To see the other types of publications on this topic, follow the link: Costimulation.
Dissertations / Theses on the topic 'Costimulation'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Costimulation.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Watson, Martin Peter. "Lymphocyte costimulation in corneal allograft rejection." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498610.
Full text
2
Lute, Kenneth D. "Costimulation and tolerance in T cell immunotherapy." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1141850521.
Full text
3
Parra, Eduardo. "Molecular basis for costimulation of human T lymphocytes." Lund : Lund University, 1998. http://books.google.com/books?id=SgFrAAAAMAAJ.
Full text
4
Suzuki-Jaecks, Ivy. "Fas ligand-mediated costimulation in peripheral T lymphocytes /." Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/8319.
Full text
5
Kumar, Gaurav. "Infections humaines et molécules de costimulation lymphocytaires T." Nice, 2012. http://www.theses.fr/2012NICE4057.
Full textAbstract:
Les maladies infectieuses, causées par divers microorganismes, sont la première cause de mort à travers le monde. Les lymphocytes T sont une population variée de cellules qui participent aux immunités innée et adaptative. Nous cherchons à caractériser les réponses lymphocytaires T lors des infections bactériennes et virales chez l’homme. Notre recherche, menée à partir de prélèvement humains, s’est portée sur l’infection osseuse (IO) bactérienne chronique, sur le Syndrome de Détresse Respiratoire Aiguë de l’adulte (SDRA), et sur l’infection par le Virus de l’Immunodéficience Humaine (VIH). Les IO sont caractérisées par une augmentation de l’activation et une diminution de la prolifération lymphocytaire T, associées à une diminution de CD28 et une augmentation de la molécule de costimulation CTLA4 au sein de la population CD4. La sous-population T CD4+CD28- a des capacités cytolitiques accrues comparativement aux lymphocytes T CD28+, avec une augmentation de la sécrétion de perforine. Au cours du SDRA, l’activation et la prolifération des lymphocytes T alvéolaires sont associées à une augmentation de l’expression de CLTA4, en lien avec la présence de clones TH-17. L’IL17 participerait à une attraction de l’expression de CTLA4, en lien avec la présence de clones TH-17. L’IL17 participerait à l’attraction des polynucléaires neutrophiles pouvant initier la fibrose observée lors d’un SDRA. Au cours du VIH, l’introduction d’un anti-intégrase en complément d’une trithérapie usuelle efficace diminue l’ADN viral intracellulaire dans les T CD4, et est associé à une augmentation de CD28 et une diminution de CTLA4 sur ces mêmes cellules, et à une inhibition relative du taux d’apoptose. En conclusion, les modifications de molécules de costimulation lymphocytaires T sont dépendantes du site d’infection et/ou du stade aigu ou chronique de l’infection, et non de l’agent pathogène en cause. Les traitements anti-infectieux peuvent modifier l’expression de ces molécules de costimulation, les thérapies ciblant ces molécules devant donc intégrer ces critères cinétiquesInfectious diseases, caused by various microorganisms are the major cause of death worldwide. T-lymphocytes are a diverse population of cells that participate in both innate and adaptive immunity. We are defining human T lymphocyte responses to viral and bacterial infection and their role on protective immunity and disease pathogenesis. Our research focuses on chronic and acute bacterial and viral infection in Osteomyelities, Acute respiratory distress syndrome (ARDS) and human Immunodeficiency virus (HIV). Our research is largely clinically based because these diseases do not have good experimental animal models. We report increased T-cell activation and decreased proliferation along with the alteration of its costimulatory pathways as hallmarks of bacterial bone infections in humans. A remarkable decrease in the CD28 expression on CD4 T cells was observed in infected bone tissues along with increased CTLA4 expression. On further analysis of CD28 negative CD4 T cell population, it seemed that it has enhanced cytotoxic capabilities in comparison to their CD28 positive counterparts, being obvious by increased perforine secretion. In ARDS we observed increased activated and proliferating T cell phenotype with increased CTLA4 expression, suggesting that increased CTLA4 seems to play a suppressive role in order to achieve normal T cell homeostasis after going through the active phase of activation. Also we observed IL-17 secretion in ARDS, which may suggest the role of IL-17 as a chemoattractant for neutrophils at the site of infection. In AIDS, the included patients had a stable HAART treatment with undetectable viral load for at least six months. In our study we did not observed major alteration in T cell phenotype and its costimulatory molecules after Raltegravir introduction, but we observed a decrease in viral load in CD4 T cells. In conclusion, alteration of the costimulatory molecules appeared to be disease-related but not pathogen specific
6
Tuladhar, Rashmi. "ROLE OF COSTIMULATION IN EXPERIMENTAL LEISHMANIA MEXICANA INFECTION." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1395619402.
Full text
7
Cameron, Mark J. "Cytokine- and costimulation-mediated therapy of type 1 diabetes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0021/NQ58397.pdf.
Full text
8
May, Kenneth F. "T cell costimulation in anti-tumor immunity and autoimmunity." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1085004772.
Full textAbstract:
Thesis (Ph. D.)--Ohio State University, 2004.Document formatted into pages; contains xv, 178 p. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2006 May 20.
9
Briggs, Zoe Louise. "CD28 costimulation in T cells : requirements, outcomes and regulation." Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/5378/.
Full textAbstract:
The costimulatory receptor CD28 and its inhibitory counterpart CTLA-4 share the same ligands and comprise a crucial checkpoint in T cell activation. CTLA-4 removes its ligands from antigen presenting cells by trans-endocytosis, which reduces the availability of costimulatory ligands for CD28 engagement to regulate T cell activation. This project examined the functional implications of reducing the availability of costimulatory molecules for CD4 T cell responses, and investigated the use of trans-endocytosis by other T cell receptors. Surprisingly, it was revealed that PD-1 and OX40 can also internalise their ligands, although perhaps not via the same mechanism as CTLA-4 trans-endocytosis. It was also shown that altering the availability of CD28 ligands affects the extent of T cell proliferation, suggesting that CTLA-4 trans-endocytosis can finely tune the T cell response. Furthermore, it was observed that CD28 costimulation is not always required for T cell activation and proliferation, but CD28 engagement is required for the optimal upregulation of a number of effector proteins and for TH2 cytokine production. Interestingly, T cells activated in the absence of CD28 signalling were not classically anergic. Strikingly, it was also found that memory T cells are dependent on CD28 costimulation.
10
May, Kenneth F. Jr. "T cell costimulation in anti-tumor immunity and autoimmunity." The Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1085004772.
Full text
11
Cucchetti, Margot. "Rltpr, a lymphoid-specific protein essential for CD28 costimulation." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM4043.
Full textAbstract:
La reconnaissance d'antigènes par le TCR active des protéines tyrosine kinases qui phosphorylent d'autres substrats intracellulaires dont LAT. Ceci engendre l'activation de molécules telles que PKCθ et CARMA-1. La mutation LatY136F associe des TCR "estropiés" dans le développement de cellules T effectrices générant des désordres lymphoprolifératifs. Nous avons essayé de comprendre les gènes aggravant ou empêchant cette lymphoprolifération en utilisant la mutagénèse ENU. Nous avons identifié une mutation appelée Basilic empêchant le déroulement de la pathologie LatY136F. Basilic est une mutation du gène Rltpr qui constitue une phénocopie de Cd28-/- sur fond sauvage et sur fond LatY136F. Rltpr est un une nouvelle protéine ayant de multiples domaines, qui appartient à la famille CARMIL et qui est exprimée dans les cellules T et B. L'objectif de ce travail était d'élucider les mécanismes au cours desquels CD28 et Rltpr coopèrent avec le TCR pour différencier des cellules T naïves en cellules T effectrices. Ce travail visait aussi à caractériser Rltpr, dont la structure/fonction et l'interactome sont encore inconnus. En utilisant des techniques de microscopie confocale, nous avons montré que la localisation et le recrutement de Rltpr et de RltprBas à la synapse immunologique sont tous deux CD28-dépendants. Les deux molécules colocalisent avec CD28 tout au long du processus d'activation. En outre, Rltpr est essentiel pour la translocation à la synapse de PKCθ et CARMA-1, qui sont induits lors de la co-stimulation par CD28. Ces résultats permettent une meilleure compréhension du fin réglage du système immunitaire adaptatif qui est mis en place lors de l'activationTCR recognition of antigens triggers the activation of protein tyrosine kinases that phosphorylate other intracellular substrates including LAT. LAT phosphorylation leads to the activation of PKCθ and CARMA-1. The point mutation LatY136F associates TCRs with crippled signaling abilities to the development of effector T cells generating lymphoproliferative disorders (LPDs). We tried to shed light on genes exacerbating or preventing the LatY136F LPD by using an ENU mutagenesis screening. We identified one point mutation called Basilic that prevents the unfolding of the LatY136F pathology. Basilic is a point mutation of the Rltpr gene and is a phenocopy of a Cd28-/- mutation both on a wild-type and on a LatY136F background. Rltpr is a newly-discovered, multidomain protein belonging to the CARMIL family that is expressed in T and B cells. The objective of the present work was to elucidate the mechanisms during which CD28 and Rltpr cooperate withthe TCR to differentiate naïve into effector T cells. I also aimed at characterizing the Rltpr molecule, whosestructure/function and interactome are still largely unknown. Using confocal microscopy in collaborationwith Takashi Saito's group and Christoph Wülfing we showed that the localization and the recruitment ofboth Rltpr and RltprBas at the immune synapse are CD28-dependent. The two molecules colocalize with CD28all along the activation process. Moreover, Rltpr is essential for the synapse translocation of PKCθ andCARMA-1, which are induced upon CD28 costimulation. Those results allow a better understanding of theadaptive immune system fine tuning upon activation
12
Sun, Mingyi. "The mechanism of Fas ligand-mediated costimulation through reverse signaling /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8363.
Full text
13
Jangalwe, Sonal. "Regulation of Alloreactive CD8 T Cell Responses by Costimulation and Inflammation." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/907.
Full textAbstract:
CD8 T lymphocytes are a crucial component of the adaptive immune system and mediate control of infections and malignancy, but also autoimmunity and allograft rejection. Given their central role in the immune system, CD8 T cell responses are tightly regulated by costimulatory signals and cytokines. Strategies targeting signals that are critical for T cell activation have been employed in a transplantation setting to impede alloreactive T cell responses and prevent graft rejection. The goal of my thesis is to understand how costimulatory signals and inflammation regulate alloreactive CD8 T cell responses and how to target these pathways to develop more effective tools to prevent graft rejection.
Costimulation blockade is an effective approach to prolong allograft survival in murine and non-human primate models of transplantation and is an attractive alternative to immunosuppressants. I describe a novel murine anti-CD40 monoclonal antibody that prolongs skin allograft survival across major histocompatibility barriers and attenuates alloreactive CD8 T cell responses. I find that the pro-apoptotic proteins Fas and Bim function concurrently to regulate peripheral tolerance induction to allografts. Activation of the innate immune system by endogenous moIecules released during surgery or infections in transplant recipients can modulate T cell responses. However, the direct impact of inflammation on alloreactive CD8 T cell responses is not clear. Using a T cell receptor (TCR) transgenic mouse modeI, I demonstrate that inflammatory stimuli bacterial lipopolysaccharide (LPS) and the viral dsRNA mimetic poly(I:C) differentially regulate donor-reactive CD8 T cell responses by generating distinct cytokine milieus. Finally I demonstrate the role of pro-inflammatory cytokines stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) in improving human B cell development in humanized NOD-scid IL2Rγnull (NSG) mice.
14
Miller, David M. "TLR Activation Prevents Hematopoietic Chimerism Induced by Costimulation Blockade: A Dissertation." eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/368.
Full textAbstract:
Costimulation blockade based on a donor-specific transfusion and anti-CD154 mAb is effective for establishing mixed allogeneic hematopoietic chimerism and inducing transplantation tolerance. Despite its potential, recent evidence suggests that the efficacy of costimulation blockade can be reduced by environmental perturbations such as infection or inflammation that activate toll-like receptors (TLR). TLR agonists prevent costimulation blockade-induced prolongation of solid organ allografts, but their effect on the establishment of hematopoietic chimerism has not been reported.
In this dissertation, we hypothesized that TLR activation during costimulation blockade would prevent the establishment of mixed hematopoietic chimerism and shorten skin allograft survival. To test this hypothesis, costimulation blockade-treated mice were co-injected with TLR2 (Pam3Cys), TLR3 (poly I:C), or TLR4 (LPS) agonists and transplanted with allogeneic bone marrow and skin grafts. Supporting our hypothesis, we observed that TLR agonists administered at the time of costimulation blockade prevented the establishment of mixed hematopoietic chimerism and shortened skin allograft survival.
To investigate underlying cellular and molecular mechanisms, we first determined that LPS administration during costimulation blockade did not increase production of alloantibodies or activate natural killer cells. Similarly, costimulation blockade-treated mice depleted of CD4+ or CD8+ cells did not become chimeric when co-injected with LPS. In contrast, mice depleted of both CD4+ and CD8+cell subsets were resistant to the effects of LPS.
We next observed that alloreactive T cells were activated by TLR agonists in mice treated with costimulation blockade, and this activation correlated with LPS-induced maturation of donor and host alloantigen-presenting cells. In contrast, TLR4-deficient mice treated with costimulation blockade and LPS did not upregulate costimulatory molecules on their APCs, and mixed chimerism and permanent skin allograft survival were readily achieved. We further observed that injection of recombinant IFN-β recapitulated the detrimental effects of LPS, and that LPS-injected mice deficient in the type I IFN receptor were partially protected. Importantly, alloantigen-presenting cells did not upregulate costimulatory molecules in response to LPS, and mixed chimerism and permanent skin allograft survival were readily established in type I IFN receptor and MyD88 double deficient mice treated with costimulation blockade. We conclude that the TLR4 agonist LPS prevents the establishment of mixed hematopoietic chimerism and shortens skin allograft survival in mice treated with costimulation blockade by inducing the production of type 1 IFN and MyD88-dependent factors that upregulate costimulatory molecules on APCs, leading to the generation of activated alloreactive T cells.
15
Moro, Monica. "Manipulation of anti-tumour immune response by tumour targeting with soluble immuno-modulatory molecules." Thesis, Open University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323271.
Full text
16
Wong, Kenneth Kak Yuen. "Studies on notch signalling and B7 mediated costimulation in models of transplantation." Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396301.
Full text
17
Dowell, Alexander Charles. "Studies of human T cell costimulation : potential for the immunotherapy of cancer." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1106/.
Full textAbstract:
Costimulation is required for the generation of an effective T cell based immune response. The presentation of tumour associated antigens may occur in the absence of effective costimulation, inducing tolerance. Conversely effective costimulation can overcome immunosuppressive mechanisms present within the tumour. Costimulation may therefore hold significant potential for cancer immunotherapy. Using recombinant adenoviral vectors encoding the costimulatory molecules CD80 and 4-1BBL (CD137L) and the cytokine IL-12 tumour cell lines were transduced to express these molecules individually or in combination in vitro. Using PBMC from healthy donors the effect of costimulation in response to pan-T cell stimulation with the anti-CD3 antibody OKT-3 were initially studied. The combination of CD80+4-1BBL supported the proliferation of CD8+ T cells and was superior to either molecule alone. Proliferation was further enhanced by the addition of IL-12 to the combination of CD80+4-1BBL. Unexpectedly in the absence of OKT-3 costimulation with 4-1BBL or IL-12 was observed to predominantly induced the proliferation of natural killer (NK) cells. The effects of 4-1BBL on human NK cells are not clearly defined in the literature. Further experiments were therefore conducted to investigate the ability of 4-1BBL and IL-12 to stimulate NK cells. The combination of 4-1BBL+IL-12 was superior to either stimulation alone for the activation, proliferation and function of NK cells from healthy lab donors. 4-1BBL was also shown to promote the long term expansion of NK cells. Importantly renal cell carcinoma patient NK cells were shown to require a combination of 4-1BBL+IL-12 for short and long term expansion; stimulated NK cells were also shown to be functional. These data highlight the need for understanding of the pleiotropic effects of costimulatory molecules and the necessity to choose optimal combinations for the activation of not only the adaptive III but also the innate immune response. The combined intratumoural delivery of 4-1BBL and IL-12 via adenoviral vectors could potentially stimulate beneficial T cell and NK cell responses, and therefore warrant further investigation as a potential immunotherapy.
18
Sutavani, Ruhcha V. "CD55 costimulation induces differentiation of human T regulatory type - 1 (Tr1) cells." Thesis, University of Nottingham, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.727951.
Full textAbstract:
Unlike other helper T cells, the co-stimulatory ligands responsible for T regulatory type-1 (Trl) cells differentiation remain undefined. Understanding the molecular interactions driving peripheral Trl differentiation is important because Trls potently regulate immune responses, by IL-10 production. In this study we show that co-stimulation of human naïve CD4+ cells through the CD97-CD55 interaction drives Trl activation, expansion and function. T cell activation and expansion was equipotent with CD55 or CD28 co-stimulation, however CD55 co-stimulation resulted in two IL-10 secreting populations. The majority of the IL-10 was secreted by the minor, Trl population (IL-10high IFN-y- IL-4-, <5% cells) that express Trl markers CD49b, LAG-3 and CD226. This Tr 1 phenotype was not re-stimulated by CD28. But on CD55 re-stimulation, Trls proliferated and maintained their differentiated IL-10 high phenotype. The Trls significantly suppressed effector T cell function in an IL-10 dependent manner. The remaining (>95%) cells adopted a Thl- like IFN-y + phenotype. However, in contrast to CD28 derived This, CD55 derived This demonstrated increased plasticity with the ability to co-express IL-10 when re-stimulated through CD55 or CD28. These data identify CD55 as a novel co-stimulator of human Trls and support a role for alternative co-stimulatory pathways in determining the fate of the growing number of T helper populations. In this study we also show a defect in Trls in the autoimmune disease Multiple Sclerosis (MS). In response to CD55 costimulation, naïve CD4+ cells from a cohort of MS patients did not differentiate into Trl cells as normal, however the CD55 induced Thl response was unaffected. These patients showed persistent lack of an IL-10h1gh Trl population on primary and secondary CD55 costimulation. Also, MS patients mounted stronger IFN-y responses compared to healthy controls. These data demonstrate an altered immune balance in MS and highlight a defect in the Trl response as a contributing factor of this change. Overall, this study demonstrates that CD55 acts as a potent co-stimulator and activator of human naive CD4+ cells resulting in the differentiation of a discrete Trl population that inhibits T cell function in an IL-10 dependent manner and maintains the Trl phenotype upon re-stimulation, in healthy individuals. However, there is a defect in this normal Tr 1 response in the autoimmune condition Multiple Sclerosis.
19
Morin, Stéphanie. "CD28 : nouvelles données sur un récepteur majeur de la costimulation lymphocytaire T." Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0508.
Full textAbstract:
La progression tumorale est le résultat d’une interaction dynamique entre les cellules tumorales et leur microenvironnement. Parmi toutes les cellules qui composent le stroma tumoral, dont les cellules du système immunitaire (SI) comme les lymphocytes T (LT), les adipocytes sont majoritairement présents dans le micro-environnement de certaines tumeurs, comme le cancer du sein. Je travaille sur une molécule clé de la costimulation des LT naïfs, la molécule CD28. L’expression de ses ligands B7 sur les cellules tumorales favorise leur reconnaissance et leur élimination par le SI. L’obésité s’accompagne d’un état micro-inflammatoire chronique. L’importance des phénomènes de costimulation dans le processus inflammatoire lié à l’obésité, en particulier dans un contexte de progression tumorale, est le cœur de mon travail doctoral. Tout d’abord, j’ai participé à la caractérisation de modèles murins d’obésité où le SI est altéré (déficience en CD28), puis j’ai utilisé ces systèmes pour suivre des progressions tumorales. Pour cela, j'ai réalisé des analyses fonctionnelles sur des souris CD28 KO obèses, et afin d'augmenter nos systèmes d'études autour du rôle de CD28, j'ai caractérisé un nouveau modèle : des souris CD28 KI où le récepteur CD28 est dépourvu de sa partie cytoplasmique. Enfin, j'ai mis au point un système de développement tumoral chez la souris à partir d'une lignée syngénique de cancer du sein permettant d'analyser différents paramètres dans le contexte d'un micro-environnement adipocytaire. Au final, notre objectif était de démontrer l’influence combinée du SI et des adipocytes sur la progression tumorale chez des souris obèses plus ou moins immunocompétentesTumor progression is the result of a dynamic interaction between tumor cells and the tumor microenvironment. Immune cells such as T lymphocytes and adipocytes are present in the tumor stroma. Adipocytes are the most numerous cells in some tumor microenvironment such as in breast cancer. I work on a key molecule of naïve T cells costimulation, the CD28 molecule. CD28 and its ligands B7 play an important role in the induction of the inflammatory response. The expression of B7 molecules on tumor cells promotes their recognition and their elimination by the immune system. Obesity is accompanied by a chronic micro-inflammatory state. We studied the role of CD28 in obesity’s inflammation process. Adipose tissue is the site of infiltration of pro-inflammatory immune cells. The importance of costimulation in obesity’s inflammation process is the core of my doctoral work. We studied consequences of this process in the context of tumor progression. First, we characterized mouse models of obesity in CD28 deficient background. Since their immune system is impaired (CD28 deficiency) we followed-up tumor progression. We then performed functional analyzes on obese CD28 KO mice compared to WT mice. In order to study more precisely the role of CD28, we generated a CD28 “knock-in” (KI) mouse model. In this model, the endogenous CD28 receptor lacks its intracytoplasmic part. Finally, we set up a pre-clinical model to study breast tumor development (adipose tissue) using a syngenic cancer cell line. Our objective was to demonstrate the combined influence of the immune system and adipocytes on tumor progression, this by developing new immunodeficient and obese mice models
20
Kerr, J. P. "Cytotoxic T cell costimulation : biology and potential for generating long-lasting immunity." Thesis, University of Southampton, 2011. https://eprints.soton.ac.uk/375471/.
Full text
21
Saoulli, Catherine. "CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0008/MQ40765.pdf.
Full text
22
Lau, Peggy. "The role of 4-1BB/4-1BB ligand costimulation in T cell responses." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ58825.pdf.
Full text
23
Gardner, Nicola Jane. "Costimulation blockade and selective depletion of activated T cells : therapeutic potential in transplantation." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440535.
Full text
24
Poirier, Nicolas. "Immunothérapie en allotransplantation chez le primate : inhibition du complément et de la costimulation." Nantes, 2009. http://archive.bu.univ-nantes.fr/pollux/show.action?id=cae1dcff-424a-4280-9667-353324ea6724.
Full textAbstract:
Cette thèse a eu pour but d'explorer deux stratégies thérapeutiques innovantes en transplantation rénale chez le primate non-humain : le blocage sélectif de la molécule de costimulation CD28 et l'inhibition précoce de l’activation de la voie classique du complément. La première partie à consisté en l'évaluation préclinique de sc28AT, un antagoniste monovalent sélectif de CD28 dans le but d'inhiber les interactions activatrices CD28/B7 tout en laissant intactes les interactions inhibitrices CTLA-4/B7. Nous avons montré que cette stratégie synergise avec l'effet des inhibiteurs de la calcineurine et conduit à une surégulation en périphérie des lymphocytes T régulateurs (Treg) après transplantation, leur accumulation dans les greffons, ainsi qu'à la surexpression transcriptionnelle de molécules immunorégulatrices. Nous avons montré que les monovalents anti-CD28 ne possèdent pas de propriétés superagonistes et qu'ils sont compatibles avec la fonction suppressive des Treg contrairement aux stratégies bloquant toute la voie CD28/B7/CTLA-4. De même, nous avons montré que seul le blocage sélectif de CD28 permet d'empêcher la formation de synapse immunologique stable par un mécanisme CTLA-4-dépendant. L'objectif de la seconde partie a été de développer un modèle préclinique de rejet aigu humoral en transplantation rénale chez le porc puis chez le primate pour tester de nouvelles stratégies thérapeutiques. Nous avons montré que deux injections consécutives de PBMC du donneur sont suffisantes pour induire une alloimmunisation et le développement d’anticorps cytotoxiques spécifiquement dirigés contre le CMH de classe I du donneur. Ces animaux immunisés développent un rejet violent très rapidement avec des signes histologiques d’atteintes humorales et la déposition de fragments du complément au sein des greffons. Enfin, l'efficacité de la molécule recombinante humaine du C1-inhibiteur a été testée in vitro et in vivo dans ce modèle. Elle permet d’inhiber la cytotoxicité induite par les anticorps et de prévenir tout rejet aigu humoral durant la phase de traitement. Ces recherches ont contribué à apporter des éléments nouveaux quant aux rôles et mécanismes de nouvelles stratégies thérapeutiques immunorégulatrices spécifiques en transplantation avec un possible impact chez l'homme à court termeThe aim of this PhD work was to explore two innovative strategies in non-human primate kidney transplantation: the selective blockade of the costimulatory molecule CD28 and the early inhibition of the classical complement pathway. The objective of the first part was to evaluate sc28AT, a selective monovalent CD28 antagonist, to inhibit activating CD28/B7 interactions while preserving CTLA-4/B7 inhibitory interaction. In this transplantation study, we showed that sc28AT synergize with calcineurine inhibitors and conducts in the periphery to an upregulation of regulatory T cells (Treg), their accumulation in the grafts, where immunomodulatory transcripts were also over-expressed. Monovalent anti-CD28 antibodies have no superagonist activities and are compatible with the suppressive function of Treg in contrast to B7-blockade strategies. Moreover, only selective CD28 blockade prevent the formation of a stable immune synapse trough a CTLA-4-dependent mechanism. The aim of the second part was to develop a preclinical model of acute humoral rejection in renal allotransplantation in order to test new strategies to prevent it. We showed that two subsequent indradermal injection of donor PBMC induced alloimmunisation and cytotoxic antibodies directed specifically against donor class I MHC molecules. Immunized recipients developed a fast rejection with histological signs of humoral rejection and complement deposition in the graft. Finally, a human recombinant C1-inhibitor was tested in vitro and in vivo in this model. This compound inhibited cytotoxicity induced by antibodies and prevented humoral rejection during effective time of treatment. These researches illustrate new insights and mecanisms in specific and immunomodulatory therapeutic strategy in transplantation with possible short impact in humans
25
Musgrave, Bruce L. "Requirement for CD2 signaling in the costimulation and induction of murine cytotoxic T lymphocytes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2002. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ66670.pdf.
Full text
26
Rankin, Alasdair Menzies. "An investigation of CD28/B7 family binding interactions and costimulation, using immunoglobulin fusion proteins." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360469.
Full text
27
Thomas, Ian James. "Investigation of the differential effects of CD80 and CD86 costimulation on CD8 T cells." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424069.
Full text
28
Lambert, Julie. "Autoimmune Diabetes and Transplantation Tolerance Induced by Costimulation Blockade in NOD Mice: a Dissertation." eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/344.
Full textAbstract:
NOD mice model human type 1 diabetes and have been used to investigate tolerance induction protocols for islet transplantation in a setting of autoimmunity. Costimulation blockade-based tolerance protocols that induce prolonged skin and permanent islet allograft survival in non-autoimmune mice have failed in NOD mice. To investigate the underlying mechanisms, we generated NOD hematopoietic chimeras. We were able to show that dendritic cell maturation defects seen in NOD mice are partially corrected in mixed hematopoietic chimeras. Furthermore, skin allograft survival was dependent upon the phenotype of the bone marrow donor, demonstrating that in the NOD the resistance to tolerance induction resides in the hematopoietic compartment. In addition, we studied congenic NOD mice bearing insulin dependent diabetes (Idd) loci that reduce diabetes incidence. The incidence of diabetes is reduced in NOD.B6 Idd3 mice, and virtually absent in NOD.B6 Idd3Idd5 mice. Islet allograft survival in NOD.B6 Idd3 mice is prolonged as compared to NOD mice, and in NOD.B6 Idd3Idd5 mice islet allograft survival is similar to that achieved in C57BL/6 mice. Alloreactive CD8 T cell depletion in NOD mice treated with costimulation blockade is impaired, but is partially restored in NOD.B6 Idd3 mice, and completely restored in NOD.B6 Idd3Idd5 mice. Idd3 results from variations in Il2 gene transcription. We hypothesized insufficient levels of IL-2 in NOD mice contributes to impaired deletion of alloreactive CD8 T cells and shortened islet allograft survival. We observed using synchimeric mice that co-administration of exogenous IL-2 to NOD mice treated with costimulation blockade led to deletion of alloreactive CD8 T cells comparable to that in C57BL/6 mice and prolonged islet allograft survival. However, some Idd loci impaired the induction of transplantation tolerance. These data suggest that Idd loci can facilitate or impair induction of transplantation tolerance by costimulation blockade, and that Idd3 (IL-2) is critical component in this process.
29
Parry, Richard Vaughan. "The regulation of PI 3-kinase and its downstream effectors in T-lymphocyte costimulation." Thesis, University of Bath, 1998. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268195.
Full text
30
Auchabie, Johann. "Modulation de la triade de costimulation CD28 / CD80-86 / CTLA-4 en transplantation rénale." Nantes, 2015. https://archive.bu.univ-nantes.fr/pollux/show/show?id=d2ab7e3d-d947-48e7-8625-491a0019997d.
Full textAbstract:
En transplantation rénale, la durée de vie des greffons reste limitée par l'apparition d'une dysfonction chronique secondaire à la néphrotoxicité des CNI, mais aussi à la survenue d'un rejet chronique humoral. La triade CD28 / CD80-86 / CTLA-4, principale voie de costimulation, constitue une cible privilégiée. L'antagonisation de CD80-86, le ligand commun de CD28 et CTLA-4 par le Belatacept (CTLA4-Ig) a démontré améliorer la fonction du greffon tout en limitant l'apparition d'allo-anticorps, mais elle est associée à une augmentation du taux de rejet aigu faisant suspecter un effet délétère du blocage de CTLA-4. Préserver cette voie est le principal atout du FR104, un anti-CD28 Fab' pegylé, développé par notre équipe et ayant fait la preuve de son efficacité préclinique en transplantation rénale chez le primate. L'objectif de cette thèse était, après avoir évalué le FR104 en association avec d'autres immunosuppresseurs, de le comparer directement avec le Belatacept dans un protocole d'immunosuppression sous-optimal, dans lequel 80% des animaux sous Belatacept ont présenté des rejets cortico-résistants contrairement à ceux sous FR104 (40% de rejet, tous cortico-sensibles, avec une fonction rénale stable pendant 1 an). Cette supériorité pouvait être rapportée aux fonctions extrinsèques du CTLA-4 principalement dues aux Tregs, mais aussi aux signaux inhibiteurs directement médiés par CTLA-4. En effet la plus forte expression d'IL-21 dans les biopsies protocolaires des animaux sous CTLA4-Ig faisait suspecter un meilleur contrôle des Tfh (principale source d'IL-21), par le FR104, ce qu'ont confirmé des données in vitro chez l'homme et in vivo dans un modèle murinKidney graft half-life remain limited by the development of a chronic dysfunction due to CNI nephrotoxicity, but also to the occurrence of a chronic antibody mediated rejection. The major costimulation pathway CD28 / CD80-86 / CTLA-4 triad, represent a new privileged target. Antagonizing CD80-86, the common ligand of CD28 and CTLA-4 with Belatacept (CTLA4-Ig) demonstrated an improvement of renal function associated with a low occurrence of allo-antibody. However Belatacept is associated with an increased risk of acute rejection, suggesting that CTLA-4 blockade could be deleterious. Preserving this pathway, is the main advantage of FR104, an anti-CD28 Fab' antibody pegylated, developed in our team, which proved preclinical efficacy in a model of allotransplantation in primate. The goal of this thesis was, after evaluating FR104 in association with major immunosuppressive drugs, to compare it in head to head with Belatacept in a protocol of suboptimal immunosuppression. In Belatacept group 80% of the animals presented steroid resistant rejection as opposed to animals under FR104 (40% of rejection ever steroid sensitive, followed by a stable renal function during one year). This superiority might be explain by CTLA-4 extrinsic function mainly due to Treg, but also by CTLA-4 intrinsic inhibitory signaling. Indeed IL-21 gene expression was stronger in protocol biopsies of CTLA4-Ig treated animals suggesting that follicular helper T cells, his main source, were better controlled by FR104, as supported by in vitro experiment and data in vivo in mice
31
Ukyo, Naoya. "Costimulation through OX40 is crucial for induction of an alloreactive human T cell response." Kyoto University, 2004. http://hdl.handle.net/2433/147531.
Full text
32
Buggins, Andrea Gail Sherman. "Role of provision of costimulation and soluble inhibitory factors on immune responses to myeloid leukaemia." Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322286.
Full text
33
Berger, DeAnna L. "Investigation of the role of CD137 (4-1BB) costimulation in human CD8⁺ T cell responses." Free to MU Campus, others may purchase, 2004. http://wwwlib.umi.com/cr/mo/fullcit?p1421114.
Full text
34
Dilek, Nahzli. "Inhibition sélective de la costimulation CD28-CD80/86 en transplantation : mécanismes d'action des cellules régulatrices." Nantes, 2011. https://archive.bu.univ-nantes.fr/pollux/show/show?id=f4b951f2-c214-406e-8dca-8c4bbb5329b3.
Full textAbstract:
La transplantation est actuellement un des seuls recours pour palier à une dysfonction chronique d'un organe. Cependant, elle implique obligatoirement un traitement immunosuppresseur à vie ayant d'importants effets secondaires (cancer, infection, néphrotoxicité,…). L'établissement d'une tolérance spécifique au donneur demeure donc un objectif majeur en transplantation, car elle seule permettrait de renoncer à l'immunosuppression chronique. C'est dans cette démarche, que le travail de cette thèse a porté sur le blocage sélectif de la voie de costimulation CD28/CD80-86, et non CTLA-4/CD80-86, promouvant l'induction de mécanismes régulateurs voire tolérogènes en transplantation, en bloquant la voie activatrice tout en maintenant intacte la voie inhibitrice. Ainsi, l'objectif de notre travail a été d'étudier, dans un premier temps, les mécanismes mis en place dans un modèle de tolérance dû au blocage de CD28 en allotransplantation rénale chez le rat, associé à une accumulation de cellules myéloïdes suppressives dans le sang. L'analyse du transcriptome de ces cellules nous a permis de mettre en évidence une diminution de l'expression de la chemokine CCL5 dans ces cellules, mais également dans le sang des animaux tolérants. Par ailleurs, la formation d'un gradient de CCL5 en faveur des greffons chez les animaux tolérants induirait le recrutement de lymphocytes T régulateurs CCR5+ au niveau des greffons, favorisant ainsi l'établissement d'une tolérance. Dans un second temps, cette thèse a eu pour but d'explorer les effets de FR104, un antagoniste monovalent non activateur de CD28, sur la synapse immunologique chez l'homme. Ainsi, seul le blocage sélectif de CD28 permet d'empêcher la formation de synapse immunologique stable entre le lymphocyte T effecteur et la cellule présentatrice d'antigène (CPA), alors qu'au contraire il augmente le temps de contact entre le lymphocyte T régulateur et la CPA, ces mécanismes étant dépendants de CTLA-4. Ces recherches ont contribué à apporter des éléments nouveaux quant aux rôles et mécanismes d'une nouvelle stratégie thérapeutique immunorégulatriceTransplantation is currently used for treatment of end-stage organ diseases. However, solid-organ transplantation requires a heavy treatment for the patients who are subjected to chronic immunosuppression which has several secondary effects, such as infections, cancers, nephrotoxicity. Therefore the establishment of a donor-specific tolerance remains a major goal in transplantation. Thus, this PhD work focused on the selective blockade of the CD28/CD80-86 costimulatory pathway, without impairing CTLA-4/CD80-86, thereby promoting the induction of tolerogenic or regulatory mechanisms in transplantation by blocking the activating interaction while preserving the inhibitory pathway. The first objective of our work was to study those mechanisms involved in a tolerance model in renal allotransplantation in rats, where an accumulation of myeloid suppressor in the blood was found. Transcriptome analysis of these cells allowed us to observe a decreased expression of CCL5 chemokine in these cells, but also in the blood of tolerant animals. The formation of a CCL5 graft-to-periphery gradient in tolerant animals induces the recruitment of CCR5+ regulatory T cells in the grafts, thus promoting tolerance establishment. In a second part, this work aimed at exploring the effects of FR104, a monovalent antagonistic CD28 antibody, on the immunological synapse in humans. Only the CD28 selective blockade prevented formation of stable immunological synapses between T effector cells and antigen-presenting cell (APC), whereas on the contrary it increased the contact time between regulatory T cells and APC, these mechanisms being CTLA-4 dependent. Thus, these researches illustrate new elements regarding the roles and mechanisms of a new specific immunoregulatory therapeutic strategy
35
Xia, Fan. "Décryptage des mécanismes de signalisation précoce de la costimulation dans l' activation des lymphocytes T naifs." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM4064.
Full textAbstract:
L'objectif de notre travail est de comprendre la contribution relative des voies de signalisation précoces du TCR et de CD28 dans l'activation des lymphocytes T naïfs. Notre étude a d'abord montré que dans les cellules T CD4+ naïves, la stimulation du TCR augmente de manière significative la liaison en deux dimensions (2D) de CD28 avec ses ligands B7, et ceci dépend à la fois du domaine cytoplasmique de CD28 et de l'activité des src kinases. Par la suite, notre analyse biochimique a démontré que l'engagement du TCR par son ligand (CMHp) potentialise la phosphorylation de CD28 stimulée par son ligand B7. En outre, la stimulation conjointe du TCR et de CD28 augmente fortement la phosphorylation des protéines de signalisation proximales telles que les molécules Vav-1 et PLCγ-1. Nous avons également examiné la mobilisation des ions calcique (Ca++). Nous avons trouvé que l'engagement du TCR ou de CD28 seul est capable de déclencher une élévation de la concentration intracellulaire d'ions Ca++ dans des cellules T naïves. Cette élévation qui se caractérise par de fortes fluctuations de la concentration calcique impliquerait principalement 2 types de canaux calciques de la membrane plasmique. De façon attendue, une stimulation conjointe des lymphocytes par le TCR et CD28 augmente l'amplitude moyenne de la réponse calcique. Nos données ont révélé que seule une stimulation conjointe, et non individuelle, du TCR et de CD28 augmente significativement le temps de résidence du Ca++ libres fluctuants par rapport aux cellules non stimulées. Par conséquent, cette augmentation du temps de résidence caractérise spécifiquement la réponse calcique induite par TCR et CD28In this work, we aimed at determining the relationship between and specific contribution of TCR and CD28 early signaling pathways in naïve CD4+ T cell activation. Our data showed that in naïve CD4+ T cells, TCR stimulation significantly increased the 2D binding of CD28 to its B7 ligands and this increase depended on both cytoplasmic tail of CD28 and activity of src kinases. Our biochemical analysis then demonstrated that TCR engagement with its ligand pMHC strongly enhanced the CD28 tyrosine phosphorylation triggered by B7. Moreover, the conjoint stimulation of TCR and CD28 markedly augmented activation of proximal signaling molecules such like Vav-1 and PLCγ-1 compared to the stimulation with each receptor alone. We next went to examine the calcium ion (Ca2+) mobilization. We found that in naïve CD4+ T cells, engagement with ligand of TCR or CD28 alone was able to trigger rise of the fluctuating cytosolic-free Ca2+ level. Unexpectedly, such rises implicated predominantly the involvements of two different types of calcium channels: Cav and CRAC channels. The conjoint stimulation with both TCR and CD28 enabled the augment of average amplitude of the calcium response. Through the time series analysis, our data unveiled that the conjoint, but not separate, TCR and CD28 stimulation in naïve CD4+ T cells significantly increased the fluctuating cytosolic-free Ca2+ dwell time relative to that found in unstimulated cells. The increase of the cytosolic-free Ca2+ dwell time therefore uniquely characterized the calcium response triggered by TCR and CD28 and presumably corresponded to a fundamental feature for the high efficiency of T cell activation induction
36
Kinnear, Gillian. "Role of OX40-OX40L interactions in the immune response to solid organ allografts." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:3a1f1658-eed2-4d5f-9331-d0ed884ec7ca.
Full textAbstract:
Transplantation is the treatment of choice for end stage organ failure however current immunosuppressive therapies whilst effective at preventing acute allograft rejection, fail to prevent late graft loss due to chronic rejection and are associated with an increased risk of infection and malignancy. Therefore there is a clear unmet clinical need for improved strategies to prevent allograft rejection. OX40 is a member of the TNFR superfamily that has potent costimulatory properties. Although the impact of blockade of the OX40-OX40L pathway has been well documented in models of autoimmune disease, its effect on the rejection of allografts is less well defined. Therefore the aim of this thesis was to determine the impact of OX40 blockade on conventional and regulatory T cell responses to allografts. We found that activation of CD4+ and CD8+ naïve and memory T cells resulted in the induction of OX40 expression and that blockade of OX40-OX40L interactions partially inhibited the response of alloreactive T cells in vitro and prevented skin allograft rejection but did not result in the induction of tolerance. OX40 blockade was found to have no effect on the activation and proliferation of T cells but rather effector T cells failed to accumulate and migrate to skin allografts. This was shown to be the result of an enhanced degree of cell death amongst proliferating effector cells. In addition, blockade of OX40-OX40L interactions at a time of exposure to alloantigen resulted in a pool of Treg with an enhanced ability to suppress T cell responses to alloantigen in vitro and in vivo. Counter-intuitively, OX40 blockade was found to increase the potency of alloreactive Treg by promoting survival following re-activation. Finally, although OX40 blockade impacted both conventional and regulatory T cell responses, anti-OX40 administration did not promote skin or heart allograft survival in immunocompetent recipients and failed to synergise with blockade of other costimulatory molecules to prevent allograft rejection. In conclusion, these data demonstrate that blockade of OX40-OX40L interactions can attenuate naïve and memory T cell responses to alloantigen whilst promoting the survival of alloreactive Treg. Therefore, we propose that anti-OX40 would be a worthwhile adjunct to pre-existing strategies to induce tolerance.
37
Dias, Silvy da Rocha. "The function of CTLA-4 in the mechanism of negative regulatory costimulation of TCR mediated signals." Tese, Porto : Edição do Autor, 2002. http://catalogo.up.pt/F?func=find-b&local_base=UPB01&find_code=SYS&request=000090479.
Full text
38
Dias, Silvy da Rocha. "The function of CTLA-4 in the mechanism of negative regulatory costimulation of TCR mediated signals." Doctoral thesis, Porto : Edição do Autor, 2002. http://hdl.handle.net/10216/64574.
Full text
39
Murray, Nicholas. "Costimulation of T cells and its role in T cell recognition of malignant colorectal cells in vitro." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301247.
Full text
40
Nicol, Jonathan. "Effet différentiel de la costimulation par la molécule B7.2 sur les lymphocytes T CD4+ versus T CD8+." Sherbrooke : Université de Sherbrooke, 2002.
Find full text
41
Pearson, Todd. "The Genetic Basis of Resistance to Transplantation Tolerance Induced by Costimulation Blockade in NOD Mice: a Dissertation." eScholarship@UMMS, 2003. https://escholarship.umassmed.edu/gsbs_diss/16.
Full textAbstract:
The NOD mouse is a widely studied model of type 1 diabetes. The loss of self-tolerance leading to autoimmune diabetes in NOD mice involves at least 27 genetic loci. Curing type I diabetes in mice and humans by islet transplantation requires overcoming both allorejection and recurrent autoimmunity. This has been achieved with systemic immunosuppression, but tolerance induction would be preferable. In addition to their genetic defects in self-tolerance, NOD mice resist peripheral transplantation tolerance induced by costimulation blockade using donor-specific transfusion and anti-CDl54 antibody. Failure has been attributed to the underlying autoimmunity, assuming that autoimmunity and resistance to transplantation tolerance have a common basis. Hypothesizing that these two abnormalities might be related, we investigated whether they had a common genetic basis. Diabetes-resistant NOD and C57BL/6 stocks congenic for various reciprocally introduced Idd loci were assessed for their ability to be tolerized. Surprisingly, in NOD congenic mice that are almost completely protected from diabetes, costimulation blockade failed to prolong skin allograft survival. In reciprocal C57BL/6 congenic mice with NOD-derived Idd loci, skin allograft survival was readily prolonged by costimulation blockade. Unexpectedly, we observed that (NOD x C57BL/6)F1 mice, which have no diabetes, nonetheless resist induction of tolerance to skin allografts. Further analyses revealed that the F1 mice shared the dendritic cell maturation defects and abnormal CD4+ T cell responses of the NOD but had lost its defects in macrophage maturation and NK cell activity. Finally, using a genome wide scan approach, we have identified four suggestive markers in the mouse genome that control the survival of skin allografts following DST and anti-CD154 mAb therapy. We suggest that mechanisms controlling autoimmunity and transplantation tolerance in NOD mice are not completely overlapping and are potentially distinct, or that the genetic threshold for normalizing the transplantation tolerance defect is higher than that for preventing autoimmune diabetes. We conclude that resistance to allograft tolerance induction in the NOD mouse is not a direct consequence of overt autoimmunity and that autoimmunity and resistance to costimulation blockade-induced transplantation tolerance phenotypes in NOD mice are not under identical genetic control.
42
Chaux, Pascal. "Rôle des cellules dendritiques intratumorales et du système de costimulation B7/CD28 dans la réponse immunitaire antitumorale." Lyon 1, 1995. http://www.theses.fr/1995LYO1T297.
Full text
43
Guillonneau, Carole. "Etude du rôle de différentes voies de costimulation dans le rejet d' allogreffe cardiaque chez le rat." Paris 7, 2005. http://www.theses.fr/2005PA077097.
Full text
44
Renick, Paul J. "CD28 Costimulation Requirement for Interferon-y Secretion by Natural Killer T cells During Hepatitis B Virus Infection." Wright State University / OhioLINK, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=wright1040657636.
Full text
45
Nicol, Jonathan. "Effet différentiel de la costimulation par la molécule B7.2 sur les lymphocytes T CD4+ versus T CD8+." Mémoire, Université de Sherbrooke, 2002. http://savoirs.usherbrooke.ca/handle/11143/3289.
Full textAbstract:
Dans le but de mieux comprendre le rôle in vivo de la molécule B7.2 dans la réponse immune, un modèle de souris transgénique (Tg) exprimant de façon constitutive B7.2 sur les lymphocytes B et T a été généré. Il a été démontré que l'expression constitutive de B7.2 sur les lymphocytes B mène à leur élimination par les lymphocytes T (Fourrier et ai., 1997; Van Parijs., et al 1997). Afin de déterminer quelle population de lymphocyte T (T CD4+ et/ou T CD8+ ) est responsable de l'élimination des lymphocytes B exprimant de façon constitutive la molécule B7.2, nous avons généré des souris B7.2 Tg déficientes en lymphocytes T CD4 + (CMH II déficientes) et déficientes en lymphocytes T CD8+ (CMH I déficientes). Les résultats nous portent donc à croire qu'il pourrait exister un effet différentiel suite à la costimulation par la molécule B7.2 chez les lymphocytes T CD8+ vs T CD4+ et que la stimulation dépendante de B7.2/(CD28/CTLA-4) pourrait jouer un rôle important dans l'homéostatie des lymphocytes T CD8+ en périphérie."--Résumé abrégé par UMI
46
Brisebois, Marcel. "Caractérisation d'un modèle Murin B7.2 transgénique de démyélinisation spontanée." Thèse, Université de Sherbrooke, 2006. http://savoirs.usherbrooke.ca/handle/11143/4222.
Full textAbstract:
Le but du travail de recherche présenté dans cette thèse était de déterminer les mécanismes impliqués dans le développement de symptômes neurologiques observés dans une lignée de souris transgénique pour l’expression de la molécule B7.2/CD86. La molécule B7.2 est un des ligands du récepteur CD28 qui transmet des signaux intracellulaires nécessaires à la prolifération des lymphocytes T et au développement de leurs fonctions effectrices. Nos travaux démontrent que ces souris développent spontanément une pathologie démyélinisante auto-immune conséquemment à l’expression transgénique de la molécule B7.2 sur les cellules de la microglie du système nerveux central. Les souris affectées présentent une infiltration de lymphocytes T au niveau du système nerveux central et périphérique proximal et cet infiltrat est prédominé par une population de lymphocytes T CD8[indice supérieur +] mémoires/effectrices. Nos études indiquent que la population de lymphocytes T CD8[indice supérieur +] joue un rôle effecteur dans le développement de la pathologie tandis que la population des lymphocytes T CD4[indice supérieur +] la régulent de façon négative. Nos résultats démontrent également que l’activation des cellules de la microglie survient très tôt lors de la pathogenèse et que cette activation des cellules de la microglie ainsi que le processus de démyélinisation sont entièrement dépendants de la signalisation par le récepteur de l’IFNy. Ce modèle de démyélinisation reflète l’émergence de cellules T autoréactives spécifiques au système nerveux à partir d’un répertoire périphérique polyclonal, un processus immunopathogénique qui se produit possiblement durant la pathogenèse de la sclérose en plaques. De plus, il présente certaines caractéristiques pathologiques similaires à celles de la sclérose en plaques tels que le développement spontané du processus de démyélinisation et de dommages aux axones ainsi qu’une connexité avec l’activité de l’IFNy. Plusieurs données de la littérature suggèrent que les lymphocytes T CD8[indice supérieur +] pourraient jouer un rôle dans les maladies auto-immunes affectant le système nerveux, mais la contribution exacte et les mécanismes pathogéniques spécifiques des lymphocytes T CD8[indice supérieur +] ne sont pas encore clairement établis. Le travail de recherche présenté dans cette thèse a donc permis d’établir que la lignée de souris transgénique qui exprime de façon constitutive le ligand de costimulation B7.2/CD86 sur les cellules de la microglie représente un nouveau modèle animal qui permettra d’étudier et de comprendre ces mécanismes pathogéniques spécifiques aux lymphocytes T CD8[indice supérieur +] ainsi que les processus qui régulent la participation des lymphocytes T CD8[indice supérieur +] dans la destruction de la gaine de myéline.
47
Brossay, Angélique. "Costimulation des lymphocytes T et différenciation dendritique des monocytes humains dans un modèle de présentation indirecte de xénoantigènes." Tours, 2002. http://www.theses.fr/2002TOUR3316.
Full textAbstract:
Des travaux antérieurs ont démontré l'existence de la seule voie indirecte de présentation de xénoantigènes dans un modèle fondé sur la coculture de cellules endothéliales d'aorte de porc, et de monocytes et lymphocytes T CD4+ humains. Le blocage de la voie CD2, suggérant l'expression par l'endothélium d'un ligand de CD2, orthologue du CD58 humain, nous a amené, dans une première partie, à amplifier puis cloner la totalité de la séquence codante du CD58 porcin. Dans une seconde partie, nous avons démontré l'origine humaine (monocytaire) de la costimulation lymphocytaire (cis-costimulation), en dépit de l'expression de molécules de costimulation sur les cellules endothéliales de porc. Enfin, nous avons mis en évidence une différenciation dendritique des monocytes humains au contact d'un endothélium porcin. Ces cellules dendritiques sont capables de capter des antigènes, d'induire des proliférations lymphocytaires et de se domicilier dans les ganglions lymphatiques en exprimant CCR7We have previously demonstrated the presence of an indirect presentation pathway in a model based on the coculture of porcine aortic endothelial cells, human monocytes and T lymphocytes. In a simplified model without human monocytes, an anti-human CD2 monoclonal antibody blocked the lymphocyte proliferation suggesting that a porcine ortholog of human CD58 was expressed by porcine endothelial cells. We have cloned and sequenced the entire sequence of porcine CD58 and demonstrated that despite the expression of costimulatory molecules on endothelial cells, costimulatory signals were provided in cis by human monocytes. Next, we demonstrated that a monocyte-to-dendritic cell differentiation occur in this model. Dendritic cells obtained after a coculture human monocyte/porcine endothelial cells captured antigen, induced a lymphocyte proliferation and expressed the CCR7 receptor which favor migration toward lymphoid organs
48
Bourdenet, Gwladys. "Étude physiopathologique de la myopathie auto-immune des souris NOD invalidées pour la voie de costimulation ICOS/ICOSL." Thesis, Normandie, 2017. http://www.theses.fr/2017NORMR062/document.
Full textAbstract:
Les myopathies inflammatoires (MI) représentent un groupe hétérogène de maladies caractérisépar une faiblesse musculaire chronique et symétrique associée à une augmentation du taux sérique decréatine phosphokinase (CPK). Les MI sont actuellement subdivisées en 5 entitées : les dermatomyosites,les myopathies nécrosantes auto-immunes, la myosite à inclusion, la polymyosite et les myosites dechevauchement. A ce jour, le diagnostic des MI repose sur l’association de signes cliniques, decaractéristiques anatomopathologiques sur la biopsie musculaire et la présence d’auto-anticorps (aAc). Eneffet, la découverte d’aAc spécifiques et/ou associés aux myosites (MSA/MAA) a considérablementamélioré le diagnostic et le pronostic de la maladie. Cependant, un nombre non négligeable de patientsatteints de MI sont séronégatifs pour les MSA/MAA connus. Par ailleurs, la biopsie musculaire nécessaireau diagnostic est parfois guidée par imagerie par résonance magnétique (IRM), bien qu’il n’ait pas étéprouvé que les données d’imagerie soient corrélées aux signes histologiques. Enfin, le traitement des MIrepose sur l’utilisation d’immunosuppresseurs systémiques, une approche non spécifique de laphysiopathologie de la maladie. Les modèles animaux de MI les plus utilisés sont induits et nonspontanés : ils reposent principalement sur l’immunisation d’animaux contre des protéines telles que lamyosine, la protéine C ou l’histidyl-tRNA synthétase.Les souris NOD (non obese diabetic) sont le modèle classique d’étude du diabète de type 1.Lorsque ces souris sont invalidées pour la voie de costimulation lymphocytaire ICOS/ICOSL, les souris nedéveloppent plus de diabète mais présentent alors une atteinte musculaire. Dans ce travail, nous avonsétudié le phénotype et caractérisé l’atteinte musculaire des souris NOD Icos-/- et NOD Icosl-/-. Nous avonsainsi établi le 1er modèle murin spontané de MI, dont la physiopathologie est médiée par leslymphocytes T CD4+ et la sécrétion d’IFN-γ. Par ailleurs, ces souris présentent un déficit en lymphocytes Trégulateurs. Nous avons également identifié 4 auto-antigènes (aAg) candidats cibles d’aAc chez ces souris.La recherche des aAc correspondants aux aAg orthologues dans le sérum des patients atteints de MI apermis d’identifier, pour l’un d’entre eux, une minorité d’individus séropositifs grâce au développementd’un nouveau test ALBIA (addressable laser bead immunoassay). Il pourrait donc s’agir d’un nouveaubiomarqueur. Dans la perspective de nouvelles évaluations thérapeutiques, nous avons établi desdonnées préliminaires montrant que l’interleukine 2 à faibles doses permet de retarder l’apparition de lamaladie. Enfin, nous avons mis à profit ce modèle et démontré la corrélation entre les données généréespar IRM et par analyse histologique de l’inflammation, confortant le rôle de cette technique d’imagerie àla fois pour le diagnostic et le suivi des MIInflammatory Myopathies (IM) are a heterogeneous group of diseases characterized bychronic and symmetrical muscle weakness associated to increased creatine phosphokinase (CPK)levels, according to entity concerned. Currently, IM are divided into 5 main entities:dematomyositis, immune-mediated necrotizing myopathies, inclusion body myositis, polymyositisand overlap myositis. Nowadays, IM diagnosis is based on clinical signs associated to pathologicfeatures on muscle biopsy and presence of auto-antibodies (aAb). Indeed, the discovery of myositisspecific and/or associated auto-antibodies (MSA/MAA) had considerably improve disease diagnosisand prognosis. However, substantial proportion of IM patients do not display any knownMSA/MAA. Furthermore, diagnosis requires muscle biopsy. This biopsy is sometimes guided bymagnetic resonance imaging (MRI), even though correlation between MRI findings and pathologicalfeatures is not established. Lastly, therapeutics used in IM treatment are systemicimmunosuppressive agents, i.e. not specific to IM pathophysiology. Animal models of IM are mainlybased on active immunization against different proteins as myosin, C protein orhistidyl-tRNA synthetase, while spontaneous models are required to identify pathophysiologicalmechanisms that new therapeutics should target.NOD (non obese diabetic) mice are the main model of type 1 diabetes. When invalidatedfor ICOS/ICOSL costimulation pathway, these mice do not develop diabetes but present musculardisorders. In this work, we study Icos-/- and Icosl-/- NOD mice phenotype and characterize theremuscle lesion. Thus, we have established this model as the first paradigm of IM. Pathophysiologicalstudy in these mice demonstrated that disease is CD4+ T cell dependent and associated to IFN-γproduction. Furthermore, we shown a quantitative defect in regulatory T cells. We have alsoidentified 4 candidate autoantigens (aAg) in Icos-/- and Icosl-/- NOD mice. Searching forcorresponding aAb against ortholog proteins in patients with IM, we identified for one of them, alow percentage of seropositive individuals using a new ALBIA (addressable laser beadimmunoassay). It could be identified as a new biomarker. In order to evaluate new therapies, weestablished preliminary data showing that low dose interleukin 2 therapy allow to delay diseaseonset. Lastly, we took advantage of this new model to demonstrate the correlation betweenMRI findings and histological inflammation features, confirming the valuable role of MRI for thediagnosis and monitoring of IM
49
Edelmann, Kurt H. "Murine T cell immunity to primary herpes simplex virus infection : roles for costimulation and MHC class I antigen presentation /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/5037.
Full text
50
Doty, Raymond Thomas. "The role of the cytoplasmic tail of antigen-presenting cell surface molecule CD80 in delivery of T cell costimulation /." Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/8327.
Full text