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Dissertations / Theses on the topic 'Cellular rejection'
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Sleater, Michelle Leigh. "Cellular and molecular effector mechanisms of islet allograft rejection /." Connect to full text via ProQuest. IP filtered, 2006.
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Thesis (Ph.D. in Immunology) -- University of Colorado at Denver and Health Sciences Center, 2006.Typescript. Includes bibliographical references (leaves 151-168). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Chen, Raymond Hsin-Chih. "Cellular infiltration in transplanted organs : detection of cytotoxic granule-associated proteins." Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357410.
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Bathgate, Andrew John. "The pre-transplant prediction of acute cellular rejection following liver transplantation." Thesis, University of Edinburgh, 2000. http://hdl.handle.net/1842/22544.
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The aim of this thesis was to investigate the effect of various parameters in patients with chronic liver disease pretransplant which may influence the occurrence of acute rejection post transplant. This may be useful in tailoring immunosuppression to avoid adverse effects in patients less likely to develop acute rejection. The role of cytokines in acute rejection is not clear but animal and human studies had suggested that tumour necrosis factor alpha (TNF-a) played some role. Polymorphisms in the genes encoding TNFa, interleukin 10 and transforming growth factor beta1 (TGFb1) which influence in vitro production of cytokines were examined in transplant patients. This showed an increase in the TNFa 2 polymorphism at position -308 in patients with acute rejection but no association with IL-10 or TGFb1 polymorphisms. Pretransplant levels of TNFa and IL-10 were measured following stimulation of peripheral blood mononuclear cells with lipopolysaccharide from patients with chronic liver disease. PBMC were preincubated with different immunosupressants. There was increased production of stimulated TNFa pretransplant in patients who went on to develop acute rejection. No relationship was found between IL-10 production and acute rejection. There were differences in the effects of tacrolimus, cyclosporin and dexamethasone on the production of both cytokines. The pretransplant immune status of patients was assessed by contact sensitisation to diphenylcyclopropenone (DPC). This demonstrated that patients unable to mount an immune response to DPC did not require treatment for acute rejection following liver transplantation. It also demonstrated a correlation between the strength of reaction to DPC and the severity of acute rejection.
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Flynn, T. H. "Clinical and experimental studies on the cellular mediators of corneal allograft rejection." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1306706/.
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Despite significant advances in our knowledge of the cellular and molecular elements of transplant immunology the 10 year survival probability for all human corneal grafts is 0.73. In some "high-risk" recipients it is as low as 0.37. To date almost all our knowledge about the cellular events during acute corneal graft rejection comes from animal models. In mice, the presence of pre-existing host corneal vascularisation confers "high-risk" status on a graft and has been shown to accelerate rejection. In the first part of this thesis the effect on survival of grafting to an inflamed conjunctival bed was investigated. Using a mouse model of allergic conjunctivitis significantly reduced survival was seen in graft recipients with perioperative conjunctival inflammation. This appeared to be due to the local effects of conjunctivitis rather than systemic effects of allergy/ atopy. Subsequent experiments investigated the effect of perioperative allergic conjunctivitis on the cellular components of both early (surgical trauma-induced, alloantigen-independent) and late (alloantigen-dependent; rejection) post-keratoplasty anterior segment inflammation and demonstrated significant effects on both. Grafts recipients with allergic conjunctivitis had significantly greater early post-operative corneal inflammation and associated corneal and conjunctival lymphangiogenesis. Analysis of graft infiltrating cells during rejection in mice confirmed that large numbers of CD4+ cells, CD8+ cells and macrophages were recruited. Flow cytometric analysis of human aqueous during acute endothelial rejection demonstrated for the first time the presence of CD4+ cells, CD8+ cells and a surprisingly high proportion of macrophages therein. In mouse recipients with allergic conjunctivitis eosinophils were found in both the graft itself and the ciliary body during rejection although the role of these cells during rejection is uncertain. Chemokine analysis during both murine and human corneal graft rejection demonstrated increased expression of the chemokine IP-10 (CXCL-10) suggesting a potentially important role for this protein in the rejection process.
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McLean, Adam George. "Patterns of graft infiltration and cytokine gene expression during the first ten days of kidney transplantation." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390513.
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Wilson, Nicole K. "Borderline Lesions Exhibit Clinical and Graft Survival Characteristics Common to Acute Cellular Rejection." University of Cincinnati / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627665576477761.
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Salah, Adeeb Ahmed Kassim. "Application of Complement Component 4d Immunohistochemistry to ABO-Compatible and ABO-Incompatible Liver Transplantation." Kyoto University, 2015. http://hdl.handle.net/2433/199180.
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Webley, Kayonne. "INTERFERENCE REJECTION PERFORMANCE AS A MEANS OF FREQUENCY OPTIMISATION IN A MIXED CELLULAR/MANET NETWORK." International Foundation for Telemetering, 2006. http://hdl.handle.net/10150/604076.
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ITC/USA 2006 Conference Proceedings / The Forty-Second Annual International Telemetering Conference and Technical Exhibition / October 23-26, 2006 / Town and Country Resort & Convention Center, San Diego, CaliforniaResearch at Morgan State University shows a means of enabling both a mobile ad-hoc network (MANET) and a cellular network to operate simultaneously in the same spectrum. This enhanced frequency efficiency would facilitate the creation of a hybrid or Mixed Cellular/MANET network (MCMN) in which each of the MCMN sub-networks would have access to the entire allotted spectrum. Interference rejection and excision have been identified as a means of distinguishing between and isolating the two different kinds of signals. This paper shows the promising performance of such techniques within the MCMN environment as a part of the integrated Network Enhanced Telemetry (iNET) project.
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He, Rong. "AMPS co-channel interference rejection techniques and their impact on system capacity." Diss., This resource online, 1996. http://scholar.lib.vt.edu/theses/available/etd-10022008-063026/.
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Bodez, Diane. "Etude des profils transcriptionnels myocardiques et sanguins du rejet aigu de greffe cardiaque." Thesis, Paris Est, 2017. http://www.theses.fr/2017PESC0009.
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La greffe cardiaque est le traitement ultime de l’insuffisance cardiaque. Le rejet aigu pose plusieurs problématiques, en particulier sa survenue imprévisible même sous traitement immunosuppresseur, et un diagnostic histologique qui nécessite des biopsies endomyocardiques (BEM) invasives répétées, et qui souffre de nombreuses limites. Le besoin de critères diagnostiques et prédictifs, idéalement non invasifs, nous a conduits à étudier le rejet aigu de greffe cardiaque sur le plan moléculaire. Nous avons caractérisé les profils d’expression génique (PEG) myocardiques et sanguins lors de différentes phases du rejet cellulaire (RC) et du rejet médié par les anticorps (RMA), par analyse sans a priori des transcriptomes sur puce à ADN. Par une première étude des PEG myocardiques menée sur une collection historique de BEM, nous avons montré la modification des PEG tissulaires lors du RC. Pour le même grade histologique, deux profils de RC aux degrés d’activation immunitaire différents ont été identifiés. De plus, les PEG myocardiques étaient modifiés dès un mois avant la survenue d’un RC, quand l’analyse histologique ne montrait encore aucune anomalie. Par une seconde étude conduite sur une collection prospective de BEM et échantillons sanguins, nous avons confirmé les résultats de la première étude, et de plus montré l’existence de modulations des PEG également dans le sang périphérique, aussi bien pendant un épisode de RC qu’un mois avant. Enfin pour la première fois la modulation tissulaire et périphérique des PEG a été montrée dans le RMA en transplantation cardiaque. L’existence de voies modulées dans les deux types de rejet devrait conduire à la recherche de biomarqueursHeart transplantation is the last treatment in case of terminal heart failure. Acute rejection after heart transplantation raises several issues due to its occurrence despite immunosuppressive therapies and the requirement of invasive and repeated endomyocardial biopsies (EMB) that have several histological grading limitations. The need of non-invasive diagnostic and predictive criteria led us to study the acute rejection of cardiac allograft using a molecular approach. We characterized myocardial and peripheral blood gene expression profiles (GEP) during acute cellular rejection (CR) and antibody-mediated rejection (AMR) by mean of microarray analyses. By a retrospective study conducted on a historical EMB collection, we first showed a strong immunologic modulation during CR. For the same CR histological grading, two transcriptional profiles were identified according to the inflammation level. Moreover, myocardial GEP modifications were observed one month before the occurrence of CR, while histological characteristics showed no abnormality. A second study conducted on a prospective collection of both EMB and peripheral blood samples confirmed the results obtained on EMB and showed peripheral blood GEP modulations during both CR and even one month earlier. Finally, we have also shown for the first time in heart transplantation, myocardial and peripheral GEP modulations in AMR. Identification of modulated pathways in both types of rejection should allow for the determination of rejection biomarkers
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Engstrand, Mats. "Cellular Immune Responses to Allografts and Cytomegalovirus." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3441.
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Horne, Phillip Howard. "Activation and effector function of unconventional acute rejection pathways studied in a hepatocellular allograft model." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1188397900.
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Liu, Zhenzhen. "The Roles of Interleukin-27 in Tumor Immunity." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354656185.
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Tible, Marion. "Rejet en transplantation cardiaque : au-delà du C4d, les nouveaux marqueurs biologiques, immunologiques et cellulaires." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05S009/document.
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La transplantation cardiaque est aujourd'hui la seule option de traitement à long terme pour les patients souffrant d'insuffisance cardiaque terminale. Malgré des progrès considérables dans les traitements immunosuppresseurs, le rejet d'allogreffe reste une cause majeure de la perte du greffon. Dans ce domaine, des études récentes ont souligné l'importance du rejet humoral (AMR) comme un facteur contributif important à l’évolution, précoce ou tardive, de la maladie vasculaire du greffon et, in fine, à la perte de ce greffon. La pierre angulaire du diagnostic de rejet repose sur la biopsie endomyocardique (BEM) et l'évaluation histopathologique classique. Cependant, les épisodes de rejet observés sont aujourd'hui plus rares et plus complexes qu'auparavant, du fait de la présence de formes tronquées, indolentes et mixtes empêchant un diagnostic précis avec une évaluation conventionnelle. En outre, la BEM est une procédure invasive, entrainant des coûts importants, un inconfort pour le patient et un risque non négligeable de complications graves. Par conséquent, l'évaluation histologique conventionnelle ne reflète pas la complexité du rejet de greffe cardiaque et a besoin d'améliorations en termes de diagnostic. Le travail présenté dans cette thèse explore deux types de biomarqueurs, la voie mTOR, marqueur in situ, et les micro-ARNs, marqueurs circulants, qui permettraient une meilleure classification du rejet et constitueraient une aide diagnostique et/ou prédictive à la pratique clinique quotidienne lors du suivi des patients transplantésCardiac transplantation is currently the only option for long-term treatment for patients with terminal heart failure. Despite considerable advances in immunosuppressive therapy, allograft rejection remains a major cause of graft loss. In this regard, recent studies have highlighted the importance of antibody-mediated rejection (AMR) as an important contributory factor in the evolution of vascular graft disease and, ultimately, graft loss. The cornerstone of the rejection diagnosis is based on endomyocardial biopsy (EMB) and the classical histopathological evaluation. However, rejection episodes observed today are becoming scarce and more complex than before, due to the presence of truncated, indolent and mixed forms preventing an accurate diagnosis with a conventional assessment. In addition, the biopsy is an invasive procedure, resulting in significant costs, discomfort for the patient and a significant risk of serious complications. Therefore, conventional histological assessment does not reflect the complexity of cardiac transplant rejection and needs improvement in terms of diagnosis. The work presented in this thesis explores two types of biomarkers, the mTOR pathway, an in situ marker, and the micro-RNAs, circulating markers that would allow a better classification of rejection and provide diagnosis and/or predictive help to daily clinical practice during the monitoring of transplant patients
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Almeida, Thais de Andrade. "Expressão de marcadores imuno-histoquímicos em biópsias renais de pacientes transplantados." Universidade do Estado do Rio de Janeiro, 2012. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=5697.
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A partir da década de 60, com a utilização do transplante renal em larga escala como terapia substitutiva para pacientes com falência do órgão, surgiu a preocupação quanto ao desenvolvimento do processo de rejeição do enxerto. Tal intercorrência, em geral, cursa com sinais e sintomas clínicos apenas quando o evento está bem estabelecido, ou mesmo quando lesões irreversíveis já se instalaram. Assim, é fundamental um acompanhamento rigoroso, visando detectar os casos subclínicos. O presente trabalho, a fim de fornecer novas ferramentas que auxiliem o diagnóstico precoce de rejeição do enxerto, avaliou a expressão imuno-histoquímica dos anticorpos CD3, CD5, CD20, CD68, CD25, FoxP3 e C4d em biópsias renais realizadas entre os anos de 2007 e 2009 em pacientes transplantados acompanhados pelo Serviço de Nefrologia do Hospital Universitário Pedro Ernesto, UERJ - RJ, correlacionando os resultados obtidos com o diagnóstico histológico. Para tal, as biópsias foram reavaliadas por três médicos patologistas que as classificaram, segundo Critérios de Banff 2007, quanto à presença ou não de rejeição do enxerto e seu tipo, aguda ou crônica. A partir de então, os blocos de parafina foram processados pela técnica Tissue Microarray for all (Pires, ARC. e cols.) e submetidos à imuno-histoquímica. A positividade dos marcadores foi avaliada e graduada e os resultados encontrados foram correlacionados, em um primeiro momento, com a presença ou ausência de rejeição. Posteriormente, os casos com diagnóstico histológico de rejeição tiveram seu perfil imuno-histoquímico analisado em função da positividade para C4d, marcador definidor de rejeição humoral. Neste momento, buscou-se averiguar se os anticorpos estudados seriam úteis em detectar, neste grupo, rejeição humoral e celular. Após a análise estatística, realizada pelo Teste Exato de Fisher, pode-se, então, concluir que o comportamento do marcador CD3 é capaz de inferir a presença de rejeição e que os anticorpos CD5 e CD25 permitem sugerir rejeição celular e humoral, respectivamente. Foi observado também que casos sem diagnóstico histológico de rejeição podem apresentar marcação para C4d em mais de 10% de seus capilares peritubulares.From the 60's, with the use of renal transplantation on a large scale as replacement therapy for patients with organ failure, came out the concern about the development process of graft rejection. This intercurrence, generally, evolves with clinical signs and symptoms only when the event is well established, or even when irreversible damage has already been installed. So, is essential a close monitoring, looking forward to detect subclinical cases. The present work, in order to provide new tools that help in the early diagnosis of rejection of the graft, evaluated the immunohistochemical expression of CD3, CD5, CD20, CD68, CD25, FoxP3 and C4d in renal biopsies performed between the years 2007 and 2009 in transplanted patients accompanied by the Department of Nephrology of Pedro Ernesto University Hospital, UERJ - RJ, correlating the results with the histological diagnosis. To this, the biopsies were evaluated by three pathologists who classified them, according to Banff 2007 Criteria, for the presence or absence of graft rejection and its type, acute or chronic. Thereafter, the paraffin blocks were processed by Tissue Microarray for all technique (Pires, ARC. & cols.) and submitted to immunohistochemistry. The positivity of the markers was evaluated and graded and the results were correlated, at first, with the presence or absence of rejection. Later, cases with histological diagnosis of rejection had their immunohistochemical profile considered according to the positivity for C4d, a defining marker of humoral rejection. At this point, we sought to determine whether the antibodies would be useful in detecting, in this studied group, humoral and cellular rejection. After statistical analysis, performed by Fisher's Exact Test, it could be, therefore, concluded that the behavior of the CD3 marker is able to infer the presence of rejection and that CD5 and CD25 antibodies may suggest cellular and humoral rejection, respectively. It was also observed that cases without histological diagnosis of rejection may have markings for C4d in more than 10% of their peritubular capillaries.
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Lanaya, Hanane. "Rôle des cellules myéloïdes immatures GR1+CD11b+ dans le rejet du mastocytome P815." Doctoral thesis, Universite Libre de Bruxelles, 2008. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210372.
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The failure of the immune system to provide efficient protection against tumour cells has been considered as a major issue in immunology. It is now well established that inadequate function of the host immune system is one of the main mechanisms by which tumours escape from immune control contributing to the limited success of cancer immunotherapy. Several cell populations have been described which display immunosuppressive properties and may impede tumor-specific immunity. Among them, GR1+CD11b+ immature myeloid suppressor cells and CD4+CD25+ regulatory T cells seem to play an important role. These cells accumulate in the spleens of tumour bearing mice and patients with cancer and contribute to immunosuppression by inhibiting the function of CD8+ T cells and/or by promoting tumour angiogenesis.The aim of our work was to define the mechanisms by which a single dose of cyclophosphamide (CTX), a chemical agent commonly used in chemotherapy treatment, induces the rejection of established P815 mastocytoma.
Our data show that CTX treatment leads to the selective loss of GR1medCD11b+ splenic myeloid cell producing TGF-â, a cytokine which is known to suppress antitumoral response. Furthermore, injection of CTX causes a decrease in the number of naturally occurring regulatory T cells (CD4+CD25+Foxp3+) in the spleen and the tumor. Finally, CTX treatment induces the differentiation of GR1highCD11b+ splenic myeloid cells into mature GR1highCD11b+CD11c+ (possibly dendritic cells?) which express high levels of CD11c, MHC class II and CD86 molecules. Of note, these cells are mainly detected in tumour necrosis areas.
Collectively, these results suggest that CTX prevents suppressive mechanisms and induces a population of CD11c+ myeloid cells which may present tumor antigens and activate T lymphocytes, an hypothesis in line with the requirement for CD4+ cells in CTX-induced long term resistance.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished
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Cross, Amy. "The significance of chronic inflammation and HLA-DQ alloantibodies in endothelhial immunoregulation during antibody-mediated rejection." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC248.
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En transplantation d’organes solides, la principale cause de perte de greffons à long terme est le rejet humoral. Le rejet humoral est une maladie de la vasculature du greffon, caractérisé par une inflammation et une forte concentration sérique des anticorps dirigés contre le greffon. Les études récentes ont souligné la forte prévalence des anticorps spécifiques à HLA-DQ parmi des anticorps spécifiques du donneur formés post-transplantation. Cette thèse explore l’importance de l’expression de HLA-DQ par les cellules endothéliales dans la pathogenèse du rejet humoral. Afin d’étudier l’expression de HLA-DQ, des cellules endothéliales microvasculaires ont été stimulées avec des cytokines pro-inflammatoires. L’inflammation induite altère l’immunogénicité des cellules endothéliales et donc modifie la qualité des synapses immunologiques avec les lymphocytes T CD4+ alloréactifs. Ainsi, l’inflammation chronique a diminué la capacité des cellules endothéliales à induire l’expansion des lymphocytes T CD4+ régulateurs FoxP3high (Treg). De plus, la fixation des anticorps anti-HLA-DQ aux cellules endothéliales, en synergie avec l’inflammation, réduit davantage l’expansion des lymphocytes T CD4+ régulateurs. Cette baisse des cellules anti-inflammatoires peut altérer la tolérance des allogreffes, promouvoir les réponses pro-inflammatoires et aggraver le rejetIn solid organ transplantation, antibody-mediated rejection is currently the major cause of allograft failure. Antibody-mediated rejection is a disease of the allograft vasculature, characterised by inflammation and circulating donor-specific antibodies. Recent studies have exposed the particularly high prevalence of antibodies targeting HLA-DQ amongst de novo donor-specific antibodies produced post-transplantation. This thesis explores the significance of endothelial HLA-DQ expression in the pathogenesis of antibody-mediated rejection. HLA-DQ expression in in vitro microvascular endothelial cell cultures required sustained exposure to inflammatory cytokines. Such inflammation modified endothelial immunogenicity and subsequent synapses with alloreactive CD4+ T lymphocytes. As a consequence, sustained inflammation compromised the capacity of endothelial cells to expand anti-inflammatory regulatory T cells. Moreover, the binding of HLA-DQ alloantibodies to the endothelial cells synergised with inflammation to further diminish regulatory T cell expansion. This reduction in anti-inflammatory cells may impair allograft tolerance, promote proinflammatory responses and exacerbate rejection
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Koenig, Alice. "Rôle de l’activation des cellules « Natural Killer » par le « missing self » dans la génération de lésions de rejet vasculaire chronique après transplantation d’organe." Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1158/document.
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La transplantation d'organe est le meilleur traitement en cas de défaillance terminale d'un organe vital. Cependant, la survie sur le long terme est limitée par la perte inexorable de la fonction des greffons. Cette dernière est attribuée à l'inflammation microvasculaire (1MV) causée par la réponse anticorps contre les alloantigènes (rejet humoral chronique (RHC)). En analysant une cohorte de 129 transplantés rénaux présentant de l'1MV sur une biopsie de greffon, nous avons trouvé que, dans la moitié des cas, les lésions n'étaient pas médiées par les anticorps. Chez ces patients, des études génétiques ont révélé une prévalence plus élevée de « mismatches » entre les molécules HLA de classe 1 (HLA-1) du donneur et les « Killer-cell immunoglobulin-receptors » (K1R) inhibiteurs des NK du receveur. Nous avons émis l'hypothèse que la nature allogénique de l'endothélium du greffon pouvait créer un « pseudo-missing-self ». De ce fait, les NK du receveur, exposés à des stimuli inflammatoires, ne reçoivent plus les signaux inhibiteurs transmis par le HLA-1 de la part des cellules endothéliales du donneur. Dans un modèle de co-culture de cellules endothéliales et de NK humains, nous avons démontré que l'absence d'un ligand HLA-1 du soi sur la cellule endothéliale peut activer les NK. Cette activation dépend de la voie mTOR dans les NK, qui peut être bloquée par la rapamycine, un inhibiteur de mTORC1 disponible en clinique. Enfin, nous avons confirmé l'existence de rejets NK induit par le « missing-self » et leur sensibilité à la rapamycine dans un modèle murin de transplantation cardiaque. Notre travail identifie un nouveau type de rejet chronique, exclusivement médié par l'immunité innée, les NK, ayant le même impact délétère sur la survie des greffons que le RHC. Cependant, alors qu'il n'y a pas de traitement disponible pour le RHC, les inhibiteurs de mTOR préviennent efficacement le développement de lésions dans un modèle murin de rejet vasculaire chronique induit par le « missing self »Organ transplantation is the best treatment for terminal organ failure. However, long-term outcome of organ transplantation remains limited by inexorable loss of graft function, which the prevalent dogma links to the microvascular inflammation (MVI) triggered by the recipient's antibody response against alloantigens (antibody-mediated chronic rejection, AMR). Analysing a cohort of 129 renal transplant patients with MVI on graft biopsy, we found that, in half of the cases, histological lesions were not mediated by antibodies. In these patients, genetic studies revealed a higher prevalence of mismatches between donor HLA-I and inhibitory Killer-cell immunoglobulin-receptors (KIR) of recipient's NK cells. We hypothesized that the allogeneic nature of graft endothelium could create a "pseudo-missing self" situation, thereby the recipient's NK cells exposed to inflammatory stimuli would not receive HLA I-mediated inhibitory signals from donor endothelial cells. In co-culture experiments with human NK cells and endothelial cells, we demonstrated that the lack of self HLA-I on endothelial cells can activate NK. This activation triggers mTOR pathway in NK, which can be blocked by rapamycin, a commercially available inhibitor of mTORC1. Finally, we confirmed the existence of missing self-induced rejection and its sensitivity to mTOR inhibition in a murine heart transplantation model. Our work identifies a new type of chronic rejection, exclusively mediated by innate NK cells, with the same detrimental impact on graft survival as AMR. However, while no therapy is available for AMR, mTOR inhibitors efficiently prevent the development of lesions in murine models of NK cell-mediated chronic vascular rejection
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Pagie, Sylvain. "Mécanismes effecteurs du rejet aigu humoral : contribution de la voie Notch et du ligand DLL4 à l’interface endothélium/macrophages et à la polarisation des macrophages." Thesis, Nantes, 2016. http://www.theses.fr/2016NANT1006/document.
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Le rejet aigu humoral (RAH) est une complication post-transplantation qui peut conduire à la dysfonction puis la perte du greffon. Le RAH est caractérisé, au niveau histologique, par la présence de lésions endothéliales et d’un infiltrat de macrophages intravasculaires. Cette étude avait pour objectif d’identifier les mécanismes et voies de signalisation impliqués dans l’altération des cellules endothéliales (CE) au cours du RAH et de nouvelles molécules régulatrices. Nous montrons que l’induction du ligand de la voie Notch Dll4 dans les CE et les macrophages est caractéristique du RAH dans les greffons cardiaques. L’expression endothéliale de Dll4et la sécrétion de l’IL-6 par les CE induit la polarisation des macrophages vers un profil pro-inflammatoire de type M1. Nous identifions aussi Dll4 comme un régulateur négatif et pro-apoptotique de la différentiation vers un phénotype suppressif de typeM2. Nous montrons que les cellules microvasculaires sont les cibles cellulaires privilégiées des anticorps non HLA préformés associés à certains RAH en transplantation rénale. Enfin, nous avons mis en évidence l’activité d’une famille de coumarines issues de végétaux sur l’expression endothéliale de molécules de l’inflammation et de l’immunité. Pour conclure,notre étude montre l’importance de la voie Notch dansl’inflammation liée au RAH et identifie DLL4 et IL-6comme de nouveaux médiateurs de l’inflammation et d’une interaction spatiale et fonctionnelle des CE et des macrophages. Ces travaux proposent donc DLL4 etl’IL-6 comme des cibles moléculaires et les coumarines comme nouvelles molécules bioactives pour le contrôle de l’inflammation et du RAH en transplantationAcute humoral rejection (RAH) is a post-transplantcomplication that can lead to dysfunction and graftloss. RAH is characterized histologically by thepresence of endothelial lesions and of an infiltrate ofintravascular macrophages. This study aimed toidentify the mechanisms, the signaling pathwaysinvolved in the alteration of endothelial cells (EC) upon RAH as well as new regulatory molecules fortherapeutic approaches. Here, we show that theinduction of the Notch ligand DLL4 in both the EC andmacrophages is a feature of RAH in cardiac allografts.The expression of Dll4 and secretion of IL-6 inducedpolarization of macrophages into proinflammatory M1-type. We further identify Dll4 as a negative and pro-apoptoticregulator of macrophage differentiation towards a suppressive phenotype M2-type. We foundthat glomerular microvascular cells are the cell targetsof preformed non HLA antibodies causing RAH inkidney transplantation. Finally, we have demonstratedthe inhibitory activity of a series of coumarins issued from plants on the endothelial expression of a panel of inflammation and immunity molecules. In conclusion,our study shows the importance of the Notch pathwayin inflammation-related RAH and identifies DLL4 and IL-6 as new mediators of inflammation and spatial andfunctional interaction of the EC and macrophages. Thiswork therefore propose DLL4 and IL-6 as moleculartargets and coumarins as new bioactive molecules forthe control of inflammation and RAH
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Roders, Nathalie. "Régulation de l'activation de lymphocytes B / cellules plasmatiques pendant le rejet chronique : Le rôle de SYK dans la modulation de Mcl-1." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS439/document.
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L'insuffisance rénale est un problème majeur de santé publique et la transplantation rénale est l’option thérapeutique principale, mais elle comporte le risque de rejet d'organe. Les cellules B jouent un rôle important dans le rejet médié par les anticorps (AMR). Au cours de l'AMR chronique, les structures lymphoïdes tertiaires, semblables aux centres germinatifs (GC), apparaissent dans l'organe rejeté, associées à la production des plasmocytes et des lymphocytes B mémoires spécifiques du donneur. Ces populations de lymphocyte B sont souvent mal contrôlées par les traitements actuels. La myeloid cell leukemia 1 (Mcl-1), un membre anti-apoptotique de la famille de B-cell lymphoma 2 (Bcl-2), est essentiel pour maintenir l’organisation de GC et de la différenciation des cellules B. Nous rapportons ici l'infiltration de cellules B exprimant Mcl-1 dans le rein de patients atteints d'AMR chronique, comme cela a été observé pour les cellules (pré) GC. Suite à l’abrogation de la signalisation du récepteur des cellules B (BCR), par l'inhibition de la spleen tyrosine kinase (SYK) nous avons observé une diminution de la viabilité des cellules GC, par l'intermédiaire d'une régulation de Mcl-1. La régulation négative de Mcl-1 est coordonnée au niveau de la transcription, potentiellement par l'intermédiaire du transducteur de signal et de l'activateur de la transcription 3 (STAT3), comme cela a été observé par (1) une translocation altérée de STAT3 dans le noyau suivant l'inhibition de SYK, et (2) les niveaux inférieurs de transcription de Mcl-1. Par ailleurs, la surexpression de Mcl-1 inhibe l'apoptose après l'inhibition du SYK. Des études avec des cellules B primaires, issues d'amygdales, ont confirmé que l'inhibition de SYK a diminué la survie cellulaire. Nous avons également constaté que l'inhibition du SYK a diminué les niveaux de protéines Mcl-1 dans les cellules B primaire, et que l’activation de ces cellules a été inhibée, tel que déterminé par l'expression de CD80 et des taux inférieurs de sécrétion d'IgG dans les cellules B primaires activées in vitro. Nos travaux suggèrent que la voie SYK-Mcl-1 peut offrir de nouvelles opportunités pour le traitement et la prévention de l'AMRRenal failure is a major public health concern and renal transplantation is the main therapeutic option, however it comes with the risk of organ rejection. B-cells play an important role in antibody-mediated rejection (AMR). During chronic AMR, tertiary lymphoid germinal center (GC)-like structures appear in the rejected organ, associated with de novo production of donor-specific plasma and memory B-cells. Which are B-cell populations that are often poorly controlled by current treatments. Myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic member of the B-cell lymphoma-2 (Bcl-2) family, is essential for maintaining the GC reaction and B-cell differentiation. We report here the infiltration of B-cells expressing Mcl-1 in the kidney of patients with chronic AMR, as observed for (pre-)GC cells. The impairment of B-cell receptor (BCR) signaling, by inhibition of spleen tyrosine kinase (SYK), reduced viability and Mcl-1 protein levels in GC like cells. This downregulation is coordinated at the transcriptional level, potentially via signal transducer and activator of transcription 3 (STAT3), as shown by (1) impaired translocation of STAT3 to the nucleus following SYK inhibition, and (2) the lower levels of Mcl-1 transcription upon STAT3 inhibition. Moreover, overexpression of Mcl-1 prevented cells from entering apoptosis after SYK inhibition. In vitro studies with primary tonsillar B-cells confirmed that SYK inhibition decreased cell survival. We also found that SYK inhibition decreased Mcl-1 protein levels in primary B-cells, and that B-cell activation was inhibited, as determined by CD80 expression and lower levels of IgG secretion in tonsillar B-cells activated in vitro. Overall, our data suggest that the SYK-Mcl-1 pathway may provide new opportunities for the treatment and prevention of AMR
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Chopard-Lallier, Sophie. "Suivi fonctionnel de la greffe d'îlots de Langerhans : interêt de l'imagerie IRM et de l'immuno-monitoring cellulaire." Thesis, Besançon, 2013. http://www.theses.fr/2013BESA3001.
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La greffe d'îlots de Langerhans permet de traiter le diabète de type 1 en restituant une insuline-sécrétion. La moitié des patients reprend l'insuline dans les 5 ans. Cette perte de fonction s'explique par l'absence d'outils de monitoring. Le but de notre travail était de déterminer l'efficacité de l'IRM à diagnostiquer un rejet de greffe, et d'évaluer l'intérêt du monitoring cellulaire chez les patients.Imagerie IRM chez le ratMéthodes : Des îlots syngéniques, allogéniques ou xénogéniques ont été greffés par voie intra-portale à des rats diabétiques après marquage avec une nanoparticule de fer (ferucarbotran). Les IRM étaient réalisées dans une IRM clinique 3T.Résultats : La décroissance du signal était différente suivant les 3 types de greffes. Le signal IRM des greffes allogéniques était significativement plus bas à J4 alors que la glycémie était normale. En prenant un seuil de 84% à J4, l'IRM permet d'obtenir une sensibilité de 91% et une spécificité de 70% Innnuno-monitoring cellulaireMéthodes : Des réactions lymphocytaires mixtes étaient réalisées entre les PBMC des patients greffés, et les splénocytes des donneurs. La réaction immunitaire était évaluée par la sécrétion d'IFNy (ELISpot), par la prolifération cellulaire (cytométrie du flux du Ki67), et par le dosage des cytokines (Bioplex). Le résultat était corrélé à la fonction du greffon évaluée par le (3-score).Résultats : Les patients avec une mauvaise fonction montraient une plus grande réactivité anti-donneur avec l'ELISpot IFNy (p=0,007, r=-0,50) et l'index de prolifération (p=0,006, r=-0,51). Les patients avec une mauvaise fonction avaient des taux d'IFNy, IL-5 et IL-17 plus élevésLangerhans islet transplantation allows curingtype 1 diabetes by restoring an endogenous insulin secretion. Halfof patients will resume insulin withinyears. This loss of function may be explained by the lack of monitoring tools able to diagnose an ongoing graft failure. The aims of our work were toevaluate the efficiency of MRI to diagnose islet graft rejection, and to assess the feasibility of immune cellular monitoring in transplanted patients.MRI in the rat mortelMethods: Syngeneic, allogeneic and xenogeneic islets were transplanted intra-portally to diabetic rats after labeling with superparamagnetic ironoxide nanoparticles (ferucarbotran). Images were acquired on a clinical 3T MRI scanner.Results: The signal decreasing was different between the 3 types of transplantations. At day 4, the MRI signal in allogeneic group was significantlylower while glycaemia remained normal. With a cut-off value of 84% at day 4, sensitivity of 91% and specificity of 70% were obtained.Cellular immune monitoringMethods: Mixed lymphocyte cultures were performed with peripheral blood mononuclear cells from recipients and splenocytes from donors. Immunereactivity was assessed by the release of IFNy (ELISpot), cell prolifération (flow cytometry of Ki67), and cytokine quantification (Bioplex). Theresults were correlated to the islet graft function assessed by (5-score.Results: Patients with low islet function showed higher cellular reactivity against donor cells assessed by ELISpot IFNy ((p=0,007, r=-0,50) andproliferation index (p=0,006, r=-0,51). Patients with low graft function had higher levels of IFNy, IL-5 and 1L-17
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Fernandes, Isa Elói. "Heart transplantation : lowered survival and tumoral development ahead of acute cellular rejection." Master's thesis, 2016. http://hdl.handle.net/10316/36304.
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Trabalho final de mestrado integrado em Medicina área científica de Cirurgia Cardiotorácica e Anatomia Patológica, apresentado á Faculdade de Medicina da Universidade de CoimbraIntrodução e objetivos: O impacto da rejeição celular aguda durante os primeiros anos após o transplante cardíaco na sobrevida a longo prazo ainda não está bem estabelecido, assim como o seu papel no desenvolvimento da doença vascular do enxerto. Os novos imunossupressores conduziram a uma diminuição da incidência da rejeição celular aguda, mas consequentemente levaram a um aumento do risco de infeções e tumores. O objetivo do nosso trabalho foi analisar o impacto da rejeição celular na sobrevida e a ocorrência de neoplasias, infeções e doença vascular do enxerto em doentes selecionados. Métodos: De novembro de 2003 a maio de 2013, 218 doentes foram submetidos a transplante cardíaco. Doentes com menos de 18 anos, sujeitos a outro transplante de órgão prévio ao transplante cardíaco e recetores que faleceram nos primeiros 14 dias após a cirurgia devido a falência do enxerto, foram excluídos. Transplantados com pelo menos um episódio de rejeição celular aguda classificada como 2R ou 3R (Grupo A n=47) foram comparados com recetores livres de episódios de rejeição ou com episódios de rejeição classificados como 1R nos primeiros 3 anos após transplante cardíaco (Grupo B n=171). Os critérios de seleção dos dadores e recetores foram idênticos em ambos os grupos. Resultados: A incidência da rejeição celular aguda foi mais elevada nos primeiros 6 meses após transplante cardíaco (P<0.001). Não foram encontradas diferenças estatisticamente significativas na sobrevida a longo prazo (P=0.101) ou na incidência da doença vascular do enxerto (P=0.144) entre ambos os grupos. No entanto, verificámos uma ligeira tendência para a diminuição da sobrevida a longo prazo (61.7 ± 7.3% vs 77.1 ± 3.7%) e sobrevida livre de doença vascular do enxerto (75.9 ± 6.6% vs 86.0 ± 3.5%) no grupo A. As neoplasias de novo tiveram uma maior incidência no grupo B (P=0.026) enquanto as infeções foram mais frequentes no grupo A (P=0.036). Conclusão: A taxa da rejeição celular aguda na nossa população de estudo verificou-se ser baixa e a maioria dos episódios ocorreram nos primeiros 6 meses após o transplante. O tratamento imunossupressor associado talvez a um estado sobre-terapêutico podem potenciar o aumento da incidência de tumores. Este estudo sugere-nos ainda que pacientes que sofreram de episódios de rejeição celular aguda nos primeiros 3 anos após o transplante têm uma maior tendência a sofrer de doença vascular do enxerto e a uma menor sobrevida a longo prazo, no entanto sem significância estatística.
Background The impact of acute cellular rejection (ACR) on long-term survival during the first years after heart transplant has not yet been established, as well as its role on cardiac allograft vasculopathy (CAV). New immunosuppressors have led to a decline of the incidence of ACR and led to increased risk of infections and tumors. We analysed the impact of ACR on long-term survival and considered the occurrence of malignancy, infections and cardiac allograft vasculopathy in the selected patients. Methods Between November 2003 and May 2013, 218 heart transplants were performed. Patients under 18-years old, patients undergoing organ transplantation before heart transplant and recipients who died within the first 14 days after heart transplant (HT) due to graft failure, were excluded. Recipients with at least one episode of ACR event graded as 2R or 3R (Group A n=47) were compared with recipients free of rejection events or with an ACR event graded minor than 2R in the first 3 years after heart transplantation (Group B n=171). Patient/donor criteria were selected as identical in both groups. Results Incidence of ACR was higher in the first 6 months after heart transplantation (P < 0.001). There was no significant statistical difference in long-term survival (P =0.101) or incidence of CAV (P=0.144) between the two groups. A slightly tendency for a lower 7 long-term survival (61.7 ± 7.3% vs 77.1 ± 3.7%) and survival free of CAV (75.9 ± 6.6% vs 86 ± 3.5%) was verified in Group A. Malignancy de novo had an higher incidence in Group B (P=0.026) while infections (P=0.036) were more frequent in Group A. Conclusion With this study, we verified that we have a small rate of ACR and mostly occurs in the first 6 months. The effective immunosuppression regimen maybe together with over-immunosuppression may lead to a higher incidence of tumors. This study also suggests that recipients with ACR events are more likely to suffer from CAV and to have a lower long-term survival however with out statistical significance.
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Pavlova, Yelena. "Genetické a molekulární faktory ovlivňující výsledky transplantací solidních orgánů." Doctoral thesis, 2014. http://www.nusl.cz/ntk/nusl-326158.
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Since its beginning, graft rejection remains the key problem of solid organ transplantation. This reaction of the recipient's immune system against mismatched antigens of the transplanted organ causes graft damage and consequently loss of its function. Rejection involves cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms. Among the genetic factors which may have a prognostic value in rejection risk evaluation are the Human Leukocyte Antigens (HLA) genotype, the Killer Immunoglobuline-like Receptor (KIR) gene repertoir, cytokine and other gene polymorphisms. These factors could be screened for before transplantation to find the best possible combination of genetic characteristics of the donor and recipient and to reveal patients with "risky" genotypes, who may need more intensive immunosuppression and more careful post-transplant follow-up. Molecular factors, such as HLA and non-HLA antibodies, soluble CD30 molecule (sCD30), Hepatocyte Growth Factor (HGF) and other cytokines, measured before and/or after transplantation in the recipient's blood may be helpful for rejection risk estimation and may also be used as post-transplant rejection onset markers. In our study, we focused on some of the above mentioned factors. We found that ethnicity plays a significant role in the...
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Knowles, Kellen A. "Adipose stromal cells enhance keratinocyte survival and migration in vitro, and graft revascularization in mouse wound healing model." Thesis, 2013. http://hdl.handle.net/1805/3752.
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Indiana University-Purdue University Indianapolis (IUPUI)In the US, more than 1 million burn injuries are reported annually. About 45,000 injuries due to fires and burns result in hospitalization and ten percent of these result in death every year. Advances in burn treatment have led to a reduction in mortality rate over the last decades. Since more patients are surviving the initial resuscitation phase even with very large areas of skin being burned away, wound care has become increasingly important to ensure continued patient survival and improvement. While currently a common treatment for third degree burn wounds, skin grafts have several drawbacks. The availability of donor sites for autografts may be limited, especially in incidences of extensive skin loss. The rejection associated with the use of allografts and xenografts may render them inadequate or undesirable. Even if a suitable graft is found, poor retention due to infection, hematoma, and low vascularity at the recipient site are other drawbacks associated with the use of skin grafts as a primary treatment for severe burn wounds. As such, research has been done into alternative treatments, which include but are not limited to artificial skin, cell therapy, and growth factor application. We propose the delivery of adipose derived stem cells (ASC) in combination with endothelial progenitor cells (EC) via Integra Dermal Regenerative Template (DRT) to promote faster graft vascularization and thus faster healing of wounds. Integra DRT is an acellular skin substitute that consists of a dermal layer composed of bovine collagen and chondroitin-6-sulfate glycosaminoglycan, and an "epidermal" layer, which consists of silicone polymer. This silicone layer is removed after the collagen matrix is adequately vascularized (usually takes 2-3 weeks), and then a thin layer autograft is applied to the top of the neo-dermis. ASC are derived from the stromal-vascular fraction (SVF) of adipose tissue and are a readily available, pluripotent, mesenchymal cell known to promote angiogenesis. They are being explored as a treatment for a myriad of diseases and conditions, including wound healing. In combination with ECs, they form stable microvessel networks in vitro and in vivo. In our work, we found that ASC+EC form stable microvessel networks when cultured on Integra DRT. Also, ASC and ASC+EC conditioned media promoted both survival and migration of human epidermal keratinocytes compared to control medium. In a full thickness wound healing model, using healthy NSG mice, the ASC+EC case showed a significantly higher rate of wound closure compared to control. Based on best linear unbiased estimates (BLUE), the difference between the healing rates of ASC alone treatment and the Control treatment group is -0.45 +/- 0.22 mm²/day (p=0.041), which is not less than 0.025 and thus not statistically significant (Bonferroni Adjusted). However, the BLUE for the difference between the ASC+EC group and the Control group healing rates is -0.55 +/- 0.28 mm²/day (p = 0.017<0.025, Bonferroni Adjusted), which is statistically significant. Histology revealed a significantly higher number of vessels compared to control in both ASC alone and ASC+EC case. CD31 staining revealed the presence of human vessels in ASC+EC treatment scaffolds. We conclude that the combination of ASC and EC can be used to accelerate healing of full-thickness wounds when delivered to site of the wound via Integra. This result is especially compelling due to the fact that the mice used were all healthy. Thus our treatment shows an improvement in healing rate even compared to normal wound healing.