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Hamilton, Melisa June. "Immunosuppressive myeloid cells under normal and neoplastic conditions." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/39661.
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Although the importance of immunomodulatory myeloid cells in both normal physiology and carcinogenesis is well established, many questions remain regarding the specific roles and regulation of these cells. In this thesis, we explore the immunosuppressive features of macrophages [Mφs] and elucidate the mechanisms by which they suppress T cell proliferation/activation, the factors that regulate their suppressive properties, the relative potency of macrophage suppression compared to other myeloid cells, such as myeloid-derived suppressor cells (MDSCs), and the role these cells play in promoting tumor growth and metastasis.
We demonstrate herein that in response to interferon (IFN)-beta, which is secreted by activated T cells, resident macrophages from non-tumor-bearing mice acquire immunosuppressive properties that are mediated by nitric oxide (NO). Moreover, our data reveal a novel role for Toll-like receptor (TLR)-induced IFN-beta in regulating the immunosuppressive properties of macrophages.
We also demonstrate for the first time that in vitro culture conditions profoundly affect the immunosuppressive functions of MDSCs. Specifically, we show that serum antagonizes the suppressive abilities of MDSCs from 4T1 tumor-bearing mice and that the major serum protein albumin mediates these effects, in part by reducing reactive oxygen species (ROS) production from MDSCs. These findings have important implications, since the accurate detection and quantification of immunosuppression is critical for both the identification and functional analysis of tumor-induced MDSCs.
We also explore the phenotypic and functional heterogeneity of tumor-induced myeloid cells and compare the immunosuppressive functions of different populations isolated from normal and tumor-bearing mice. We show that tumors that induce the accumulation of myeloid cells also enhance the suppressive functions of these cells. In addition, we demonstrate that, in vitro, tumor-induced macrophages are significantly more potent immune suppressors than tumor-induced MDSCs on a per cell basis, and suppress T cell responses via distinct mechanisms. Finally, we present data showing that treating metastatic mammary tumor-bearing mice with all-trans-retinoic acid (ATRA) decreases MDSCs, increases macrophages, and enhances metastatic growth.
Taken together, these findings advance our understanding of the factors that regulate myeloid cell functions in normal and neoplastic tissues and may lead to improved immunotherapies to treat human disease.
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Alves, Inês Sofia Moutinho. "Contribution of ER stress to tumor immunosuppressive microenvironment." Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/14290.
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Mestrado em Bioquímica - Bioquímica ClínicaBreast cancer is the most prevalent cancer among women and also one of the oncologic pathologies that causes more deaths. In the last decades several studies have reported that solid tumors generate an immunosuppressive microenvironment. This microenvironment (acidosis, hypoxia, glucose deprivation and cytokines) is favourable to endoplasmic reticulum (ER) stress induction. ER stress is primarily a response towards the re-establishment of homeostasis; however if not resolved it usually results in cell death by apoptosis. Nevertheless, ER stress and unfolded protein response (UPR) play a paradoxical role in cancer physiopathology: the three branches of UPR, PERK, IRE1 and ATF6 actively contribute to signalling of survival and metastasis mechanisms. Recently it was reported a possible transmission of ER stress from tumor cells to immune cells, modulating the phenotype and function of recipient cells. Thus, the aim of the present work is to assess the ability and the respective mechanisms by which T-47D tumor cells transmit ER stress to THP-1 monocytes, and the consequences of this transmission. ER stress transmission was only observed when pharmacological ER stress inducers were used, such as tunicamycin, contrarily to physiological stimulation, as glucose deprivation. Additionally, it was found that tunicamycin seems to be transported within exosomes which, in turn, directly induces ER stress on monocytes. It was also observed that exosomes derived from glucose deprived T-47D cells do not transmit ER stress; however these exosomes conduct monocytes towards a particular proinflammatory profile, accompanied by the decrease of its maturation status. Overall, our results question the ER stress mechanism originally described, showing that pharmacological ER stress inducers can be transported within exosomes and directly inducing ER stress on recipient cells.
O cancro da mama é o cancro de maior incidência entre as mulheres, sendo também uma das situações oncológicas que mais mortes causa. Na última década inúmeros estudos têm demonstrado que os tumores sólidos geram um microambiente favorável à evasão/subversão do sistema imune. Esse microambiente (acidose, hipoxia, deprivação de glucose, citoquinas) é muita das vezes propicio à indução de stress do reticulo endoplasmático (RE). O stress do RE é primariamente uma resposta no sentido de restabelecer a homeostasia no entanto se não resolvido resulta normalmente na morte celular por apoptose. O stress do RE e a respetiva resposta às proteínas mal conformadas (UPR), desempenham um papel paradoxal na fisiopatologia do cancro: os três ramos da UPR, PERK, IRE1 e ATF6, contribuem ativamente para a sinalização de alguns mecanismos de sobrevivência e metastização. Recentemente, foi descrita uma possível transmissão do stress do RE das células tumorais para as células do sistema imunitário, modulando a ação destas. Desta forma, pretendeu avaliar-se com o presente trabalho a capacidade e os mecanismos pelos quais células tumorais T-47D transmitem o stress do RE para células monocíticas THP-1, e quais as consequências desta transmissão. A transmissão foi apenas observada aquando da utilização de indutores farmacológicos como a tunicamicina, não se registando para estímulos fisiológicos como a deprivação de glucose. Por outro lado, verificou-se que a tunicamicina parece ser transportada via exossomas e desta forma induzir diretamente stress do RE nos monócitos. Observou-se ainda que os exossomas provenientes das células T-47D em stress do RE por deprivação de glucose apesar de não transmitirem o referido stress conduzem os monócitos para um perfil pró-inflamatório específico diminuindo ainda a sua capacidade de maturação. Em geral, os nossos resultados questionam seriamente o mecanismo de transmissão de stress ER tal como originalmente descrito, mostrando que no uso de indutores farmacológicos o que parece ocorrer é o transporte do fármaco em vesículas e a indução direta nas células recetoras.
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Glennie, Sarah Jane. "The molecular mechanisms mediating the immunosuppressive effects of mesenchymal stem cells." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417349.
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Khanolkar, Rahul Chaitanya. "Molecular analysis of ABIN1 expression and immunosuppressive function in immature myeloid cells." Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=202767.
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The leukocyte immunoglobulin like receptors (LILRs) are a group of receptors with immunomodulatory effects. Group 1 LILRs comprise of LILRB1, among others, and bind to class 1 MHC molecules and transmits inhibitory signals. Studies have shown that LILRB1 ligation during the monocyte differentiation process into dendritic cells (DCs) results in the generation of a population of cells that are tolerogenic. Here we hypothesize that this tolerogenic nature of the resultant cells is due to the high expression of nuclear factor kappa – light chain enhancer of activated B cells (NF-κB) inhibitor – A20 binding inhibitor of NF-κB signalling 1 (ABIN1). In this study we analyzed the effect that ABIN1 exerts on the maturation of DCs and CD14+HLA-DRlow/- monocytes - a population of cells that have been recently been identified as myeloid derived suppressor cells (MDSCs) in humans. LILRB1 ligated DCs and CD14+HLA-DRlow/- monocytes, when treated with ABIN1 siRNA, displayed an increase in the expression of antigen presentation and co-stimulatory molecules such as CD80, CD86, HLA-DR and HLA-ABC and displayed a greater capacity to produce cytokines like IL-12 and IFN-α. Additionally, they displayed a greater capacity to stimulate the adaptive component of the immune system in terms of IFN-γ production, cell proliferation and adapter molecule and mitogen activated protein kinase (MAPK) activation in T cells. Based on the results we obtained, it can be concluded that ABIN1 plays a significant role in maintaining the immature and suppressive phenotype of immature myeloid cells (IMCs) by dampening NF-κB signalling, while also exerting a negative effect on antiviral signalling.
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Delaney, Michael Paul. "Immunosuppressive drug interactions and resistance in mononuclear cells from renal transplant patients." Thesis, University of Warwick, 2001. http://wrap.warwick.ac.uk/3703/.
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Existing anti-rejection drug regimes are inadequate since patients receive drugs despite serious side effects and poor response. New drugs are being developed which ultimately may allow for prescribing of rational, patient-specific immunosuppressive drug protocols. During this thesis the investigation of lymphocyte responses from renal transplant recipients to the immunosuppressant drugs Cyclosporin A (Cy A), FK506 and SDZ RAD were explored to understand the variation in sensitivity of lymphocytes to Cy A and FK506, the development of drug resistance, including resistance mechanisms, and the interactions between FK506 and SDZ RAD. Cy A and FK506 are substrates for P-glycoprotein (P-gp), the product of the multidrug-resistance (MDR1) gene in man. A hypothesis established during this thesis was that P-gp dependent mechanisms explain variations in lymphocyte sensitivities to Cy A and FK50. Lymphocytes from renal transplant recipients were assessed for their sensitivity to Cy A and FK506 and subsequently for P-gp expression and functional activity by flow cytometry. In further lymphocyte cultures the effect of the specific P-gp inhibitor, PSC 833 on sensitivity was investigated. Finally, the effects of the combination of FK506 and SDZ RAD in lymphocyte cultures were analysed. Results demonstrate a wide range in lymphocyte sensitivity to both Cy A and FK506, with the development of selective resistance to the drug used for treatment. All patients demonstrated P-gp functional activity but P-gp expression was not demonstrable. P-gp function did not account for the variation in lymphocyte sensitivity. There was no evidence of antagonism of effect of SDZ RAD in combination with FK506. In conclusion, these results suggest that non-P-gp mechanisms account for variations in lymphocyte sensitivity to Cy A and FK506. Combination therapy with SDZ RAD and FK506 is unlikely to be antagonistic in future treatment protocols.
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Duque, Marta. "The immunosuppressive potential of human amniotic membrane extract." Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/15498.
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Mestrado em Bioquímica - Bioquímica ClínicaBoth mesenchymal stromal cells (MSCs) and human amniotic membrane (hAM) possess immunoregulatory potential, driving several studies to focus on their application in the prevention and treatment of immunological disorders, and especially on their ability to modulate T cell responses. However there is little information regarding the concrete effects over different activation and differentiation stages of T cells. The main objective of this study was to determine whether or not a hAM extract (hAME) had a differential effect over different T cell subpopulations (CD4+ and CD8+ T naïve, central memory, effector memory and effector cells). Thus, peripheral blood mononuclear cells (PBMC) were cultured in the presence or absence of hAME and stimulated with phorbol myristate acetate (PMA) plus ionomycin. Cell proliferation was evaluated through a thymidine incorporation assay and the percentages of pro-inflammatory cytokine producing T cells were determined by flow cytometry. The phenotype of hAM-derived cells was also assessed by flow cytometry. Plus, the mRNA expression of selected genes was evaluated in purified CD4+ and CD8+ T cells, regulatory T cells (Treg) and γδ T cells. The hAM-derived cells contained hAM epithelial cells and MSCs. The extract displayed an antiproliferative effect and reduced the frequency of tumor necrosis factor-alpha (TNFα), interferon gamma (IFNγ), and interleukin-2 (IL-2) producing cells, within all T cell subsets. The hAME also diminished the frequency of IL-17 and IL-9 producing T cells. The pattern of inhibition varied between CD4+ and CD8+ T cells, between T cell subsets, and depending on the cytokine under study. The hAME also produced a decrease in mRNA expression of granzime B, perforin and activating receptor NKG2D by CD8+ T cells, γδ T cells as well as an upregulation of Foxp3 and IL-10 gene expression in CD4+ T cells and an upregulation of IL-10 mRNA expression in Treg cells. These results show that the hAME differentially regulates different T cell subsets and therefore the effect of the hAME over T cells responses will depend on the T cell subpopulations involved. Still, the hAME has an overall antiinflammatory action.
Tanto as células mesenquimais do estroma (MSCs) como a membrana amniótica humana (hAM) possuem capacidade imunoreguladora, levando a que vários estudos se debrucem sobre a sua aplicação na prevenção e tratamento de doenças imunológicas, e especialmente sobre a sua capacidade de modular células T. No entanto, há pouca informação acerca dos efeitos concretos sobre diferentes fases de ativação e diferenciação de células T. O principal objetivo deste estudo foi determinar se um extrato de hAM (hAME) exerce efeito diferencial sobre diferentes subpopulações de células T (células T CD4+ e CD8+ naïve, memória central, memória efetoras e efetoras). Para esse efeito, células mononucleares do sangue periférico (PBMC) foram cultivadas na presença ou ausência de hAME e estimuladas com acetato miristato de forbol (PMA) mais ionomicina. A proliferação celular foi avaliada por um ensaio de incorporação de timidina e as percentagens de linfócitos T produtores de citocinas pró-inflamatórias foram determinadas por citometria de fluxo. O fenótipo de células derivadas de hAM foi também determinado por citometria de fluxo. Foi ainda estudada a expressão de mRNA em células T CD4+ e CD8+, células T reguladoras (Treg) e células T γδ purificadas. As células derivadas de hAM continham células epiteliais e MSCs. O extrato exibiu um efeito anti-proliferativo e reduziu a frequência de células produtoras de fator de necrose tumoral alfa (TNFα), interferão gama (IFNγ), e interleucina-2 (IL-2) em todas as subpopulações de células T estudadas, assim como a frequência de células T produtoras de IL-17 e IL-9. O padrão de inibição variou entre células T CD4+ e CD8+, entre cada subpopulação celular, e dependendo da citocina em estudo. O hAME provovou também diminuição da expressão de mRNA de granzima B, perforina e recetor de ativação NKG2D em células T CD8+e células T γδ, assim como o aumento de expressão de Foxp3 e IL-10 em células T CD4+, e aumento de expressão IL-10 em células Treg. O hAME regula diferencialmente diferentes subpopulações de células T e, portanto, o efeito do hAME sobre respostas de células T será dependente das subpopulações de células T envolvidas, ainda assim, hAME tem uma ação global anti-inflamatória.
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Nurmenniemi, P. (Petri). "Inflammatory cells and mitotic activity of keratinocytes in gingival overgrowth induced by immunosuppressive- and nifedipine medication." Doctoral thesis, University of Oulu, 2006. http://urn.fi/urn:isbn:9514279964.
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Abstract
Both immunosuppressive and nifedipine medication have been associated with drug-induced gingival overgrowth. There are several hypothetical mechanisms for drug-induced gingival overgrowth, such as the influence of genetic predisposition, alterations in gingival tissue homeostasis, especially in the function of fibroblasts, and drug-induced action on growth factors. Clinical studies have also shown that, those with poor oral hygiene status drug-induced gingival overgrowth is more prevalent and severe than those with good oral hygiene status.
The working hypothesis was that immunosuppressive medication and/or nifedipine medication affects inflammatory cell profile and mitotic activity of keratinocytes in human overgrown gingiva. We studied gingival samples, collected from nifedipine-medicated cardiac outpatients and immunosuppression-medicated organ-transplant recipients. Patients were placed into four groups: 1) the immunosuppression group, patients receiving cyclosporin-A (CsA), azathioprine (AZA) and prednisolone (Pred) 2) the immunosuppression plus nifedipine group, patients receiving CsA, AZA, Pred. and nifedipine 3) the nifedipine group patients receiving only nifedipine and 4) the non-medicated control group. All of the samples related to moderate to severe degrees of gingival overgrowth, covering half to two thirds of the clinical crown. The aim of the study was to investigate the occurrence of Langerhans cells, macrophages, mast cells and mitotic activity of keratinocytes in human drug-induced overgrown gingiva, and consequently to assess their possible role in the pathogenesis of drug-induced gingival overgrowth.
We found that immunosuppressive medication increased the numbers of reparative macrophages (RM3/1) and decreased the numbers of tryptase- and chymase-positive mast cells (MCTC) cells. We have also shown that immunosuppressive and nifedipine medication decreased the numbers of Langerhans cells (CD1a) and increased the numbers of 27E10-macrophages parallelly. Additionally we found increase in the mitotic activity of gingival keratinocytes and even two-fold thickening of gingival epithelium in immunosuppressive and nifedipine medication-induced gingival overgrowth as compared with healthy gingiva. Immunosuppressive medication activated gingival epithelium (27E10 expression in gingival keratinocytes) more than nifedipine medication.
In conclusion, our results suggest that gingival overgrowth among immunosuppressive- and nifedipine-medicated patients is related to alteration of tissue homeostasis. First, this suggestion is supported by changes found in the numbers of cells that directly affect connective tissue turnover, e.g. reparative macrophages (RM3/1) and mast cells. Changes in the numbers of these cells could alter the cytokine- and growth factor-profile, which affects fibroblast function. Secondly, we found changes in the numbers of cells involved in regulation of inflammation, e.g. Langerhans cells and monocytes as compared with healthy controls. Immunosuppressive medication could directly activate gingival keratinocytes. We suggest that our findings mainly reflect the effects of immunosuppressive medication, but the role of inflammation cannot be excluded. The changes observed above represent differences of the pathogenesis of drug-induced gingival overgrowth between immunosuppressive and nifedipine medication. It must be however remembered that drug-induced gingival overgrowth is a result of multicausal intrinsic and extrinsic factors. Age, gender, concomitant medication with multiple drugs, plaque accumulation, and genetic disposition are additional risk factors. The abnormal distribution of specific immune system cell subpopulations does not alone prove a functional relationship to gingival overgrowth.
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Freeman, Lisa. "An investigation into the regulation of immunosuppressive steroids by human monocyte-derived dendritic cells." Thesis, University of Birmingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433428.
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Centuori, Sara Mozelle. "NEGATIVE REGULATION OF REGULATORY T CELLS BY MYELOID-DERIVED SUPPRESSOR CELLS IN CANCER." Diss., The University of Arizona, 2011. http://hdl.handle.net/10150/145099.
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Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play an essential role in the immunosuppressive networks that contribute to tumor immune evasion. The mechanisms by which tumors promote the expansion and/or function of these suppressive cells and the cross-regulation between MDSC and Treg remain incompletely defined. The current work evaluates the influence of MDSC, expanded in two mouse cancer models, on immunosuppressive Treg. We demonstrate that tumor-induced MDSC endowed with the potential of suppressing conventional T lymphocytes surprisingly impair TGF-β1-mediated generation of induced Treg (iTreg) from naïve CD4⁺ T lymphocytes. Suppression of iTreg generation by MDSC occurs early in the differentiation process, and is cell contact dependent. This inhibition of FoxP3-expressing T lymphocyte differentiation by MDSC does not depend on arginase 1, cystine/cysteine depletion, iNOS/NO, or PD-1/PD-L1 signaling. These findings therefore indicate that MDSC from tumor-bearing hosts have the heretofore unreported ability to restrict some immunosuppressive Treg subpopulations.
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Ochando, Jordi Cano. "In vitro studies of the effects of fungal-derived immunosuppressive agents on MCF7 breast cancer cells and MOLT4 leukaemia cells." Thesis, De Montfort University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393220.
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Nakanishi, Yasutaka. "Regulatory T cells with superior immunosuppressive capacity emigrate from the inflamed colon to draining lymph nodes." Kyoto University, 2018. http://hdl.handle.net/2433/235982.
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Ramos, Rodrigo Nalio. "The immunosuppressive microenvironment in cancer : local and systemic effects on patients' monocytes." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10270.
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Chez les patients atteints de cancer, les cellules néoplasiques échappent au contrôle du système immunitaire en raison de leur faible immunogénicité et d'une capacité exacerbée à moduler le micro-environnement. Nous décrivons ici les effets de ce micro-environnement tumoral sur la différenciation locale et systémique des monocytes et l'impact de la présence de Macrophages-Associés aux Tumeurs (TAM) CD163+ sur la survie des patientes atteintes de cancer du sein. Par une analyse de cytométrie en flux, nous décrivons un composition hétérogène des sous-types de TAM CD163low et CD163high, où nous avons observé l'association entre une fréquence élevée de TAM CD163high et une faible infiltration des lymphocytes T CD3+. Par immunohistochimie sur une analyse rétrospective (±12 ans), nous avons démontré une forte corrélation entre la fréquence élevée de TAM CD163+ et un risque accru de progression pour les patientes (log-rank *p<0.05, n=238). In vitro, les monocytes CD14+ conditionnés par le micro-environnement tumoral présentent une différenciation biaisée en faveur des MΦ CD163highCD86lowIL-10high, que non seulement ne stimulent pas la prolifération des lymphocytes T CD4+ naïfs, mais inhibent fortement l'expansion et la production d'IFN-γ et de TNF-α par les lymphocytes T CD4+ préalablement activé. Cette différenciation de MΦ en M2-like (CD163highIL-10high) est associée à des quantités élevées de TGF-β, M-CSF et VEGF dans le micro-environnement tumoral. Par ailleurs, les monocytes circulants des patientes atteintes de cancer du sein présentent un profil cytokinique immunosuppresseur et sont biaisés vers une différenciation en MΦ et Mo-DCs qui présentant des capacités suppressivesIn cancer patients, the neoplastic cells escape from the immune control because of their low immunogenicity and their exacerbated capacity to modulate the microenvironment. Here we describe the local and systemic effects of the tumor microenvironment on monocyte differentiation and the impact of the presence of Tmor Associated Macrophages (TAM) CD163+ on the survival of breast cancer patients. By flow cytometry analysis, we describe a heterogeneous composition of CD163low and CD163high TAM subtypes, where we observed the association between high frequency of CD163high TAM infiltration and low CD3+ T lymphocytes presence. By immunohistochemistry on a retrospective analysis (±12 years), we have shown a strong correlation between high frequency CD163+ TAM and an increased risk of progression for patients (log-rank *p<0.05, n= 238). In vitro, CD14+ monocytes conditioned by tumor microenvironment exhibit a biased differentiation towards a CD163highCD86lowIL-10high macrophages (MΦ) phenotype, that not only failed to stimulate the proliferation of naive CD4+ T cells, but strongly inhibited the expansion and the production of IFN-γ and TNF-α by activated-CD4+ T cells. This differentiation into M2-like MΦ (CD163highIL-10high) is associated with high levels of TGF-β, M-CSF and VEGF found in the tumor microenvironment. Furthermore, circulating monocytes of breast cancer patients produced an immunosuppressive cytokine profile and are biased towards the differentiation into MΦ and Mo-DCs that show suppressive capacities
O desenvolvimento do câncer é normalmente associado a desvios no sistema imune, principalmente devido a sua falha em perceber, reconhecer e eliminar células neoplásicas de maneira eficiente. Nesse contexto, duas Células Apresentadoras de Antígenos (APCs), Células Dendríticas (DCs) e Macrófagos (MΦ), têm um papel crucial na identificação de alterações nos tecidos e na estimulação da imunidade adaptativa antitumoral. No entanto, fatores derivados de tumores modulam essas APCs, impedindo a iniciação das respostas imunes e culminando no estabelecimento do câncer. Investigamos aqui como o microambiente tumoral poderia modular a diferenciação de monócitos em APCs in vitro e de modo sistêmico. Nossos dados revelaram que em cânceres de mama e ovário, Macrófagos-Associados a Tumores (TAMs) são a subpopulação mais frequente em leucócitos CD45+MHCII+, e são encontrados em uma frequência variável de TAMs CD163low ou TAMs CD163high. O último, (TAMs CD163high) expressaram maiores níveis de PD-L1 e elevada produção de IL-10 sob a ativação de LPS. Além disso, a análise retrospectiva por imunohistoquímica revelou uma forte correlação entre a presença de TAMs CD163+ e uma baixa taxa de sobrevida em pacientes com câncer de mama. Ainda, a alta frequência de TAMs CD163high foi correlacionada com um baixo infiltrado de células T CD3+. Monócitos saudáveis condicionados por sobrenadantes de tumores de mama tiveram sua diferenciação in vitro direcionada para um fenótipo CD163highIL-10high, células capazes de suprimir a expansão de células T naive CD4+ e a produção de IFN- γ e TNF-α via IL-10. Esse fenótipo adquirido por monócitos condicionados foi associado à presença de altos níveis de CCL22, M-CSF, TGF-β1, TGF-β3, e VEGF no microambiente tumoral. Interessantemente, avaliando os efeitos sistêmicos dos tumores, monócitos circulantes de pacientes com câncer de mama falharam em diferenciar-se em M1- MΦ na presença de GM-CSF/IFN-γ e mantiveram um fenótipo alterado CD163+/-IL-10+TNF-α+
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Kim, Wooki. "Molecular mechanisms of immunosuppressive effects of dietary n-3 pufa, curcumin and limonin on murine cd4+ t cells." [College Station, Tex. : Texas A&M University, 2008. http://hdl.handle.net/1969.1/ETD-TAMU-3212.
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Lopez, Rodriguez Yelica Virginia. "Immunosuppressive properties of Wharton's jelly derived mesenchymal stromal cells in the treatment of graft versus host disease in rat model." Diss., Kansas State University, 2013. http://hdl.handle.net/2097/16331.
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Doctor of PhilosophyDepartment of Anatomy and Physiology
Mark L. Weiss
Graft Versus Host Disease (GVHD) is the major complication following hematopoietic stem cell transplantation. GVHD is activated by immunocompetent T cells presented in the donor grafted tissue. Due to the increased use of bone marrow transplantation to treat diverse malignancies, the incidence of GVHD has shown a notable increase. Depending of the degree of immunological mismatch between donor and host, 50-70% of patients develop GVHD after allogeneic Bone Marrow Transplantation (BMT). Once GVHD develops, mortality reaches up to 50% in humans. Several studies using Mesenchymal Stromal Cells (MSCs) to prevent and treat GVHD have produced controversial results. It is thought that distinct MSCs sources used in those studies might be an important factor that produces different outcomes. For cellular therapy, the most attractive characteristics of MSCs are their reduced immunogenic potential, and their abilities to modulate immune responses. This dissertation addressed the hypothesis that Wharton’s jelly cells (WJCs) would prevent the pathology and death associated with GVHD after BMT. To accomplish this, I created a clinically relevant model of GVHD by transplanting allogeneic bone marrow across minor histocompatibility antigen (HA) barriers in the rat. To enhance alloreactive T-cell stimulation, bone marrow (BM) was co-administered with a fraction of CD8[superscript]+ cells magnetically selected from spleen to induce GVHD. Bone marrow tissue was isolated from a donor rat Fischer 344 (F344, RT1lv) and transplanted into lethally irradiated (10 Gray) Lewis rat (LEW, RT1l). Once GVHD was induced, MSCs derived from umbilical cord WJCs were either co-transplanted at day 0 with bone marrow, or given on day 2 post-BMT intravenously. The prophylactic potential of WJCs in an in vivo GVHD model was assessed as survival time, clinical symptomatology occurrence, and histopathology injuries in target tissues. Results indicate that while co-administration of WJCs with hematopoietic cells on day 0 failed to alleviate GVHD associated symptomatology and mortality. WJCs administered on day 2 post-induction ameliorated GVHD-associated symptomatology, improved engraftment and survival.
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Gerard, Claire. "Développement d’une stratégie thérapeutique immunosuppressive dérivée de cellules myéloïdes dans la maladie du greffon contre l’hôte." Thesis, Bourgogne Franche-Comté, 2020. https://nuxeo.u-bourgogne.fr/nuxeo/site/esupversions/a02d57d7-6368-477d-8e8d-0badac13bda0.
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Résumé :Notre équipe a développé une thérapie cellulaire originale dérivant de la lignée monocytaire. Cette sous-population de cellules humaines suppressives d’origine myéloide, appelée Human Monocyte-derived Suppressor Cells (HuMoSC, cellules CD33+), est capable d’inhiber la prolifération des lymphocytes T effecteurs et d’induire des CD4 et CD8 Treg. De plus, les HuMoSC préviennent l’apparition de la maladie du greffon contre l’hôte (GvHD).Dans un premier temps, nous avons montré qu’un environnement inflammatoire ou la présence d’immunosuppresseurs ne diminuaient pas la capacité des HuMoSC à inhiber la prolifération lymphocytaire et à favoriser l’induction de CD4 et CD8 Treg. Enfin, nous avons montré que l’effet graft-versus-leukemia (GvL) est préservé en présence des HuMoSC. Toutes ces données confirment l’intérêt des HuMoSC dans la prévention de la GvHD.Cependant, en raison d’un faible rendement de génération des HuMoSC et d’un problème de disponibilité de billes de tri CD33+ GMP, nous avons aussi modifié notre protocole pour isoler les cellules CD14+, appelées CD14-HuMoSC. Ainsi, dans un second temps, nous nous sommes intéressés aux propriétés des surnageants des HuMoSC et des CD14- HuMoSC. Ces modifications du protocole ont permis d’obtenir un grand nombre de cellules CD14-HuMoSC et de grandes quantités de surnageant produit en conditions GMP. Nous avons montré que les deux surnageants diminuaient l’activation et la prolifération des LT, diminuaient la réponse Th1 au profit de la réponse Th2, favorisaient l’induction des Treg et diminuaient la capacité des cellules dendritiques à induire la prolifération des LT. In vivo, les surnageants préviennent le développement de la GvHD dans un modèle murin de GvHD xénogénique. Enfin, pour montrer que ces deux surnageants seront efficace chez les patients, nous avons montré qu’un environnement inflammatoire ou que la présence d’immunosuppresseurs n’altéraient pas l’effet immunosuppressif des surnageants. Ces résultats confirment leur intérêt thérapeutique. L’étude proteomique de ces deux surnageants a permis d’identifier des protéines immunosuppressives qui pourraient être responsables de leurs capacités immunosuppressives.En conclusion, les HuMoSC et les surnageants des cellules dérivées des HuMoSC représentent un arsenal thérapeutique prometteur dans la prévention de la GvHD mais aussi dans les maladies inflammatoiresAbstract :Our team has developed an original cell therapy derived from monocytes. This sub-population of human suppressor cells of myeloid origin, called Human Monocyte-Derived Suppressor Cells (HuMoSC, CD33+ cells) is able to inhibit effector T cell proliferation and to induce CD4 and CD8 Treg. It has been demonstrated that HuMoSC prevent from graft-versus-host disease (GvHD).In a first time, we showed that an inflammatory environment or the presence of immunosuppressive drugs did not decrease HuMoSC abilities to inhibit T cell proliferation and to promote CD4 and CD8 Treg induction. Finally, we showed that graft-versus-leukemia (GvL) effect is preserved in presence of HuMoSC. Taken together, those data confirm the interest of HuMoSC in GvHD prevention.Nevertheless, due to a low yield of HuMoSC generation with this protocol and problem with avaibility of CD33 GMP beads, we also modified our protocol to isolate CD14+ cells, called CD14-HuMoSC. This is why in a second time, we took interest in HuMoSC and CD14-HuMoSC supernatant properties. These protocol modifications allow us to obtain large number of CD14-HuMoSC cells and large quantities of supernatant produced under GMP conditions. We showed that both supernatants decrease T cell activation and proliferation, decrease Th1 response in favor of Th2 response, promote Treg induction and decrease capacity of dendritic cells to induce T cell proliferation. In vivo, supernatants prevent from GvHD in a murine model of xenogenic GvHD. Finally, in order to assess that these supernatants will be efficient in patient, we showed that an inflammatory environment or presence of immunosuppressive drugs did not alter both supernatant immunosuppressive effects. These results confirm their therapeutic interest. Proteomic analysis allowed us to identify immunosuppressive proteins which could be responsible for supernatants immunosuppressive capacities.In conclusion, HuMoSC and supernatant derived from HuMoSC represent a promising therapeutic arsenal for GvHD prevention but also in inflammatory diseases
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Guo, Hong, and 郭紅. "Effects of anti-DNA antibodies on pleural mesothelial cells: in vitro studies to explore thepathogenetic mechanism of pulmonary lupus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B26631945.
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The Best M.Phil Thesis in the Faculties of Dentistry, Engineering, Medicine and Science (University of Hong Kong), Li Ka Shing Prize, 2001-2003.published_or_final_version
abstract
toc
Medicine
Master
Master of Philosophy
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Jansson, Monika. "Detection of donor cells in recipient tissues after stem cell transplantation using FISH and immunophenotypi Stem cell transplantationng /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-222-4/.
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Ng, Yee-ching Claudia. "Effects of anti-DNA antibodies and mycophenolic acid on inflammatory and fibrotic processes in proximal tubular epithelial cells and the implications in the pathogenesis of lupus nephritis." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43085234.
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Fedoric, Boris. "The effect of immunosuppressive agents on the expression and function of the inhibitory receptors ILT3 and ILT4 in dendritic cells /." Title page and abstract only, 2005. http://web4.library.adelaide.edu.au/theses/09SB/09sbf294.pdf.
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Ng, Yee-ching Claudia, and 吳綺菁. "Effects of anti-DNA antibodies and mycophenolic acid on inflammatory and fibrotic processes in proximal tubular epithelial cells and theimplications in the pathogenesis of lupus nephritis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43085234.
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Miron, Veronique. "The effects of CNS-accessible multiple sclerosis-directed immuno-modulatory therapies on oligodendroglial lineage cells, myelin maintenance, and remyelination /." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115701.
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Myelin and oligodendrocytes (OLGs) are the apparent targets of the immune-mediated injury that underlies the development of multiple sclerosis (M8). Recovery from M8 clinical relapses likely reflects remyelination attributed to recruitment and differentiation of oligodendrocyte progenitor cells (OPCs), rather than to new process formation by previously myelinating OLGs. Newly emerging M8-directed immuno-modulatory therapies (statins and FTY720) can readily cross the blood-brain barrier and have been shown to impact signaling pathways implicated in cytoskeletal regulation, differentiation, migration, and survival; these are cellular events presumably important for myelin integrity and remyelination.Statins inhibit the production of cholesterol (concentrated in the myelin membrane) and isoprenoids (post-translational attachments regulating the functions of proteins such as the Rho GTPases). We showed that treatment of human and rodent-derived OPCs with lipophilic statins induced an initial process extension associated with enhanced differentiation and impaired spontaneous migration, whereas prolonged treatment induced process retraction and cell death. Rodent and human mature OLGs demonstrated similar cytoskeletal and survival responses. Chronic simvastatin therapy of mice inhibited remyelination following demyelination induced by the OLG toxin, cuprizone, attributed to a block in OPC differentiation and consequent decrease in mature OLGs. Even fully myelinated animals treated with simvastatin over the long-term demonstrated a decrease in myelin in the brain by maintaining oligodendroglial cells in the pre-OLG state and preventing continual replacement of mature OLGs.
FTY720 is an agonist of G-protein-coupled receptors S1P1, 3, 4, and 5, that are associated with distinct receptor isotype-selective activation of Rho GTPases. In human OPCs, FTY720 could induce initial S1P3/5-dependent process retraction associated with an inhibition of differentiation, and subsequent S1P1-dependent process extension. Mature OLGs showed a dose-dependent cyclic modulation of process extension and retraction was observed over time. Both human OPCs and OLGs were rescued by FTY720 under death-promoting environments. Both cell types also demonstrated a cyclic and reciprocal modulation of S1P1 and S1P5 mRNA levels, reflected in the recurring receptor isotype-dependent functional responses over time. Studies using organotypic cerebellar slice cultures demonstrated that FTY720 did not impact myelin integrity under basal conditions, yet accelerated remyelination following lysolecithin-induced demyelination. Both treatment regimens were associated with an extension of OPC and mature OLG processes.
Our observations demonstrate that drug concentrations used to modulate immune function can have differential dose and time-dependent effects on OPCs, OLGs, as well as on myelin and remyelination processes. Our findings indicate the need to monitor the effects of putative immuno-modulatory therapies on myelin-related processes in MS patients.
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Pons, Maria J., Cláudia Gomes, Ruth Aguilar, Diana Barrios, Miguel Angel Aguilar-Luis, Joaquim Ruiz, Carlota Dobaño, Valle-Mendoza Juana del, and Gemma Moncunill. "Immunosuppressive and angiogenic cytokine profile associated with Bartonella bacilliformis infection in post-outbreak and endemic areas of Carrion's disease in Peru." Public Library of Science, 2017. http://hdl.handle.net/10757/622210.
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Analysis of immune responses in Bartonella bacilliformis carriers are needed to understand acquisition of immunity to Carrion’s disease and may allow identifying biomarkers associated with bacterial infection and disease phases. Serum samples from 144 healthy subjects from 5 villages in the North of Peru collected in 2014 were analyzed. Four villages had a Carrion’s disease outbreak in 2013, and the other is a traditionally endemic area. Thirty cytokines, chemokines and growth factors were determined in sera by fluorescent bead-based quantitative suspension array technology, and analyzed in relation to available data on bacteremia quantified by RT-PCR, and IgM and IgG levels measured by ELISA against B. bacilliformis lysates. The presence of bacteremia was associated with low concentrations of HGF (p = 0.005), IL-15 (p = 0.002), IL-6 (p = 0.05), IP-10 (p = 0.008), MIG (p = 0.03) and MIP-1α (p = 0.03). In multi-marker analysis, the same and further TH1-related and pro-inflammatory biomarkers were inversely associated with infection, whereas angiogenic chemokines and IL-10 were positively associated. Only EGF and eotaxin showed a moderate positive correlation with bacteremia. IgM seropositivity, which reflects a recent acute infection, was associated with lower levels of eotaxin (p = 0.05), IL-6 (p = 0.001), and VEGF (p = 0.03). Only GM-CSF and IL-10 concentrations were positively associated with higher levels of IgM (p = 0.01 and p = 0.007). Additionally, IgG seropositivity and levels were associated with high levels of angiogenic markers VEGF (p = 0.047) and eotaxin (p = 0.006), respectively. Our findings suggest that B. bacilliformis infection causes immunosuppression, led in part by overproduction of IL-10. This immunosuppression probably contributes to the chronicity of asymptomatic infections favoring B. bacilliformis persistence in the host, allowing the subsequent transmission to the vector. In addition, angiogenic markers associated with bacteremia and IgG levels may be related to the induction of endothelial cell proliferation in cutaneous lesions during chronic infections, being possible candidate biomarkers of asymptomatic infections.
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Roux, Clémence. "Activité immunosuppressive des cellules stromales mésenchymateuses dérivées de cellules souches pluripotentes induites humaines : induction de lymphocytes T régulateurs in vitro et in vivo et expression de PD-L1." Thesis, Université Côte d'Azur (ComUE), 2018. http://www.theses.fr/2018AZUR4226/document.
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La grande originalité de mon projet réside dans la génération de cellules stromales mésenchymateuses (MSCs) à partir de cellules souches pluripotentes induites humaines (iPS). Je rappellerai les propriétés phénotypiques, de multipotence et immunosuppressives des MSCs et m’attarderai sur leurs différents mécanismes immunomodulateurs. Cependant, leur nombre limité et leur isolation difficile limitent leur utilisation thérapeutique nécessitant une autre source de cellules.Mon travail a donc été de générer et de caractériser des MSCs issues d’iPS (huiPS-MSCs). L'avantage des huiPS-MSCs réside dans leur plus grande disponibilité et la possibilité d'en avoir à volonté. Encore faut-il valider l’intérêt thérapeutique potentiel de ces huiPS-MSCs. Premièrement, mes résultats in vitro montrent que les huiPS-MSCs présentent une activité immunosuppressive sur les lymphocytes T (LT) activés conduisant à une induction de LT régulateurs FoxP3+ fonctionnels. Deuxièmement, dans une approche plus axée sur la thérapie, j’ai analysé in vivo l’activité́ immunosuppressive des huiPS-MSCs dans un modèle de réaction xénogénique de greffon contre l'hôte (souris immunodéficientes NSG injectées avec des LT humains). Je montre clairement, après traitement avec les huiPS-MSCs, une réduction de la proportion de LT humains producteurs de cytokines inflammatoires (IFNγ et TNFα) typiques de la pathologie et l’apparition concomitante de LT présentant un phénotype régulateur (production d’IL10 et expression de FoxP3). La fin de mon travail a été de caractériser moléculairement la régulation de l’expression de PD-L1, une molécule immuno-régulatrice puissante, entre les MSCs issues de la moelle osseuse (BM-MSCs) de donneurs sains et nos huiPS- MSCs. Les huiPS-MSCs ont une expression constitutive de PD-L1, qui est absente sur les BM-MSCs. J’ai analysé les microARNs susceptibles de limiter l’expression de PD-L1, j’ai pu en identifier plusieurs. En mesurant leur expression dans les différentes MSCs à notre disposition, je montre que cette expression est inverse par rapport à celle de PD-L1. J’ai ainsi pu démontrer l’activité immunosuppressive de nos huiPS-MSCs in vitro et in vivo avec une perspective d’induction de tolérance immune, et caractériser la régulation de l’expression de PD-L1, molécule immunosuppressive exprimée par les huiPS-MSCsThe mesenchymal stromal cells (MSCs) present many features that render attractive as therapeutic cells. Their phenotype, multipotency and immunosuppressive properties are well described. Nevertheless, major restriction for their clinical use is due to the limited in vitro expansion and low quantity of cells that can be collected from adult tissues. The originality of my project consisted in the generation of mesenchymal stromal cells (MSCs) from human induced pluripotent stem cells (iPS). These huiPS-MSCs could fulfill some of the specification required to improve MSCs use in therapeutic approaches: welldefined and unlimited number of cells with reproducible functional characteristics. In a first approach, I characterized the huiPS-MSCs generated in the laboratory. My results highlight the immunosuppressive activity in vitro of the huiPS-MSCs on T-cell stimulation that induces a switch in T-cell cytokine polarization toward the generation of Treg cells. Secondly, in a more therapy-oriented approach, I analyzed in vivo immunosuppressive activity of huiPS-MSCs in a xenogeneic graft versus host model (NSG immunodeficient mice injected with human T lymphocytes). My data showed significantly reduced percentages of human-differentiated T cells producing Th1 inflammatory cytokines (IFNγ and TNFα). By contrast, T cells producing IL-10 and FoxP3+ Treg cells, absent in nontreated animals, were detected in huiPS-MSCs treated mice, confirming the in vitro results of a tolerizing process. The end of my work was to characterize the molecular regulation of the expression of PDL1, an immunoregulatory molecule expressed by the MSCs. Comparing bone marrow MSCs (BM-MSCs) from healthy donors and our huiPS-MSCs, I showed that the huiPSMSCs have a constitutive expression of PD-L1, which is absent on BM-MSCs. Analysing microRNAs that could limit the expression of PD-L1, I could identify several microRNAs which expression is inverse to the expression of PD-L1. For the first time, my results highlight the immunosuppressive activity of huiPS-MSCs on human T-cell stimulation with a concomitant generation of human Treg cells in vivo and characterize the regulation of PD-L1 expression, an immunosuppressive molecule expressed by the MSCs. They may favor the development of new tools and strategies based on the use of huiPS cells and their derivatives for the induction of immune tolerance
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Hang, Regina [Verfasser]. "ATP, HMGB1, and S100A4 promote immunosuppressive mesenchymal stromal cells by enhancing their kynurenine production : impact of necrosis on tumor-associated MSCs / Regina Hang." Ulm : Universität Ulm, 2019. http://d-nb.info/1186139927/34.
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Bertheuil, Nicolas. "Le tissu adipeux : approfondissement des connaissances fondamentales du tissu et de son compartiment vasculaire stromal, intérêt clinique pour la chirurgie plastique." Thesis, Rennes 1, 2017. http://www.theses.fr/2017REN1B051/document.
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L’objectif de cette thèse était d’améliorer les connaissances fondamentales sur le tissu adipeux, organe qui est au cœur de la pratique des chirurgiens plasticiens. En effet, ce tissu peut être transplanté de façon autologue afin de combler une perte de substance (rôle volumateur des adipocytes) mais également servir à des fins de régénération tissulaire en lien avec les cellules de la fraction vasculaire stromale (FVS) et tout particulièrement des cellules stromales mésenchymateuses (CSM). Ces cellules s’obtiennent après lipoaspiration du tissu par une digestion enzymatique de la graisse obtenue. Il s’avère que les connaissances disponibles sur ces CSM sont essentiellement issues d’études in vitro après une phase de culture cellulaire plus ou moins longue et ainsi les propriétés in vivo sont mal connues. Ce travail a donc consisté à caractériser l’hétérogénéité du compartiment stromal natif du tissu adipeux obtenu après digestion enzymatique. Nous avons isolé deux populations stromales natives distinctes : les ASC (CD34+), en grande majorité, et des cellules péricytaires (CD146+). Ces 2 types cellulaires différaient dans leurs phénotypes, leurs potentiels de clonogénécité et leurs propriétés immunomodulatrices in vitro et in vivo. Nous avons ensuite comparé la digestion enzymatique du tissu aux techniques de digestion mécanique utilisable au sein de nos blocs opératoires. Nous avons démontré que ces nouvelles techniques permettaient bien de produite les cellules de la FVS dont des CSM, cellules particulièrement intéressante pour des gestes de régénération tissulaire. De plus, l’ensemble des techniques de laboratoire acquise au cours de ce travail nous ont permis d’investiguer le rôle des techniques de lipoaspiration utilisé en chirurgie plastique sur le tissu adipeux. Nous avons démontré par cytométrie de flux et par immunofluorescence in situ qu’une partie de la trame microvasculaire était conservée. L’ensemble de ces résultats viennent s’ajouter aux données cliniques démontrant que la lipoaspiration du tissu est un geste permettant d’être plus conservateur pour le tissu et pourrait expliquer des taux de complications moindre après chirurgie de contour de la silhouetteThe aim of this work was to improve the knowledge on adipose tissue, organ that is at the heart of the practice of plastic surgeons. Indeed, this tissue can be transplanted autologously in order to fill a defect (volumizing role of the adipocytes) but also to be used for tissue regeneration in connection with the cells of the stromal vascular fraction (SVF) and especially the mesenchymal stromal cells (MSCs). These cells are obtained after liposuction of the tissue by enzymatic digestion of the extracellular matrix. It turns out that the knowledge available on these CSM is essentially derived from in vitro studies after a cell culture phase and thus the in vivo properties are poorly known. This work consisted in characterizing the heterogeneity of the native stromal compartment of adipose tissue obtained after enzymatic digestion. We isolated two distinct native stromal populations: the ASC (CD34 +), for the most part, and the pericyte cells (CD146 +). These 2 cell types differed in their phenotypes, their clonogenecity potentials and their immunomodulatory properties in vitro and in vivo. We then compared the enzymatic digestion of the tissue with the techniques of mechanical digestion usable within our operating room. We have demonstrated that these new techniques made it possible to produce the cells of the FVS including MSC, cells particularly interesting for regenerative surgery. In addition, all the laboratory techniques acquired during this work allowed us to investigate the role of liposuction techniques used in plastic surgery on adipose tissue. We have demonstrated by flow cytometry and confocal microscopy, that part of the microvasculature framework is conserved after liposuction. All of these results are in addition to clinical data demonstrating that liposuction of the tissue is a gesture to be more conservative for the tissue and could explain lower rates of complications after contour surgery
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Hassan, Zuzana. "Studies on mechanisms of busulphan cytotoxicity and pharmacokinetics : with special reference to liposomal busulphan /." Stockholm : Karoliska Univ. Press, 2001. http://diss.kib.ki.se/2001/20010504hass/.
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Premachandran, Nair Anoop Chandran [Verfasser], Jörg [Gutachter] Wischhusen, Utz [Gutachter] Fischer, and Gunter [Gutachter] Meister. "Identification and functional characterization of TGF-β inducible, immunosuppressive miRNAs in human CD8+ T cells / Anoop Chandran Premachandran Nair. Gutachter: Jörg Wischhusen ; Utz Fischer ; Gunter Meister." Würzburg : Universität Würzburg, 2015. http://d-nb.info/1108781322/34.
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Lemaitre, Florian. "Optimisation des thérapeutiques immunosuppressives par méthode pharmacologique." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA114832/document.
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Les immunosuppresseurs sont des médicaments ayant démontré leur efficacité dans la prévention du rejet de transplantation d’organe solide. Néanmoins, ces médicaments présentent une importante variabilité de la réponse pharmacologique notamment liée à une variation de leur pharmacocinétique. Cette variabilité peut être à l’origine d’un défaut d’efficacité du traitement ou de sur-expositions entrainant une toxicité. Le suivi thérapeutique pharmacologique (STP) des concentrations sanguines d’immunosuppresseur permet de limiter ces risques de sur ou de sous-exposition en facilitant l’adaptation de posologie de ces traitements. En dépit de l'utilisation intensive du STP des concentrations d'immunosuppresseurs chez le transplanté d'organe, la fréquence du rejet aigu a peu diminué au cours de ces dernières années et reste élevée. Le rejet aigu cellulaire peut, en outre, survenir chez le patient alors même que ses concentrations sanguines sont en zone thérapeutique. C'est pourquoi la recherche d'améliorations de ce suivi thérapeutique ainsi que la recherche de nouveaux moyens de monitoring sont des axes pertinents d'investigation en pharmacologie des immunosuppresseurs. L’objectif de ce travail de doctorat a été de développer de nouveaux outils pharmacologiques de monitoring de l’effet de deux immunosuppresseurs, l’évérolimus et le tacrolimus, dans le but de participer à la maitrise de la variabilité pharmacologique de l’effet immunosuppresseur. Pour la première fois, la pharmacocinétique de l'évérolimus chez le transplanté cardiaque a été modélisée par une approche de population. La modélisation pharmacologique est un des axes actuels d’amélioration du STP des immunosuppresseurs permettant d’évaluer l’impact de covariables démographiques, biologiques et/ou génétiques sur la pharmacocinétique de ces médicaments. L’élaboration de ce modèle doit permettre une individualisation des posologies conduisant à la limitation de la variabilité pharmacocinétique lors d’un traitement par cette molécule.Au cours de ce travail, deux méthodes analytiques ont également été développées par LC-MS/MS pour le dosage intracellulaire de l’évérolimus et du tacrolimus. La mesure des concentrations des immunosuppresseurs à l’intérieur même de la cellule, c’est à dire au niveau de son site d’action, apparait comme une mesure plus pertinente que la simple mesure des concentrations dans le sang. Ces méthodes ont ensuite été évaluées sur des petites cohortes de patients transplantés cardiaques. La faisabilité de tels dosages a été démontrée et a permis la réalisation de la dernière partie présentée au cours de ce travail. En effet, une étude clinique a été réalisée chez le patient transplanté hépatique de novo en vue de rapprocher les concentrations sanguines et intracellulaires de tacrolimus et l'effet sur la protéine cible, la calcineurine. Pour la première fois des pharmacocinétiques intracellulaires complètes ont pu être obtenues permettant la description de la cinétique intracellulaire du tacrolimus. Cette étude a également permis de mettre en évidence et de décrire la relation dose - concentration sanguine - concentration intracellulaire - effet sur la protéine cible du tacrolimus chez le transplanté hépatique. Ces travaux ont permis de jeter les bases nécessaires à la réalisation d'essais cliniques permettant d'évaluer la pertinence d'un suivi longitudinal des concentrations intracellulaires et/ou de l'activité de la calcineurine dans la prévention de rejet de transplantation. Les outils développés au cours de ce travail de doctorat visent, d’une part, à mieux appréhender la variabilité de la réponse pharmacologique au cours d’un traitement immunosuppresseur et, d’autre part, à être des outils de compréhension des mécanismes pharmacocinétiques et cellulaires de ces traitements. L'utilisation de ces outils doit concourir à la diminution de la fréquence du rejet de greffe et à l'amélioration globale de la prise en charge du patient transplanté d'organeImmunosuppressive drugs have proven efficacy in the prevention of acute rejection of solid organ transplantation. However, these drugs exhibit substantial variability in pharmacological response due to such a variation in their pharmacokinetics. This variability may be the cause of underexposure with a lack of efficacy or over-exposure causing toxicity. Therapeutic drug monitoring (TDM) of immunosuppressant blood levels can limit the risk of over or underexposure facilitating dosage adjustment of these treatments. Despite the extensive use of TDM, the incidence of acute rejection has declined somewhat in recent years and remains high (in the order of 8-15%). Acute cellular rejection can further occur in patients even though blood levels are within the therapeutic range. That is why improvements in the therapeutic monitoring and new ways of monitoring are relevant lines of investigation in pharmacology.The objective of this phD work was to develop new pharmacological tools for monitoring the effect of two immunosuppressive drugs, everolimus and tacrolimus in order to control the pharmacological variability of the immunosuppressive effect .For the first time, the pharmacokinetics of everolimus in heart transplant was modeled by a population approach. Pharmacological modeling is one of the current areas of improvement of immunosuppressants TDM which allows evaluating the impact of demographic, biological and / or genetic on the pharmacokinetics of these drugs covariates. The development of this model must allow individualization of dosages leading to limit pharmacokinetic variability during treatment with this drug.During this work, two analytical methods were also developed by LC-MS/MS for assaying intracellular tacrolimus and everolimus concentrations. Measuring intracellular concentrations of immunosuppressive drugs, i.e. at its site of action, appears as a more relevant than measuring blood concentrations. These methods were then evaluated on small cohorts of heart transplant patients. The feasibility of such assays has been demonstrated and led to the completion of the last part presented in this work.Indeed, a clinical study was performed in de novo liver transplant patients to evaluate blood and intracellular concentrations of tacrolimus and their effect on the target protein, calcineurin. For the first time complete intracellular pharmacokinetics have been obtained for the description of the profile of the intracellular kinetics of tacrolimus. This study also highlights and describes the relationship dose - blood concentration - intracellular concentration - effect on the target protein of tacrolimus in liver transplant patients. This work might help conducting clinical trials to assess the relevance of a longitudinal follow-up of intracellular concentrations and / or activity of calcineurin in the prevention of transplant rejection.The tools developed in this PhD work aimed, firstly, to better understand the variability of the pharmacological response in immunosuppressive therapy and, secondly, to be tools for understanding the drug mechanisms inside of the cell. The use of these tools should contribute to the decrease in the frequency of graft rejection and the overall improvement in the management of organ transplant patients
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Khong, Andrea. "Effect of murine cytomegalovirus infection on haematopoiesis and myeloid cell differentiation and function." University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0260.
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Cytomegalovirus (CMV) is a ubiquitous pathogen affecting over 95% of the worlds population. While infection is typically asymptomatic in healthy individuals, the virus persists life-long in its host and can be reactivated following withdrawal of immune control. As such, it remains a serious clinical concern in individuals who are immunocompromised, such as newborns and neonates, transplant and/or chemotherapy recipients, and HIV/AIDS patients. CMV also has the ability to cause immunosuppression, the mechanisms of which include defective antigen presentation to T cells and interference with haematopoiesis in the bone marrow (BM). Due to strict species specificity, murine CMV (MCMV) provides a relevant model for the study of CMV modulation of the immune system in vivo in its natural host. The type I interferons (IFNs) represent a major family of cytokines involved in the early response to MCMV infection. Their anti-viral activity and regulation of NK cell activation and cytotoxicity are of significant interest in the context of MCMV infection, as genetic resistance to MCMV is mediated by the ability of Ly49H+ NK cells to directly recognise and lyse infected cells. Chapter 2 comprises an analysis of acute MCMV infection in the absence of type I IFN activity. These studies were conducted in IFNAR1 and IFNAR2 deficient mice, which lack components of the type I IFN receptor. Data obtained from these studies confirmed the essential requirement for type I IFN in controlling viral titres, promoting expansion of splenic Ly49H+ NK cells, and inducing early activation of NK cell cytotoxicity. In addition, our data depicted an accumulation of infected myeloid cells in the absence of effective NK cell-mediated control. This was paralleled by a significant increase in the level of serum TNF-a and IFN-¿, an effect which in some cases has been linked to serious pathological disease. Thus, the data described in this chapter provide an insight into the consequences arising from delayed NK cell responses to MCMV infection in the absence of type I IFN. vii Type I IFN can also potentially affect BM haematopoiesis. BM atrophy and impairment of myelopoiesis are serious consequences of CMV infection. During acute MCMV infection we consistently observed a profound loss of splenic dendritic cells (DCs) in BALB/c mice. Since all DC subsets are derived from BM haematopoietic progenitor cells, the possibility that MCMV might interfere with BM haematopoiesis and DC differentiation was explored. Chapters 3 and 4 describe the impact of acute MCMV infection on BM progenitors, with particular emphasis on the differentiation capabilities of these cells in ex vivo culture systems. Chapter 3 focuses on the effect of MCMV infection on BM cellularity and frequency of specific BM progenitor populations. A thorough analysis of contributing factors, such as viral infection of BM cells, involvement of type I and II IFNs, progenitor cell trafficking and NK cell activity in the BM compartment, was conducted. Our results showed that a severe loss of BM cellularity occurs in MCMV-infected mice. Furthermore, when BM cells from MCMV-infected mice were cultured ex vivo in granulocyte macrophage-colony stimulating factor (GM-CSF), there was an impairment in their ability to differentiate into DCs.
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Lu, Tangying (Lily). "Cannabinoids suppress dendritic cell-induced T helper cell polarization." [Tampa, Fla] : University of South Florida, 2006. http://purl.fcla.edu/usf/dc/et/SFE0001790.
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Gronert, Álvarez Anna Christina [Verfasser], and Hans-Heinrich [Akademischer Betreuer] Wedemeyer. "Regulatory T cells in liver transplantation : phenotypical characterisation and effects of immunosuppressive drugs / Anna Christina Gronert Álvarez. Klinik für Gastroenterologie, Hepatologie und Endokrinologie der Medizinischen Hochschule Hannover. Betreuer: Hans-Heinrich Wedemeyer." Hannover : Bibliothek der Medizinischen Hochschule Hannover, 2014. http://d-nb.info/1050008200/34.
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Shirley, Shawna A. "The Role Of Curcumin In Human Dendritic Cell Maturation And Function." [Tampa, Fla] : University of South Florida, 2008. http://purl.fcla.edu/usf/dc/et/SFE0002666.
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Glien, Anja. "Einfluss von unterschiedlichen immunsuppressiven Strategien auf Proliferation, Stoffwechsel und Differenzierung humaner fetaler neuraler Progenitorzellen in vitro." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-161126.
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Splith, Katrin, and Sven Jonas. "Antibody-mediated rejection of arterialised venous allografts is inhibited by immunosuppression in rats." Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-137757.
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We determined in a rat model (1) the presence and dynamics of alloantibodies recognizing MHC complexes on quiescent Brown-Norway (BN) splenic cells in the sera of Lewis (LEW) recipients of Brown-Norway iliolumbar vein grafts under tacrolimus immunosuppression; and (2) the presence of immunoglobulins in the wall of acute rejected vein allografts.
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Brown, Alex Joseph. "Maintenance and modification of mesenchymal stromal cell immunosuppressive phenotype." Thesis, University of Iowa, 2017. https://ir.uiowa.edu/etd/5723.
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The purpose of this study was to identify conditioning strategies for mesenchymal stromal cells (MSC) which optimize cellular immunosuppressive potency. By identifying new treatment strategies and previously unidentified small molecules capable of stimulating MSC we hope to pave the way tailoring licensed MSC phenotypes to be used in a specific disease state, rather than a one size fits all package. We sought to determine how MSC act in response to a changing immune response or environmental condition. MSC are exquisitely sensitive to changes in their environmental conditions and we show that cellular transcriptome and secretome changes are conditionally responsive to their inflammatory stimulus. One of the main subjects of analysis here is the observations of how these cellular profiles evolve over time in the presence of an inflammatory environment. Similarly, this study observes how MSC behavior changes after an inflammatory event has been resolved to address, in part, the plasticity of MSC licensing and the ability of MSC to rapidly recall a previous immunosuppressive state upon secondary challenge with an inflammatory stimulus. Data was obtained from in vitro experiments with human bone marrow derived MSC and donor human peripheral blood mononuclear cells (PBMC), while in vivo data was obtained using C57BL6/J mice.
Overall this research demonstrated that MSC potency can be bolstered by small molecule and drug treatment conditioning, and that certain disease conditions may be more effectively paired with specific MSC conditioning strategies to improve their therapeutic effectiveness.
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Varani, Stefania. "Human cytomegalovirus and dendritic cell interaction : role in immunosuppression and autoimmunity /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-505-4/.
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Heaney, J. "Immunosuppression and virus-cell interactions in morbilliviruses." Thesis, Queen's University Belfast, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246332.
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Lappin, Michael Benedict. "The role of dendritic cells in ultraviolet-B-induced immunosuppression." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/21349.
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Exposure to ultraviolet-B light (UVB) suppresses immune responses to a variety of antigens, including contact sensitizers, in both mice and humans. A number of mediators of UVB-induced immunosuppression have been proposed including DNA damage, cis-urocanic acid, TNF-α and IL-10. UVB irradiation also causes the loss of Langerhans cells (LC) from the skin and the accumulation of LC-derived dendritic cells (CD) in the draining lymph nodes (DLN). A chronic UVB exposure protocol, using broadband (270-350nm) and narrowband (311-312nm) sources, was used to examine the effect of UVB on the skin immune system. Exposure to both sources reduced the numbers of LC in the epidermis. Exposure to broadband but not narrowband UVB induced epidermal thickening in a dose dependent manner. Although damage measured by thickening resulted from broadband UVB only, both sources led to a small increase in sunburn cells, which may represent an apoptotic keratinocyte population. Both sources were equally efficient at inducing the conversation of trans-urocanic acid to the cis-isomer, but only the broad band source suppressed contact hypersensitivity (CH) responses. Thus LC loss and the isomerization of urocanic acid may not be the primary mediators of immunosuppression during chronic UVB exposure. An acute UVB exposure protocol was used to examine the effect of UVB on DC in vivo. Mice were irradiated with an immunosuppressive dose of UVB, and the function and phenotype of DC accumulating in the DLN was examined. Exposure to UVB prior to sensitization did not reduce the ability of DC to induce proliferative responses of hapten sensitized lymph node cells (LNC). The necessary function of DC in mixed lymphocyte reactions was also unaffected by prior exposure to an immunosuppressive dose of UVB. The expression of MHC class II, intercellular adhesion molecule-1 and B7-2 (CD86) on DC was also examined.
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Mao, Huawei, and 毛华伟. "Direct infection and immunosuppression of human NK cells by influenza virus." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45197842.
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Whatcott, Andrew. "Assessing the impact of immunosuppressive drugs on regulatory T cell therapy." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:d3e538bc-0558-4f12-8be4-5f77d79c4323.
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Immunosuppressive drugs have facilitated the progression of solid organ transplantation from experimental therapy to routine practice, however transplant recipients are still susceptible to chronic rejection and co-morbidities. The emergence of regulatory T cells (Treg) as a key regulator of the immune system, together with an abundance of evidence from experimental transplant models, has led to clinical trials asking whether Treg can improve transplant outcomes. However, given that Treg cellular therapy will only be acceptable if introduced into current immunosuppressive regimens, a critical question is how Treg will respond in the presence of concomitant immunosuppression. Whilst in vitro data are available, very few credible experiments have been done asking whether individual immunosuppressive drugs have a positive, a neutral or a detrimental impact on the Treg function in vivo. Thus the aims of this thesis were firstly to generate sufficient numbers of adaptive Treg for extensive experimental use and secondly to evaluate their ability to control transplant rejection in vivo in the presence of biologically valid doses of individual, clinically relevant immunosuppressive drugs. Importantly, the model chosen was the heterotopic heart transplant model in lymphoreplete mice to avoid possible artefacts that can occur in cell reconstituted lympho-depleted mice. The model also has the added advantage that by dealing with an intact immune system, it perhaps represents a small step closer to the clinical situation. Generating sufficient numbers of stable Treg was necessary for planned in vivo experiments. Incubating CD4+ T cells with anti-CD44 antibody, prior to driving them with bone-marrow derived dendritic cells, enriched for a stable population of Treg and importantly yielded sufficient numbers of cells for in vivo experiments. It is frequently stated that alloantigen-driven Treg are more efficacious than activated autologous nTreg, however there was no difference in rejection kinetics in either a skin or heart allograft model when comparing alloantigen-driven Treg with nTreg. As generating alloantigen-driven Treg is less efficient than nTreg, pursuing the former as a potential therapy might therefore be unnecessary. This could have a considerable impact on the logistics and the practicality of clinical Treg cellular therapeutics. The timing of Treg administration is an important consideration to maximise efficacy. Pre-transplant administration led to the longest graft survival times, suggesting that this is the most effective time for cell delivery. Preclinical models provide a useful tool to ask how immunosuppressive drugs will affect adoptively transferred Treg. The data presented in this thesis suggest that combining Treg with Rapamycin, Mycophenolate Mofetil (MMF) or Tacrolimus did not completely prevent Treg function. However, Methylprednisolone (MP) did prevent Treg function, suggesting it cannot be used with adoptively transferred Treg. Overall, these results provide important data for the design of immunosuppressive regimens for future clinical trials assessing the efficacy of Treg in transplant recipients.
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RODRIGUES, DANIELLE B. "Terapia antiangiogênica de tumores utilizando células produtoras de endostatina encapsuladas em sipositivos de imunoisolamento." reponame:Repositório Institucional do IPEN, 2008. http://repositorio.ipen.br:8080/xmlui/handle/123456789/11711.
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IPEN/D
Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP
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VALLEJO, NATALIA M. "Obtenção de altos níveis séricos de endostatina murina em camundongos pela utilização de células de ovário de hamster chinês recombinantes secretando endostatina transplantadas em dispositivos de imunoisolamento." reponame:Repositório Institucional do IPEN, 2008. http://repositorio.ipen.br:8080/xmlui/handle/123456789/11667.
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Dissertacao (Mestrado)
IPEN/D
Instituto de Pesquisas Energéticas e Nucleares - IPEN/CNEN-SP
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Malick, Adrien Paul. "Tumor-induced immunosuppression: Contribution of a high molecular weight inhibitor and Prostaglandin E2." Diss., Virginia Polytechnic Institute and State University, 1987. http://hdl.handle.net/10919/53639.
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A heat-stable soluble inhibitor of T cell proliferation was demonstrated in splenic and peritoneal macrophage (Mφ) culture supernatants. Concentrated supernatants were prostaglandin E₂ (PGE₂)-free and yet inhibited proliferation in the mixed lymphocyte reaction (MLR) and mitogen assays. The high mw inhibitory factor was apparently >67 kd, as shown by S-200 Sephacryl chromatography and gel electrophoresis. DEAE-Cellulose chromatography suggested that the pl of the inhibitory factor was < 7.7. lsoelectric focusing revealed that the Mφ-mediated inhibitory activity differed in charge, with a pl of 6.5-7.6 for normal hosts and 4.0-6.0 for tumor bearing hosts (TBH). Normal and TBH Mφ supernatants showed different hydroxylapatite fractionation, with the latter being resistant to proteolytic enzymes but sensitive to neuraminidase. Lectins such as wheat germ agglutinin, concanavalin A, Ricin communi: and Bandeirea simplicifolia were not useful in affinity purification of the high mw inhibitory monokine. Sugar-BSA conjugates suggested that inhibitory activity was vested in a terminal ßl,4 linked galactose. The inhibitory activity was apparently hydrophobic and heat·stable, but heat-stability was lost if supernatants were boiled at an acidic pH. The high mw monokine inhibited the proliferation of P388D₁ and A4A cells, but enhanced the proliferation of BW 5147.3 cells. Time course addition to the MLR revealed that PGE; may be required for inhibitory activity to be manifested early (0 and 24 hr) but not if the high molecular weight (mw) inhibitor was added late (>48 hr). Indomethacin blocked activity of the inhibitory factor early in the MLR using normal host T cells and augmented the proliferation of TBH T cells in the MLR. Both normal and TBH Mo supernatants suppressed the generation of interleukin 2 but with a dose- and time·dependent difference. Cell cycle analysis of mitogen- stimulated cells revealed that TBH MPh. D.
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Correia, Aristides Tadeu. "Efeitos do basiliximab com e sem a terapia tríplice na depuração mucociliar das vias aéreas de ratos: estudo experimental." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5156/tde-13062017-162816/.
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Introdução: Uma imunossupressão eficaz é fundamental para a sobrevivência do paciente após o transplante de pulmão. Estudos prévios demonstraram que drogas imunossupressoras como ciclosporina A, tacrolimo, micofenolato de sódio e prednisona prejudicaram a depuração das vias aéreas de ratos. Para prevenir a rejeição aguda, o basiliximab tem sido utilizado como terapia de indução previamente ao transplante de pulmão em muitos centros ao redor do mundo. Entretanto, existem poucos trabalhos reportando seus efeitos adversos. Objetivo: Avaliar se o basiliximab isolado e em conjunto com a terapia tríplice (tacrolimo, micofenolato de sódio e prednisona) causa efeitos adversos no aparelho mucociliar traqueobrônquico, alterando a depuração mucociliar das vias aéreas de ratos. Método: Oitenta ratos foram distribuídos em quatro grupos conforme o tratamento: Controle, Basiliximab, Tríplice e Basiliximab+Tríplice; e dois subgrupos de acordo com o tempo de tratamento: 7 e 15 dias. Após o período de tratamento, os animais foram eutanasiados e as seguintes análises foram realizadas: análise do lavado broncoalveolar, frequência de batimento ciliar (FBC), velocidade de transporte mucociliar (VTMC), transportabilidade do muco in vitro, histologia, expressão do gene Muc5ac, concentração da proteína mucina do gene Muc5ac e avaliação de apoptose celular no epitélio das vias aéreas. Resultados: Não houve alteração do número de leucócitos no lavado broncoalveolar e da FBC entre os grupos. Já a VTMC foi menor nos grupos Basiliximab e Basiliximab+Tríplice tratados por 7 dias, enquanto nos animais tratados por 15 dias a velocidade foi menor nos grupos Trípice e Basiliximab+Tríplice. O transporte do muco in vitro foi menor no grupo Basiliximab+Tríplice tratado por 15 dias. A porcentagem dos mucos ácido e neutro não foi diferente entre os grupos tratados por 7 e 15 dias, o mesmo ocorreu para a expressão e concentração da proteína mucina do gene Muc5ac. Os grupos Tríplice e Basiliximab+Tríplice tratados por 7 e 15 dias, respectivamente, apresentaram número maior de células apoptóticas no epitélio da via aérea. Conclusão: A droga basiliximab, isolada e em conjunto com a terapia tríplice, prejudicou o aparelho mucociliar traqueobrônquico de ratos, especificamente a depuração mucociliarIntroduction: Optimal immunosuppression is critical to the survival of the patient after lung transplantation. Previous studies showed that immunosuppressive drugs such as cyclosporine, tacrolimus, sodium mycophenolate and prednisone impaired mucociliary clearance of rats. To prevent acute rejection, basiliximab has been used as induction therapy before lung transplantation in many centers around the world. However, there are few studies reporting its side effects. Objective: Evaluate if basiliximab alone and in combination with triple therapy (tacrolimus, sodium mycophenolate and prednisone) causes adverse effects on the tracheobronchial mucociliary apparatus by impairing airways mucociliary clearance of rats. Method: Eighty rats were divided into four groups according to treatment: Control, Basiliximab, Triple and Basiliximab+Triple; and according to the treatment time: 7 and 15 days. After the treatment period, the animals were euthanized and the following analyzes were performed: bronchoalveolar lavage, ciliary beating frequency (CBF), mucociliary transport velocity (MCTV), mucus transportability rate in vitro, hystology, Muc5ac gene expression, concentration of the mucin protein of the Muc5ac gene and evaluation of cellular apoptosis in the airway epithelium. Results: There was no alteration in the number of leukocytes in the bronchoalveolar lavage fluid and the CBF between groups. The MCTV was lower in the Basiliximab and Basiliximab+Triple groups treated for 7 days, while the velocity was lower in the Triple and Basiliximab+Triple groups treated for 15 days. The mucus transportability rate in vitro was lower in the Basiliximab+Triple group treated for 15 days. There was no difference in percentage of both acidic mucus and neutral mucus between groups treated for 7 and 15 days. Also, there was no difference in the expression and concentration of the mucin of the Muc5ac gene. The Triple and Basiliximab+Triple groups treated for 7 and 15 days, respectively, had a higher number of apoptotic cells in the airway epithelium. Conclusion: The basiliximab, alone and in conjunction with triple therapy, impaired the tracheobronchial mucociliary apparatus of rats, specifically the mucociliary clearance
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Gilot, Bryant Joseph. "Visualisation of cytotoxic T cells during allograft rejection and tolerance." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326006.
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Schilke, Angela J. "The parameters of Cyclosporine A induced inhibition of a T cell dependent antibody response." Virtual Press, 1990. http://liblink.bsu.edu/uhtbin/catkey/724567.
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Cyclosporine A (CsA) is a widely used immunosuppressive drug which has novel, clinically beneficial effects on the immune system. Substantial evidence indicates that CsA acts preferentially by impairing T cell lymphokine production, but there is some evidence that CsA may also affect B cells and other antigen presenting cells directly. Using an in vitro antibody response to sheep red blood cells, we have examined the effect CsA has on different populations of mouse lymphocytes. CsA appears to have a direct inhibitory effect on highly purified B cells from naive animals in a dose dependent manner at physiologically achievable levels in vitro. Even antigen stimulated B cells were found to be sensitive to the late addition of CsA when the drug was added simultaneously with lymphokine. B cells and T cells briefly pulsed with CsA do not recover to produce antibody when CsA is removed. Indeed, B cells from naive animals treated in vivo with CsA and stimulated in vitro with lymphokine and SRBC to produce antibody are profoundly inhibited from producing PFC despite the absence of CsA in culture. These findings suggest that CsA has direct irreversible, fast acting inhibitory effects on B lymphocytes aside from or in addition to its effects on T cells.Department of Biology
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El, Refaee Mohamed. "Tumour-mediated immunosuppression of antigen presenting cells: a potential target for cancer immunotherapy." Thesis, University of Nottingham, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.606810.
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Tumour escapes from immunosurvillence though tumour-mediated suppression. Tumour disrupts dendritic cells (DC) and macrophage functions and interferes with developing anti-tumour microenvironment. Indeed, DC dysfunction in cancer is a limiting factor in cancer immunotherapy. The hypothesis that alternation of DC MAPK pathway is a strategy by which tumours evade immunosurvillence was tested. Our results revealed that, tumours exploit DC through manipulation of ERK signalling pathway which resulting in inhibition of IL-12 production. In addition, tumours suppress the fibroblasts induced IL-23 production by DC. Through Interfering with IL- 12 and IL-23 production, tumours down regulate immediate inflammatory response responsible for defending against the newly developed malignancy. Similarly, our results on monocyte/ macrophage lineage showed that tumour alternate their function away from pro-inflammatory activity and closer to the regulatory profile.
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Beik, Ali Idris. "Monitoring of T cell subsets after renal transplantation." Thesis, University of Warwick, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300715.
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Lawrie, Alastair. "Mechanisms of immune escape by B-cell lymphoma." Thesis, University of Aberdeen, 2016. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=231642.
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Many cancers, including lymphoma, are associated with increased numbers of T cells with suppressive properties, and it has been suggested that immune subversion is important in cancer pathogenesis. The ability of lymphoma cells to induce conventional CD25- T cells to adopt a regulatory phenotype was evaluated, with the aim of elucidating the factors and pathways governing this process and determining the clinical relevance. Regulatory T cell phenotype in both peripheral blood and nodal material from patients with lymphoma and healthy controls was also assessed. Preferential representation of Tregs in nodal tissue was noted with higher percentages seen than in peripheral blood. Contrary to previous studies, minimal evidence to suggest that lymphoma induces a regulatory phenotype from CD4+CD25- T cells was found. Furthermore, nodal Tregs displayed high expression of Helios and FOXP3, indicating a thymically-derived rather than induced origin. PD-1 expressing T cells were present in greater numbers in PBMCs from patients compared with healthy controls, suggesting an alternative reason for the immunosuppression that may be exhibited in these patients. These data support recruitment and amplification as the mechanism for the high proportion of Tregs seen in lymphoma. Hodgkin lymphoma is typified by a prominent reactive infiltrate and is the archetype of immune subversion in lymphoma. Inherited predisposition is demonstrated through familial and twin studies. Susceptibility loci have been identified in a number of genes that affect immune response, with the strongest association seen with the HLA region. 5 individuals with classical Hodgkin lymphoma from a family originating in North East Scotland were evaluated by linkage analysis and exome sequencing. Novel, shared variants predicted to disrupt protein function were identified in 2 genes on chromosome 3. Proximity to a previously described gene in familial Hodgkin lymphoma implicates this region as an important susceptibility locus.
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Khan, Sarwat Tahsin. "An Interleukin-12-Expressing Oncolytic-Virus Infected Autologous Tumor Cell Vaccine Generates Potent Anti-Tumor Immune Responses." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37940.
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