. Die Zunahme der Intensität von Tissue Factor auf Endothel und infiltrierenden Leukozyten deutete neben gesteigerter Thrombogenese auf alternative Adhäsionsmechanismen hin. Diese Ergebnisse zeigen, dass innerhalb der ersten 10 Tage nach der Transplantation wichtige Phasen der Gewebeschädigung und Regeneration ausgelöst durch die Schädigung nach IR und weitestgehend ohne Beteiligung Alloantigen-abhängiger Faktoren ablaufen. Eine bedeutende Rolle als Mediatoren während dieser Phasen kommt dabei den Monozyten/Makrophagen zu.<br>Organ damage due to long cold preservation is associated with delayed graft function and has important effects on graft survival. Aim of this study was to determine the impact of ischemia-reperfusion (IR) injury compared to antigen-specific mechanisms and the effect of prolonged cold ischemia on intragraft injury and antigenicity during the early phase post transplantation. Rat renal grafts were four-hours cold-preserved, transplanted to syngeneic (Lew/Lew) or allogeneic recipients (F344/Lew) and harvested at 8 different time points after transplantation for further investigation of functional, immunhistochemical and histologic changes. In five additional syngen groups organs were cold preserved from 2 hours to 48 hours and harvested after 24 hours post transplantation. No significant differences in renal function, morphologic changes, cellular infiltration and expression of adhesion molecules occurred between syngeneic and allogeneic groups within the first 7 days. Initial functional impairment was accompanied by the influx of neutrophils and monocytes/macrophages together with morphologic changes reflecting acute tubular necrosis (ATN). Increasing infiltration of monocytes/macrophages paralleled functional and morphologic regeneration. Extravasation of neutrophils was mediated mainly by interaction of ICAM-1/LFA-1 and infiltration of monocytes/macrophages by VCAM-1/VLA-4. Treatment with the standard dose of Cyclosporin A (CsA) lead to a significant decrease of ED1-positive macrophage infiltration 10 days post NTx but the portion of ED2-positive macrophage subtype was not affected. Prolonged cold organ preservation lead to more severe vascular damage indicated by decreased color intensity and continuity of PECAM-1 staining on endothelial cells. Higher staining intensity for Tissue Factor (TF) on endothelium and infiltrating leukocytes implicated enhanced intragraft procoagulant capacity and alternative adhesion mechanisms. These results show that within the first 10 days post transplantation phases of tissue injury and repair after ischemia-reperfusion are largely independent of the immunologic background and monocytes/macrophages play an important role as mediators during these processes.
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Zhou, Juan. "Oral administration of alloantigen prolongs kidney allograft survival by generating intragraft regulatory cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ66663.pdf.
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Sivaganesh, Sivasuriya. "Recipient DCs presenting intact and processed MHC alloantigen mediate CD8⁸ T-cell responses." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609327.
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Bentjen, Bettina. "Molekulargenetische Untersuchungen von Alloantigenen auf Blutzellen bei Menschen und anderen Primaten /." Gießen : DVG Service, 2004. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=012800145&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Jones, Nick D. "Tolerance induction by intrathymic injection of foreign alloantigen : examination of mechanisms using TCR transgenic mice." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360362.
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Srivastava, Saket. "The generation and characterisation of alloantigen reactive regulatory T cell populations from umbilical cord blood." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10026041/.
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The use of polyclonal CD4+ CD25+ FoxP3+ regulatory T cells (Treg) have been successful in the management of acute graft versus host disease (aGvHD), a complication associated with allogeneic haematopoietic stem cell transplantation. However, polyclonal Tregs can cause broad immunosuppression of desired responses. To avoid this, the use of alloantigen reactive Tregs has been suggested, with pre-clinical data indicating that allospecific Tregs are more efficient than polyclonal Tregs in suppressing allospecific responses. This thesis demonstrates the generation and characterisation of alloantigen reactive Treg populations from umbilical cord blood (UCB). Culture conditions were established to isolate and expand CD4+ CD25- and CD4+ CD25+ lymphocytes from UCB. Phenotypic characterisation was conducted by flow cytometry, demethylation analysis of the FoxP3 gene, and TCR spectratyping. The suppressive function and allospecificity of regulatory cells was determined by their effects on responder cells stimulated with the same allogeneic or a 3rd party antigen presenting cells. The stimulation of UCB Tregs by allogeneic monocyte derived dendritic cells (MDDC) with IL-2 resulted in a 62±34-fold expansion and decreased TCR diversity. While freshly isolated UCB Tregs exhibited weak activity, expanded cells provided superior suppression of allospecific responses compared to adult Tregs. Analysis revealed the presence of CD25highCD45RO+ CD39+ Tregs that expressed increased FoxP3, CTLA-4 and Helios. CD39+ cells provided improved function compared to total allostimulated Tregs with >50% suppression obtained at a 1:256 ratio. UCB CD4+ CD25- T cells were stimulated with MDDCs, the arising CD25+ population portrayed characteristics similar to Tregs including partial FoxP3 demethylation. The suppressive function of these cells matched allostimulated Tregs, however was lost upon re-stimulation. The results described in this dissertation demonstrate the possibility to establish suppressive cells with alloantigen reactivity from UCB CD4+ T cells. UCB is of interest as a potential source of cells for therapy, and the potential use of alloreactive UCB Tregs for immunotherapy are discussed.
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Schurmans, Stéphane. "Etude d'un modèle murin d'autoimmunité après induction néonatale de tolérance à des alloantigènes." Doctoral thesis, Universite Libre de Bruxelles, 1996. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/212293.
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Brandt, Christine. "Retroviral modifizierte, alloantigen-spezifische und vIL-10 transgene T-Lymphozyten als therapeutischer Ansatz im akuten Abstossungsmodell." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968917577.
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Brandt, Christine. "Retroviral modifizierte, alloantigen-spezifische und vIL-10 transgene T-Lymphozyten als therapeutischer Ansatz im akuten Abstoßungsmodell." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2003. http://dx.doi.org/10.18452/14919.
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In den letzten zwei Jahrzehnten wurden T-Lymphozyten verstärkt als Zielzellen für genetische Modifikationen eingesetzt, mit der Absicht vererbbare oder erworbene Krankheiten zu behandeln. Vor kurzem konnte unsere Arbeitsgruppe zeigen, dass alloantigen-spezifische, genmodifizierte T-Lymphozyten ein enormes Potential besitzen, als Transport- Systeme für therapeutische Gene in allogene Transplantate zu dienen. Diese T-Lymphozyten migrieren und akkumulieren spezifisch in das allogene Transplantat, in welchem es zu einer lokalen und starken T-Zell aktivierungsabhängigen Expression des Transgens kommt. In der vorliegenden Arbeit wurde das Potential von viralem IL-10 als therapeutisches Transgen untersucht. Dazu wurde zunächst in der gemischten Lymphozyten-Kultur (MLR) eine Lewis T-Zelllinie spezifisch für Ratten-DA Alloantigene generiert. Während der MLR wurden die Lymphozyten retroviral transduziert, so dass sie vIL-10 stabil exprimieren. Der Zytokin-Level der TvIL-10-Lymphozyten liegt 48h nach der T-Zellaktivierung zwischen 1-2ng/m. Die vIL-10 transgenen T-Lymphozyten zeigen einen CD4+CD25+ Phänotyp und sezernieren neben vIL-10 auch Ratten IL-10 und IFN-g aber kein IL-4, ähnlich wie T-regulatorische Zellen Typ 1 (Treg1). Zunächst wurden die vIL-10 transgenen T-Lymphozyten hinsichtlich ihres Potentials untersucht, die alloantigen-spezifische Immunantwort in vitro zu modulieren. Dazu wurden 5% vIL-10 transgener T-Lymphozyten zu einer MLR hinzugegeben. Zuvor wurden die naiven Lewis T-Lymphozyten mit einem Membranfarbstoff markiert, um die Proliferation und die Zytokin-Expression dieser Zellen zu untersuchen. Im Vergleich zu Kontroll-MLRs ohne transgene oder mit EGFP-transgenen Lymphozyten konnte eine signifikante Inhibierung der Proliferation als auch der INF-g Expression von naiven T-Lymphozyten detektiert werden. Trotz dieses großen Potentials in vitro, führte der adoptive Transfer der vIL-10 transgenen Zellen allein oder in Kombination mit Cyclosporin (0,5mg/kg/Tag) nicht zu einer Verlängerung der Transplantatüberlebenszeit im allogenen Herztransplantationsmodell. Diese Daten zeigen, dass die Überexpression von vIL-10 im Transplantat eines starken Abstoßungsmodells nicht zur Verlängerung der Transplantatüberlebenszeit führt. Außerdem kann das in vitro gezeigte regulatorische Potential dieser T-Zellen nicht zwangsläufig auf ihr in vivo Potential übertragen werden.<br>During last two decades T lymphocytes have become key targets for genetic modification in order to treat inherited or acquired human diseases. Recently, we demonstrated the capacity of allospecific gene-engineered T lymphocytes as a transport shuttle for therapeutic transgenes into allografts. These lymphocytes migrate and accumulate specifically in allografts where alloantigen-driven T cell activation strongly enhances local expression of the gene of interest. In this study, the influence of viral IL-10 as a therapeutic transgene was addressed. Lewis T cell lines specific for DA rat alloantigens were generated in a modified mixed lymphocyte reaction protocol (MLR). During MLR, lymphocytes were genetically modified to express vIL-10 using a retroviral gene expression system. The cytokine level in the supernatant of TvIL-10-lymphocytes varied between 1-2 ng/ml 48h after T-cell activation. Like T regulatory 1 (Treg1) cells, vIL-10 transgenic T lymphocytes express the phenotype CD4+25+ and secrete, in addition to vIL-10, rat IL-10 and IFN-g but no IL-4. First we evaluated the potential of vIL-10 transgenic T cell lines to modulate alloantigen-specific immune responses in vitro. Small numbers of TvIL-10-lymphocytes were added to MLR (less than 5%). Naive cells were stained with membrane dyes to trace proliferation and to analyze cytokine expression. In comparison to control MLR with no transgenic cells or equal numbers of TEGFP-lymphocytes, the proliferation as well as the production of IFN-g of naive responder cells were significantly diminished. Despite this regulatory capacity in vitro, the vIL-10 transgenic T lymphocytes were not able, either alone or in combination with suboptimal cyclosporine (0,5mg/kg/day), to prolong the survival of DA rat cardiac allografts in LEW recipients. These data demonstrate that intragraft IL-10 overexpression is not sufficient to prolong allograft survival in a high-responder strain combination and that the regulatory capacity of T cells in vitro does not predict their in vivo efficiency.
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GENETET-PIERRON, NOELLE. "Nature de la reaction immunitaire maternelle aux alloantigenes foetaux : contribution a l'etude des relations immunitaires materno-foetales." Rennes 1, 1989. http://www.theses.fr/1989REN10005.
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Koh, Mickey Boon Chai. "Alloantigen specific T cell depletion from stem cell grafts for the prevention of graft versus host disease." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392696.
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Billing, John Stephen. "Strategies for the induction of unresponsiveness to allografts using bone marrow as a vehicle for donor alloantigen delivery." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393427.
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Martin, Alison. "Alloantigen systems and resistance to Eimeria tenella and Newcastle-B1 in chickens selected for response to sheep erythrocytes." Thesis, Virginia Polytechnic Institute and State University, 1985. http://hdl.handle.net/10919/101451.
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Chickens from lines selected for high (HA) and low (LA) antibody response to sheep red blood cell (SRBC) antigen were Used to study the role of genetic factors involved in resistance to Eimeria tenella and Newcastle disease virus (NDV). Routes of administration were intravenous for SRBC antigen and intranasal for NDV. Chicks were exposed to E. tenella either through a natural challenge via the litter or a controlled oral administration. Differences between lines were observed in resistance to cecal coccidiosis, with line HA chicks being more resistant than those from line LA. Results were similar. for both natural and controlled exposures, Differences in resistance to E. tenella were found among alleles for the I alloystern with degree of additivity from the I⁴ allele on resistance depending on the background genome.
Chicks from line HA exhibited higher antibody titers to SRBC and lower titers to NDV than did those from line LA. This pattern was the same regardless of whether antigens were given together or alone. Correlations within lines for birds which received both antigens were positive and significant in line HA and not different from zero in line LA. When NDV was given at the time birds received a booster dose of SRBC, antibody titers for NDV and for primary and booster SRBC were higher in. line HA than line LA. Correlations between all titers were positive and significant in both lines. The data suggest that relationships between titers for SRBC and NDV are influenced by both genetic and nongenetic factors.<br>M.S.
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Brede, Christian [Verfasser], and Andreas [Akademischer Betreuer] Beilhack. "Peripheral alloantigen expression directs the organ specific T cell infiltration after hematopoietic cell transplantation / Christian Brede. Betreuer: Andreas Beilhack." Würzburg : Universität Würzburg, 2013. http://d-nb.info/1111886768/34.
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Euler, Nina Kerstin [Verfasser], and Cornelia [Akademischer Betreuer] Deeg. "Identifizierung und Charakterisierung von Alloantigenen bei der Bovinen Neonatalen Panzytopenie / Nina Kerstin Euler ; Betreuer: Cornelia Deeg." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1138195758/34.
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Höger, Simone. "The alloantigen-independent factors brain death and cold ischemia prospects for a better graft survival through different donor management concepts." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 2009. http://irs.ub.rug.nl/ppn/317.
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Hoff, Uwe [Verfasser], Dominik [Gutachter] Müller, Duska [Gutachter] Dragun, and Karl F. [Gutachter] Hilgers. "Bedeutung der Alloantigen-unabhängigen Faktoren in der Frühphase nach tierexperimenteller Nierentransplantation / Uwe Hoff ; Gutachter: Dominik Müller, Duska Dragun, Karl F. Hilgers." Berlin : Humboldt-Universität zu Berlin, 2005. http://d-nb.info/1207621390/34.
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Nagahama, Kanji. "Differential control of alloantigen-specific regulatory T cells and effector T cells by anti-CD4 and other agents in establishing transplantation tolerance." Kyoto University, 2009. http://hdl.handle.net/2433/126425.
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Abramowicz, Daniel. "Glomerulonéphrite autoimmune après induction néonatale de tolérance aux alloantigènes chez la souris: rôle de lymphocytes CD4 de type TH2." Doctoral thesis, Universite Libre de Bruxelles, 1993. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/212745.
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Urh, Jennifer [Verfasser], and Matthias [Akademischer Betreuer] Stelljes. "Einfluss von Alloantigenen und deren Expressionsmuster auf den GvT-Effekt im Rahmen einer allogenen Stammzelltransplantation / Jennifer Urh ; Betreuer: Matthias Stelljes." Münster : Universitäts- und Landesbibliothek Münster, 2015. http://d-nb.info/1138242918/34.
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Robert, Stella R. [Verfasser], and Bruno M. [Akademischer Betreuer] Moerschbacher. "Untersuchung zu ubiquitär und nicht ubiquitär exprimierten Antigenen bei Alloantigen-vermittelter T-zellulärer Reaktion nach allogener Stammzelltransplantation / Stella R. Robert ; Betreuer: Bruno M. Moerschbacher." Münster : Universitäts- und Landesbibliothek Münster, 2014. http://d-nb.info/1137626844/34.
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Brandt, Christine [Verfasser], H. D. [Gutachter] Volk, R. [Gutachter] Lucius, and W. [Gutachter] Uckert. "Retroviral modifizierte, alloantigen-spezifische und vIL-10 transgene T-Lymphozyten als therapeutischer Ansatz im akuten Abstoßungsmodell / Christine Brandt ; Gutachter: H.-D. Volk, R. Lucius, W. Uckert." Berlin : Humboldt-Universität zu Berlin, 2003. http://d-nb.info/1207680265/34.
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Nikbakht-Sangari, Maryam. "Ischemia-reperfusion injury induces the expression of an immune response gene, MHC II-DR-ß, in the host peripheral T lymphocytes via an alloantigen-independent pathway, a swine model of single lung transplantation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/nq27217.pdf.
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Trenado-Bauquet, Aurélie. "Utilisation des propriétés immunosuppressives des lymphocytes T CD4+CD5+ dans l' alloréactivité pour contrôler la maladie du greffon contre l' hôte (GVH)." Paris 6, 2005. http://www.theses.fr/2005PA066254.
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Schneider, Christine. "Untersuchungen zur Häufigkeitsverteilung des leukozytären Alloantigens auf Hämatozyten." 2004. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=014189773&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Merklein, Anne Cathrin (geb Rohde). "Immunbiologie der Transplantatabstoßung : Untersuchungen zum immunmodulatorischen Effekt Transplantat-relevanter Antigene." Doctoral thesis, 2011. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-65790.
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T-Lymphozyten des Empfängers können über den direkten oder indirekten Weg der Allo-Antigenerkennung Spender-MHC-Moleküle (Allo-Antigene) erkennen. Hieraufhin werden diese aktiviert und können anschließend eine Transplantatabstoßung auslösen. In der Klinik wird die Transplantatabstoßung durch den Einsatz von Immunsuppressiva verhindert. Ein großer Nachteil ist, dass sich die Immunsuppression auf sämtliche T-Lymphozyten gleichsam auswirkt - unabhängig von ihrer Spezifität. Somit sind nicht nur T-Lymphozyten betroffen, die Allo-Antigene erkennen, sondern auch solche, die für die Abwehr von Infektionen notwendig sind bzw. die Entstehung von Malignomen verhindern. Dies korreliert mit klinischen Beobachtungen, wonach organtransplantierte Patienten ein höheres Risiko aufweisen, an schweren Infektionen oder Neoplasien zu erkranken. Wünschenswert wäre somit eine selektive Suppression ausschließlich der an der Abstoßung beteiligten T-Lymphozyten. In dieser Arbeit wurde die biologische Funktion von zwei synthetischen Allopeptid-Antigenen, RT1.B2 und RT1.D2, untersucht. Die Peptide, die mit bestimmten Sequenzen von MHC-Klasse II-Molekülen des Spenders identisch sind, aktivieren über den indirekten Weg der Allo-Antigenerkennung alloreaktive T-Lymphozyten des Empfängers. RT1.D2 erwies sich dabei als das immunogenere Peptid. Wurden die Empfänger vor Transplantation mit diesen Peptiden immunisiert, so verkürzte sich die Transplantatfunktionszeit um 2 Tage. Nicht-immunisierte Empfängertiere wiesen eine Transplantatfunktionszeit von 5,3 +/- 0,5 Tage auf, nach Immunisierung mit RT1.B2 bzw. RT1.D2 verringerte sich die Transplantatfunktionszeit auf 3,5 bzw. 3,3 Tage. Die Verkürzung der Transplantatfunktionszeit durch Immunisierung mit Allopeptiden wurde auch nach einer kurzfristigen Immunsuppression mit CsA beobachtet. Im Gegensatz dazu führte eine Verlängerung der Immunsuppression auf 30 Tage nach Transplantation zu einer Verlängerung der Transplantatfunktionszeit, wenn zuvor mit dem Allopeptid RT1.B2 immunisiert wurde. Das Konzept dieser Arbeit war, die prä- und intraoperative Applikation von Allopeptiden, die nachweislich an der Transplantatabstoßung durch Induktion alloreaktiver T-Lymphozyten beteiligt sind, mit einer niedrig-dosierten Immunsuppression zu kombinieren, die alleine nicht in der Lage ist, die spät-akute Abstoßung des Dünndarmtransplantates zu verhindern, um somit gezielt die alloreaktiven T-Lymphozyten zu eliminieren. Dies gelang nach Applikation des weniger immunogenen Allopeptides RT1.B2 in Kombination mit niedrig dosiertem CsA: Nahezu die Hälfte der so behandelten Tiere wies nach Dünndarmtransplantation eine Transplantatlangzeitfunktion auf. Histologische Untersuchungen der Transplantate zeigten keine bzw. allenfalls leichte Veränderungen im Sinne einer chronischen Transplantatabstoßung. Auf zellulärer Ebene konnten in derartig behandelten Tieren mittels indirektem Proliferationsassay an Tag 40 nach Transplantation keine RT1.B2-reaktiven T-Lymphozyten mehr nachgewiesen werden. Die Ergebnisse der Arbeit deuten darauf hin, dass die Kombination aus Immunisierung mit dem Peptid RT1.B2 und einer niedrig dosierten Immunsuppression zu einer selektiven Immunsuppression führt, bei der die RT1.B2-spezifischen T-Lymphozyten inhibiert bzw. depletiert werden<br>T-lymphocytes of the recipient recognize major histocompatibility complex molecules of the donor (alloantigens) via the direct or the indirect pathway of allorecognition. Consequently, these are being activated and, hence, may initiate graft rejection. In clinical practice rejection is prevented by administration of immunosuppressive drugs. As a major drawback, immunosuppression acts on all kinds of T cells, independently from their specificity. Thus, not only T cells which recognize alloantigens are affected but also those which are mandatory for resistance to infections or prevention of oncogenesis. Such correlates with clinical observations whereas organ transplanted patients show an enhanced risk of severe infections or neoplasms. Therefore, a selective suppression exclusively of those T Cells involved in graft rejection would be desirable. In this study, the biological function of two synthetic allopeptide antigens, RT1.B2 und RT1.D2, has been investigated. These peptides which are identical with certain sequences of MHC class II-molecules of the donor activate alloreactive T-lymphocytes of the recipient via the indirect pathway of allorecognition. In this connection, RT1.D2 proved to be the more potent immunogenic peptide. In case recipients were immunized with these peptides prior to transplantation, the period of transplantat function shortened by 2 days. Non-immunized recipient animals showed a period of transplant function of 5.3 +/- 0.5 days whereas after immunization with RT1.B2 resp. RT1.D2, the period of transplant function cut down to 3.5 resp. 3.3 days. The shortening of the period of transplant function by immunization with allopeptides has been observed also after brief immunosuppression with CsA. In contrast, a prolongation of the period of immunosuppression to 30 days after transplantation resulted in an extension of the period of transplant function in case of prior immunization with the allopeptide RT1.B2. Concept of this study has been to combine with a low dosage immunosuppression (which by itself would not suffice to prevent the late-acute rejection of the small bowel graft) the pre- and intraoperative application of allopeptides, which have demonstrated to be involved in transplant rejection by induction of alloreactive T-lymphocytes, to eliminate specifically these alloreactive T-lymphocytes. That was achieved by application of the less immunogenic allopeptide RT1.B2 in combination with low dosage CsA. Almost half of the animals treated that way have shown long-term transplant function after small bowel transplantation. Histological investigations of the grafts did not show any (respectively – if at all – slight) alterations in terms of chronic transplant rejection. At cellular level, no RT1.B2-reactive T-lymphocytes could be detected any more by means of an indirect proliferation assay at day 40 after transplantation. The results of this study suggest that a combination of both immunization with the peptide RT1.B2 and low-dose immunosuppression results in a selective immunosuppression whereas specifically the RT1.B2-specific T-lymphocytes are inhibited resp. depleted
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Hoff, Uwe [Verfasser]. "Bedeutung der Alloantigen-unabhängigen Faktoren in der Frühphase nach tierexperimenteller Nierentransplantation / von Uwe Hoff." 2005. http://d-nb.info/974978132/34.
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Brede, Christian. "Peripheral alloantigen expression directs the organ specific T cell infiltration after hematopoietic cell transplantation." Doctoral thesis, 2013. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-85365.
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In acute graft-versus-host disease (GVHD) alloreactive donor T cells selectively damage skin, liver, and the gastrointestinal tract while other organs are rarely affected. The mechanism of this selective target tissue infiltration is not well understood. We investigated the importance of alloantigen expression for the selective organ manifestation by examining spatiotemporal changes of cellular and molecular events after allogeneic hematopoietic cell transplantation (allo-HCT). To accomplish this we established a novel multicolor light sheet fluorescence microscopy (LSFM) approach for deciphering immune processes in large tissue specimens on a single-cell level in 3 dimensions. We combined and optimized protocols for antibody penetration, tissue clearing, and triple-color illumination to create a method for analyzing intact mouse and human tissues. This approach allowed us to successfully quantify changes in expression patterns of mucosal vascular addressin cell adhesion molecule–1 (MAdCAM-1) and T cell responses in Peyer’s patches following allo-HCT. In addition, we proofed that LSFM is suitable to map individual T cell subsets after HCT and detected rare cellular events. We employed this versatile technique to study the role of alloantigen expression for the selective organ manifestation after allo-HCT. Therefore, we used a T cell receptor (TCR) transgenic mouse model of GVHD that targets a single peptide antigen and thereby mimics a major histocompatibility complex (MHC)-matched single antigen mismatched (miHAg-mismatched) HCT. We transplanted TCR transgenic (OT-I) T cells into myeloablatively conditioned hosts that either express the peptide antigen ovalbumin ubiquitously (βa-Ova) or selectively in the pancreas (RIP-mOva), an organ that is normally not affected by acute GVHD. Of note, at day+6 after HCT we observed that OT-I T cell infiltration occurred in an alloantigen dependent manner. In βa-Ova recipients, where antigen was ubiquitously expressed, OT-I T cells infiltrated all organs and were not restricted to gastrointestinal tract, liver, and skin. In RIP-mOva recipients, where cognate antigen was only expressed in the pancreas, OT-I T cells selectively infiltrated this organ that is usually spared in acute GVHD. In conditioned RIP-mOva the transfer of 100 OT-I T cells sufficed to effectively infiltrate and destroy pancreatic islets resulting in 100% mortality. By employing intact tissue LSFM in RIP-mOva recipients, we identified very low numbers of initial islet infiltrating T cells on day+4 after HCT followed by a massive T cell migration to the pancreas within the following 24 hours. This suggested an effective mechanism of effector T cell recruitment to the tissue of alloantigen expression after initial antigen specific T cell encounter. In chimeras that either expressed the model antigen ovalbumin selectively in hematopoietic or in parenchymal cells only, transplanted OT-I T cells infiltrated target tissues irrespective of which compartment expressed the alloantigen. As IFN-γ could be detected in the serum of transplanted ovalbumin expressing recipients (βa-Ova, βa-Ova-chimeras and RIP-mOva) at day+6 after HCT, we hypothesized that this cytokine may be functionally involved in antigen specific OT-I T cell mediated pathology. In vitro activated OT-I T cells responded with the production of IFN-γ upon antigen re-encounter suggesting that IFN-γ might be relevant in the alloantigen dependent organ infiltration of antigen specific CD8+ T cell infiltration after HCT. Based on these data we propose that alloantigen expression plays an important role in organ specific T cell infiltration during acute GVHD and that initial alloreactive T cells recognizing the cognate antigen propagate a vicious cycle of enhanced T cell recruitment that subsequently culminates in the exacerbation of tissue restricted GVHD<br>In der akuten Graft-Versus-Host Disease (GVHD) infiltrieren allogene Spender T Zellen Haut, Leber und den Magen-Darm-Trakt des Empfängers und attackieren das Gewebe. Andere Organe sind dagegen interessanterweise nur selten betroffen. Die Mechanismen dieser selektiven Organinfliltration sind bisher weitestgehend unbekannt. In meiner Dissertationsarbeit untersuchte ich den Einfluss der Alloantigenexpression auf die selektive Organmanifestation während der GVHD. Um komplexe Immunprozesse die nach allogener Stammzelltransplantation auftreten, besser zu verstehen, entwickelten wir eine Lichtblattmikroskopietechnik (LSFM) die zelluläre und molekulare Veränderungen im intakten Gewebe detektieren kann. Wir etablierten eine neuartigen mehrfarben LSFM-Methodik, die es ermöglicht, Immunprozesse in großen Gewebsstücken von Maus und Mensch in Einzelzellauflösung dreidimensional darzustellen. Dazu kombinierten und optimierten wir Protokolle, um eine Penetration von Antikörpern tief in das Gewebe sowie die Aufklärung und die dreifache Beleuchtung des Gewebes zu ermöglichen. Diese Methode erlaubte uns die erfolgreiche Quantifizierung der Proteinexpression des Adressins mucosal vascular addressin cell adhesion molecule–1 (MAdCAM-1) als auch die Quantifizierung der T Zell Antwort im intakten Peyer’s Plaque nach allogener hämatopoetischer Transplantation (HCT). Weiterhin konnten wir die Methode zur Untersuchung der Migration unterschiedlicher T Zell-Subpopulationen nach HCT erfolgreich einsetzen und konnten einzelne, organinfiltrierende Zellen detektierten und quantifizieren. Wir benutzten die LSFM Methode um den Einfluss der Alloantigenexpression auf die selektive Organmanifestation zu studieren. Dazu verwendeten wir ein Transplantationsmodell, in dem der Haupthistokompatibilitätskomplex übereinstimmt (MHC-matched) und eine Diskrepanz nur in einem einzelnen Peptid Antigen (miHAG-mismatch) zwischen Spender und Empfänger bestand. Wir transplantierten T Zell Rezeptor (TCR) transgene (OT-I) T Zellen in myeloablativ bestrahlte Empfänger, die das Peptidantigen Ovalbumin entweder in allen Geweben (βa-Ova) oder selektiv in der Bauchspeicheldrüse (RIP-mOva) exprimieren. Die Bauchspeicheldrüse ist ein Organ, das normalerweise nicht von der akuten GVHD betroffen ist. An Tag 6 nach allogener HCT waren alle Organe die das Alloantigen exprimieren auch von Spender T Zellen infiltriert. In myeloablativ bestrahlten RIP-mOva Empfängern reichten bereits 100 transferierte OT-I T Zellen aus, um Alloantigen-exprimierende pankreatische Inselzellen zu zerstören. Dies führte zu einer Mortalität von 100% der Empfänger und spricht für eine sehr effiziente Alloantigendetektion und Gewebsinfiltration durch die Spender T Zellen. Um die Kinetik der Organinfiltration der Spender T Zellen detailliert zu untersuchen, verwendeten wir die neue Lichtblattmikroskopietechnik, welche die Analyse intakter Organe ermöglicht. In RIP-mOva Empfängern identifizierten wir erste wenige Spender T Zellen im Pankreas an Tag 4 nach Transplantation, gefolgt von einer massiven Pankreasinfiltration durch Spender T Zellen innerhalb von 24 Stunden. Dies deutet auf eine gezielte Rekrutierung der Spender T Zellen nach erstem Antigenkontakt in das Gewebe mit Alloantigenexpression. Um zu untersuchen, ob die Alloantigenexpression vom parenchymalen Gewebe oder aber durch hämatopoetische Zellen zur spezifischen Organinfiltration führt, transplantierten wir OT-I T Zellen in chimäre Empfänger, in denen das Alloantigen entweder nur im Gewebsparenchym oder ausschließlich von hämatopoetischen Zellen exprimiert wird. An Tag 6 nach der allogenen HCT fanden wir Spender T Zellen in allen Geweben, unabhängig davon welches Empfängerzellkompartment das Alloantigen präsentierte. Wir detektierten hohe IFN-γ-Werte im Serum von Ovalbumin exprimierenden Empfänger (βa-Ova, βa- Ova-Chimären und RIP-mOva). Weiterhin fanden wir, dass nach erneutem Kontakt mit dem spezifischen Alloantigen, OT-I T Zellen die in vitro aktiviert wurden, IFN-γ produzierten. Wir schließen aus diesen Beobachtungen, dass für die antigenabhängige Gewebeinfiltration IFN-γ wichtig ist. Zusammenfassend postulieren wir, dass die Alloantigenexpression im Gewebe eine wichtige Rolle in der organspezifischen Infiltration durch Spender T Zellen spielt, und dass T Zellen die Alloantigen spezifisch erkennen, dafür verantwortlich sind, dass weitere Effektor-T Zellen in das Gewebe rekrutiert werden
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Liu, Hsiao-Rou, and 劉曉柔. "The effects of regulatory T cells on alloantigen tolerance induction following allogenic hematopoietic stem cell." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/24305207795533708137.
Full textAbstract:
碩士<br>輔仁大學<br>生命科學系碩士班<br>97<br>In utero hematopoietic stem cell transplantation (IUHSCT) was used as strategy to replace bone marrow transplantation without the need of toxic conditioning therapy . The major limitation of IUT to date is limited chimersims and lack tolerance to alloantigen . Nowadays , the strategy we use to treat rejection is to take immunosuppressant drugs in a long period . Although the success rate of transplantation is increased , but immune function is decreased . The induction of donor-specific tolerance in patients after transplantation is major criteria for success of transplantation . The donor-specific tolerance is recipient who may not use immunosuppressant drugs and be able to accept allograft survival in a long term after transplantation. As well , recipients have normal immune functions. Related studies have been indicated that CD4+CD25+ T cells (Treg) can prolong donor cells survival time and induce the property of donor-specific tolerance in transplanted recipients . Treg cell is a group of T cells subset , and mature from thymus. There are 5% to 10 % in CD4+ T cells , and keep presenting CD25 maker on cell surface . In addition , CD4+ T cells also present specific marker transcription factors Foxp3. So far, CD4+ CD25+ Treg cells play important roles in preventing autoimmune diseases , organ rejection , and maintaining self-tolerance. Hence, the purpose of this research is evaluated the effects of regulatory T cells on alloantigen tolerance induction following allogenic hematopoietic stem cell transplantation induced GvHD in fetues . In present experiment, FVB mice spleen was first isolated and T cells were purified and used to induce functional regulatory T cells in vitro. Furthermore , a MHC-mismatched allogenic stem cell transplantation induced GvHD in fetues was used to evaluate the effects of Treg cells on donor allogenic cell engraftment and specific donor antigen tolerance induction. The engraftment and rate of donor cells were examined by flow cytometry and PCR with fluorescent H-2b antibody or H-2b specific primer . The allogenic skin graft and mixed lymphocyte reaction were used to value tolerance induction . Results indicated that in vitro induced regulatory T cells can release IL-10 and TGF-β cytokine to inhibit syngenic or allogenic T cell activation and proliferation. In fetus GvHD model which co-transplanted regulatory T cell , regulatory T cells can enhance the engraftment , significantly increase the number of graft cells , and decreased GvHD occurrence . Co-transplanted Treg cells with donor HSCs did not affect the graft of hematopoietic stem cells differentiated into somatic blood cells . Co-transplanted Treg cells with allogenic HSCs did induce an allogenic-specific tolerance in fetal recipients after IUT .
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Tay, Sherilyn Keng Lin, and 鄭慶玲. "ADOPTIVE TRANSFUSION OF EX VIVO DONOR ALLOANTIGEN-STIMULATED CD4+CD25+ REGULATORY T CELLS PREVENTS COMPOSITE TISSUE ALLOTRANSPLANTATION REJECTION." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/27671405884936519916.
Full textAbstract:
碩士<br>長庚大學<br>生物醫學研究所<br>98<br>Introduction: There is increasing evidence that regulatory T cells (Tregs) play an important role in preventing allograft rejection in both experiment and clinical settings of solid organ transplantation. Adoptive transfusion of alloantigen-stimulated Tregs have been shown to ameliorate rejection of solid organ transplantations, however this has not been shown in composite tissue allotransplantation. Therefore, the therapeutic potential
of Tregs were investigated in a rat hindlimb osteomyocutaneous composite tissue allotransplantation.
Methodology: The role of Tregs was first quantified in tolerant rats created using an established CTA model by flow cytometry. Using the same model of composite tissue allotransplantation, hindlimbs from Brown-Norway rats were heterotopically transplanted onto Lewis rats based on the femoral vessels. Freshly isolated (n=5) or ex vivo
alloantigen stimulated (n=3) CD4+CD25+ Tregs (3x106cells) from naïve Lewis rats were injected into the rats on day 11 after transplantation. Recipient rats were preconditioned with antilymphocyte serum on days -1 and day 2 of the transplant and given daily subcutaneous cyclosporine from day 0 to day 7. Tregs were harvested and isolated from splenocytes of naïve Lewis rats. These were sorted using magnetic beads and AutoMACS system. For ex vivo alloantigen stimulation, isolated Treg cells were co-cultured with irradiated antigen presenting cells from naïve Brown-Norway rats for 72 hours before transfer. The suppressive effect
of these cells was investigated using one-way mixed lymphocyte reaction (MLR) and the rats monitored daily for signs of rejection. Histological analyses of the flap were taken at defined points and the Treg profile assessed.
Results: Both the level of CD4+CD25+ Tregs and the CD4+CD25+/CD4+CD25- ratio were increased in both splenocytes* and peripheral blood of tolerant rats compared to naïve rats. In MLR, ex-vivo alloantigen stimulated CD4+CD25+ suppressed antigen-specific Lewis splenocyte proliferation in a dose dependant manner and this was
significant at a 1:1 ratio. Adoptive transfer of 3x106 of these cells prolonged the survival of the transplanted grafts* and resulted in long term acceptance of the graft in 33% of the rats. This rat shows minimal rejection on histological analysis and similar to tolerant rats show an
increase in CD4+CD25+ cells and the CD4+CD25+/ CD4+CD25- ratio. * denotes p&lt;0.05
Conclusion: Adoptive transfusion of ex vivo donor alloantigen-stimulated CD4+CD25+ Tregs combined with a short course of cyclosporine and T cell depletion may represent a clinically feasible strategy for preventing rejection of composite tissue transplantation and tolerance induction.
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Brandt, Christine [Verfasser]. "Retroviral modifizierte, alloantigen-spezifische und vIL-10 transgene T-Lymphozyten als therapeutischer Ansatz im akuten Abstoßungsmodell / von Christine Brandt." 2003. http://d-nb.info/968917577/34.
Full text
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Nikbakht-Sangari, Maryam. "Ischemia-reperfusion injury induces the expression of an immune response gene, MHC II-DR-[beta], in the host peripheral T lymphocytes via an alloantigen-independent pathway : (a swine model of single lung transplantation)." Thesis, 1998. http://hdl.handle.net/2429/8584.
Full textAbstract:
The complex and multifactorial pathogenesis of ischemia-reperfusion injury (IRI) has
made IRI one of the major challenges faced by organ transplantation. Recently, many attempts
have been made to establish a relationship between IRI and organ rejection. IRI is now believed
to increase the chance of organ rejection via the release of inflammatory mediators such as
platelet-activating factor (PAF) which leads to activation of inflammatory cells, causing tissue
damage and increased immunogenecity of the graft. To our knowledge, all studies have focused
on the effect of IRI on the transplanted donor organ. However, whether IRI can induce an
immune response in the host has not been investigated. The objective of this thesis was to
investigate whether ischemia-reperfusion injury, independent of tissue incompatibility, could
induce MHC H-up-regulation in host peripheral T lymphocytes in a swine model of single-lung
transplantation and whether PAF played a role in the mechanism of MHC II up-regulation due to
IRI.
Single lung transplantation was performed on three groups of domestic swine. Group
A/E (n=7) and group B (n=6) had ex vivo preservation times of 4 hr and 15 hr respectively at
4°C hypothermia. To eliminate the allogenecity effect, group C (n=6) underwent 2 hours of
warm ischemia via dissection and isolation of the left lung with ligation of its bronchial artery and
cross-clamping of the left pulmonary artery, vein, and bronchus without explantation. PAFantagonist,
TCV-309, in combination with prostaglandin Et (PGEj) was administered before and
during surgery in group E. The sham-operated group (group D, n=6) was used as the control
group. Blood samples were collected at pre, one, two, three day post-reperfusion for two-color
flow cytometry analysis using swine anti-CD3 and anti-MHC II-DR-β antibodies. Blood
samples were also collected for semi-quantitative and competitive reverse transcription
polymerase chain reaction (RT-PCR) analysis at pre, two hr, one, two, and three day postreperfusion.
Tissue culture experiments were performed using purified resting/proliferating T lymphocytes and T lymphocytes in the presence of accessory cells [peripheral blood lymphocytes
(PBL)] treated with PAF only and PAF + TCV-309. The cells were incubated for 4 days at
37°C. Samples were removed every day, and the level of MHC II intensity in T lymphocytes
was measured.
The results indicated that the level of MHC II-DR-β intensity on host's peripheral T
lymphocytes increased significantly (p<0.05) on day 2 post-reperfusion for group A, B, and C.
Comparison between groups suggested that the level of MHC II intensity increased as the ex
vivo preservation time was extended from 4 hr to 15 hr. The intensity of MHC II on peripheral
T cells in group C appeared to be higher than that in group A and B. Results from group D
indicated that administration of TCV-309 + PGEj inhibited the up-regulation of MHC II. RTPCR
analysis indicated that the steady state level of MHC II mRNA in T cells significantly
increased by 2 hr post-reperfusion (p<0.01) for group B and C. The results of tissue culture
experiments indicated that PAF at 10⁻¹ M caused a small but significant increase (p<0.05) in
MHC II surface expression in T cells only in the presence of accessory cells by day 2 posttreatment.
The results of this study indicated that IRI by itself, independent of tissue incompatibility,
induced an immune response in the host manifested by MHC II up-regulation in host peripheral T
cells. The result also suggested that MHC II up-regulation increased further as the ex vivo
preservation time increased. Furthermore, PAF appeared to play a role in the mechanism of MHC
II up-regulation in T cells. However, this effect appeared to be an indirect one via intervention of
accessory cells. TCV-309 in combination with PGE₁ appeared to have preventive effects against
IRI-induced immune response and a potential for clinical application.