Thèses sur le sujet « Cd40lg- »
Créez une référence correcte selon les styles APA, MLA, Chicago, Harvard et plusieurs autres
Consultez les 50 meilleures thèses pour votre recherche sur le sujet « Cd40lg- ».
À côté de chaque source dans la liste de références il y a un bouton « Ajouter à la bibliographie ». Cliquez sur ce bouton, et nous générerons automatiquement la référence bibliographique pour la source choisie selon votre style de citation préféré : APA, MLA, Harvard, Vancouver, Chicago, etc.
Vous pouvez aussi télécharger le texte intégral de la publication scolaire au format pdf et consulter son résumé en ligne lorsque ces informations sont inclues dans les métadonnées.
Parcourez les thèses sur diverses disciplines et organisez correctement votre bibliographie.
MERCURI, ELISABETTA. « PRECLINICAL MODELING HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF THE ADOPTIVE TRANSPLANT OF GENE CORRECTED T CELLS IN X-LINKED HYPER-IGM IMMUNODEFICIENCY ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2020. http://hdl.handle.net/10281/263922.
Texte intégralBackground The X-linked hyper-IgM syndrome type I (HIGM1) is caused by inactivating mutations in the CD40 ligand gene (CD40LG) that disrupt the T cell helper function on B cells and macrophages. This disease represents an ideal candidate for a gene correction strategy because preclinical studies of Hematopoietic Stem Cell (HSC) gene therapy have already shown i) evidence of potential efficacy even with few amounts of transduced cells; ii) critical safety issues due to unregulated transgene expression. Since in HIGM1 the genetic defect is not lethal to T cells, we aim to apply our gene editing strategy on autologous T cells that could be used to provide immediate therapeutic benefit to the patients by resolving pre-existing infections prior to a definitive HSPC transplant. Methods To establish which are the therapeutic threshold levels and transplant conditions required to achieve immune reconstitution and functional immunologic restoration with corrected cells, we infused different doses of WT T cells into HIGM1 mice pre-conditioned or not with different lymphodepleting regimens and performed competitive transplants of WT and Cd40lg-/- HSPC in the mouse model. Results While longitudinal blood analyses showed a long-term, stable T cell engraftment in all the conditions, highest engraftment rates were obtained in mice transplanted after chemotherapy treatment with cyclophosphamide (CPA). All the transplanted mice showed a partial rescue of the antigen-specific IgG response after immunization with Keyhole Limpet Hemocyanin (TNP-KLH) but a higher rescue was observed in mice pre-conditioned with CPA. These mice also showed the presence of TNP-KLH specific IgG producing B cells and germinal centers within splenic lymphoid follicles. HIGM1 mice reconstituted with increasing proportions of WT HSPC displayed a dose-dependent rescue of the T cell mediated immune response. In particular we found that 10% of WT HSPC is sufficient to partially restore serologic immunity against different antigens as well as to attenuate infection in HIGM1 mice challenged with Pneumocystis murina. Conclusions Our current efforts are aimed to demonstrate functional restoration of the immune response against Pneumocystis murina infection in HIGM1 mice that received adoptive transfer of WT CD4+ T cells. If successful, our findings will be instrumental to establish the therapeutic potential of a T cell gene correction approach for the treatment of the HIGM1 disease that could act as a bridge therapy to the HSPC-based strategy.
Yeboah, Sybil A. Parise Leslie V. « Do CD40L and CD40 contribute to sickle cell anemia ? » Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1640.
Texte intégralTitle from electronic title page (viewed Sep. 16, 2008). "... in partial fulfillment of the requirements for the degree of Master of Science in the Department of Biochemistry." Discipline: Biochemistry and Biophysics; Department/School: Medicine.
Martins, Ryan Stephen. « Tumor-Bearing Host Macrophage Dysfunction : Role of CD40/CD40L Interactions ». Thesis, Virginia Tech, 2001. http://hdl.handle.net/10919/32405.
Texte intégralMaster of Science
Oxer, Daniella Stefani. « Interação entre as vias de sinalização CD40/CD40L e os PPARs ». Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/5/5159/tde-17062009-122735/.
Texte intégralThe membrane receptor CD40 and its ligand CD40L play an important role in the interface between innate and acquired immunity. Dysfunction of this signaling pathway was described in inflammatory and autoimmune diseases. In systemic lupus erythematosus (SLE), increased serum levels of soluble CD40L have been detected, where it plays a significant role in the generation of auto-antibodies. Peroxisome proliferator activator receptors (PPARs) are transcription factors originally described in lipid metabolism. More recently, they were also characterized as inflammatory modulators. Therefore, our objective was to determine whether the activation of PPARs may modulate the inflammatory process through interaction with the CD40/CD40L signaling pathway in vitro and in vivo. Macrophages derived from the human monocytic cell line THP-1 by 24h-treatment with PMA (40 nM) were stimulated with human recombinant CD40L (rhCD40L, 1 g/ml) for different periods. Messenger RNA (mRNA) transcripts for PPAR , and were determined by real time PCR and expressed as a ratio of the housekeeping gene GAPDH transcripts. THP-1 cells express a basal level of PPAR and gene transcription, which is increased 16 and 2 hours after exposure to rhCD40L, respectively. We also stimulated the THP-1 cells with LPS (10 g/ml) and LPS+rhCD40L to see if the increase of PPAR was a response specific to the rhCD40L stimuli. The data show that there is a decrease in PPAR and genes expression upon LPS or LPS+rhCD40L stimulation, indicating that in these times (2 and 16 hours) the response is specific for the CD40/CD40L signaling pathway. Increased expression of CD36 is known as an indicator of PPARs activity. We measured CD36 and saw an increase of this receptor after rhCD40L stimulus, indicating indirectly that PPARs were active in this experimental model. To prove the direct interaction between CD40/CD40L and PPAR , we silenced the PPAR gene by siRNA and analyzed the expression of CD80, which is known to increase after CD40 activation. The results show an increase in CD40L-stimulated CD80 expression upon silencing of PPAR , showing that there is an interaction between these signaling pathways. To confirm whether these findings also occur in vivo, mononuclear cells were isolated from whole blood samples from SLE patients with active (n=17) and inactive disease (n=21), and healthy donors (n=12). The mRNA transcripts for PPARs were detected by real time PCR. In both active and inactive SLE patients, monocytes show an increase in PPAR mRNA expression, as compared to healthy donors. PPAR mRNA is increased only in active patients when compared to healthy donors and inactive lupus patients. Further in this analysis, when we separated the patients with and without the administration of corticosteroids, PPAR displayed the same pattern as above. These results suggested that PPAR may be a marker for lupus activity. To validate this hypothesis, we compared the results obtained from patients with tuberculosis and acute infections. Results showed that only active-lupus patients have an increase in PPAR , confirming the specificity of this phenomenon and hence our hypothesis Our findings suggest that PPAR and are up-regulated specifically in response to CD40/CD40L activation, in both cultured macrophages and in monocytes obtained from SLE patients. We could also suggest that PPAR may be marker for lupus activity. Our results may represent a new control mechanism of the CD40/CD40L signaling pathway and seem to be implicated in the control of the inflammatory response in both human macrophages in vitro and SLE patients
Macina, Denis. « Étude de l'implication du système CD40/CD40L dans le syndrome hyper-IGM ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq33704.pdf.
Texte intégralMorgenroth, Iris. « Charakterisierung des CD40-CD40L-Systems als wichtiger Regulator der B-Zellfunktion des Haushuhns ». Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-77513.
Texte intégralBürger, Christina [Verfasser], et Sabine [Akademischer Betreuer] Steffens. « Cell type-specific CD40-CD40L interaction in atherosclerosis / Christina Bürger ; Betreuer : Sabine Steffens ». München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1142787141/34.
Texte intégralPluvinet, Ortega Raquel. « Paper del receptor CD40 en l'activació de les cèl·lules endotelials. Rellevància de la interacció CD40-CD40L en processos immunoinflamatoris ». Doctoral thesis, Universitat de Barcelona, 2007. http://hdl.handle.net/10803/1884.
Texte intégralEls principals objectius d'aquesta tesi han estat 1) l'estudi a nivell molecular del paper de CD40 en l'activació de les cèl·lules endotelials, i 2) les conseqüències del bloqueig d'aquesta via de senyalització en la resposta immunoinflamatòria.
S'ha obtingut un siRNA potent i específic capaç de reduir l'expressió del receptor CD40 humà en un 85%, tant a nivell de mRNA com a nivell de proteïna. Aquest siRNA expressat en forma de shRNA en un vector lentiviral permet assolir un silenciament gènic eficient i estable de CD40 al llarg del temps. S'ha validat l'activitat antiinflamatòria d'aquest siRNA analitzant les conseqüències funcionals del silenciament d'aquest receptor en cèl·lules endotelials. Aquest siRNA bloqueja l'activació endotelial via CD40L impedint la inducció de l'expressió de les molècules d'adhesió ICAM-1, VCAM-1 i E-selectina, i inhibint l'adhesió leucocitària en aquestes cèl·lules en un 87%.
S'ha utilitzat el potencial antiinflamatori del siRNA dirigit contra CD40 humà per estudiar el paper d'aquest receptor en cèl·lules endotelials en inflamació. Utilitzant microarrays, s'ha realitzat una anàlisi comparativa del perfil global d'expressió gènica en cèl·lules endotelials humanes en les quals s'inactiva específicament aquesta via de senyalització mitjançant RNAi, en el context de la interacció cèl·lula endotelial i limfòcit T activat (CD40L+), com a primer pas en l'inici de la resposta immunoinflamatòria. Aquest estudi d'expressió gènica ha permès identificar nous gens i noves vies de senyalització implicades en la inducció de la resposta inflamatòria desencadenada per l'activació de CD40 en endoteli.
Per altra banda, es volia avaluar l'eficàcia del silenciament gènic de CD40 per a la inducció de tolerància immunològica en un model experimental d'al·lotrasplantament renal. Amb aquesta finalitat s'ha obtingut un siRNA anti-CD40 de rata amb una potent eficiència silenciadora i s'ha optimitzat la transferència d'aquest siRNA en el ronyó a trasplantar mitjançant electroporació in vivo de l'òrgan. L'objectiu d'aquest estudi era silenciar temporalment l'expressió d'aquest receptor en les cèl·lules renals i bloquejar la interacció CD40-CD40L essencial per a la inducció de procés inflamatori que dóna lloc al rebuig del ronyó trasplantat. Resultats preliminars mostren que la teràpia gènica local amb siRNA redueix la resposta inflamatòria posttrasplantament. El siRNA anti-CD40 causa una reducció significativa de l'expressió del mRNA de CD40, disminuint l'aparició de rebuig agut humoral i allargant el temps mig de supervivència dels animals trasplantats amb els ronyons tractats amb siRNA en comparació amb els animals control.
CD40 (TNFRSF5) belongs to the tumor necrosis factor receptor family (TNF-R). Its interaction with its physiological ligand (CD40L or CD154) regulates a wide variety of biological functions, from the activation of the immune system, to different aspects of the inflammatory response.
The main goals of this work have been 1) the molecular study of the role of CD40 in the activation of the endothelial cells, and 2) the consequences of blocking this signaling in the immunoinflammatory response. We have obtained a powerful and specific siRNA able to reduce human CD40 expression by 85%. The anti-inflammatory activity of this siRNA has been validated by analyzing the functional consequences of CD40 silencing in endothelial cells activated via CD40L. This siRNA blocks the induction of ICAM-1, VCAM-1 and E-selectin expression, and inhibits leukocyte adhesion in these cells by 87%.
We have used the anti-inflammatory potential of this siRNA directed against human CD40 to carry out a global gene expression profiling analysis in order to study the role of CD40 in endothelial cells during inflammation. Using microarrays, we have performed a comparative transcriptome analysis in human endothelial cells, in the context of the endotelial cell interaction with activated T lymphocyte (CD40L+), as the first step of the immunoinflammatory response. This study has allowed us to identify new genes and signaling pathways involved in the induction of the inflammatory response by CD40 activation in endothelium.
On the other hand, we have obtained an siRNA against rat CD40 with a powerful silencing activity and we have optimized its transfer to the kidney through in vivo electroporation. The purpose of this study was to determine the CD40 gene silencing effectiveness in inducing immunological tolerance in an experimental model of renal allotransplantation. Preliminary results show that local gene therapy with siRNA reduces the inflammatory response post-transplantation. The anti-CD40 siRNA treatment causes a significant reduction of the incidence of acute humoral rejection and increases the survival half life of animals transplanted with kidneys treated with siRNA compared to control animals.
Meunier, Sylvain. « Impact de l’interaction CD40/CD40L sur les différents intervenants de la réponse immunitaire T CD8 ». Paris 5, 2011. http://www.theses.fr/2011PA05T039.
Texte intégralMy thesis project is to study the role of different possible pathways possible for the CD40/CD40L interaction during the primary response of CD8 T cells and to characterize the response of CD8 T cell CD40-/-. The results suggest two CD40/CD40L interaction effects depending on the location of the CD40 molecule expressed on different cell types (on CD8 T cells or on antigen presenting cells). The first effect is to set up an optimal primary response from the CD8 T cells and is due to the expression of CD40 by antigen presenting cells. The second effect is the generation of memory CD8 T cells during the primary response and is due to the expression of CD40 by CD8 T cells. Our results show that the CD40/CD40L interaction via the antigen presenting cells sends signals sufficient for proliferation and cytotoxicity of CD8 primary response. However, the CD40/CD40L interaction via the CD8 T cells is essential for the generation of memory CD8 T cells. If the deficiency of CD40 by CD8 T cells does not affect the primary response, it is not the case of the secondary response. Indeed, in this case, CD8 T cells exhibit altered secondary response. Compared to a classical secondary response, the CD8 T cells CD40-/- exhibit a decreased response amplitude and delayed peak response, a response closer to a primary response. These cells also exhibit impaired cytotoxicity and survival. Finally these cells have a more sensitivity to immunoregulatory factors
Sakai, Hidemasa. « The CD40-CD40L axis and IFN-γ play critical roles in Langhans giant cell formation ». Kyoto University, 2012. http://hdl.handle.net/2433/158049.
Texte intégralHirano, Ayumi. « T dependent B cell help in cattle : immunoregulatory function of interleukin-4 and CD40-CD40L interactions / ». free to MU campus, to others for purchase, 1997. http://wwwlib.umi.com/cr/mo/fullcit?p9841150.
Texte intégralNATOLI, SILVIA. « Riduzione della risposta monocitica al CD40L in corso di sepsi ». Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2009. http://hdl.handle.net/2108/1115.
Texte intégralA defective adaptive immune response has been suggested to contribute to septic immunosuppression. Here, the response of monocytes to CD40-ligand (CD40L) has been analyzed in patients with Gram-negative sepsis. As compared to cells from controls, monocytes from septic patients showed significantly reduced production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-12 and were unable to acquire high levels of CD80 and CD86 molecules. These alterations were observed at the onset of sepsis and persisted at day 7. However, the ability of monocytes to respond to CD40L stimulation was partially, but significantly, restored in patients who recovered from sepsis. In addition, costimulation of autologous CD4+ T lymphocytes by CD40L-activated monocytes from septic patients failed to induce cell proliferation and interferon (IFNγ) production. Finally, the ability of CD40L to rescue monocytes from apoptosis was severely impaired. We conclude that downregulation of CD40L response may be an appropriate model of monocyte alteration observed during septic immunosuppression and may help in the development of novel therapeutic strategies.
Michels, Monique. « Interação entre o receptor de membrana CD40 e o seu ligante CD40L sobre mecanismos neuroinflamatórios e comportamentais associados à sepse ». reponame:Repositório Institucional da UNISUL, 2014. http://www.riuni.unisul.br/handle/12345/521.
Texte intégralA sepse e síndrome de disfunção orgânica múltipla representam um problema clínico de alta relevância, principalmente devido a sua grande incidência em pacientes críticos e aos seus altos índices de mortalidade. Apesar de medidas terapêuticas terem sido capazes de diminuir a mortalidade, sabe-se que muitos sobreviventes de sepse não são capazes de retomar suas atividades usuais. A encefalopatia associada à sepse (EAS) é muitas vezes a primeira disfunção orgânica a se manifestar. A presença da EAS está associada a maior mortalidade e pior prognóstico e muitos pacientes apresentam dano cognitivo a médio e longo prazo que pode ser irreversível. Os mecanismos associados estao em torno do aumento de citocinas pró-inflamatórias, alterações na permeabilidade da barreira hematoencefálica (BHE), ativação microglial com a potencializacao da liberação de citocinas e o estresse oxidativo resultando no dano neuronal. Por conseguinte, tais eventos podem ser potencializados através da participação de moléculas que, quando ativadas perpetuam a resposta inflamatória e a quebra da BHE. Sendo assim é possível postular que a molécula CD40 possa estar envolvida nesse processo inflamatório. O objetivo deste estudo foi investigar a interação entre as moléculas CD40-CD40L sob parâmetros neuroinflamatórios e comportamentais em ratos submetidos a modelo de sepse. Ratos Wistar machos foram submetidos à ligação e perfuração cecal (CLP) para indução de sepse. Os animais foram divididos em sham, CLP, CLP + 1ug/kg, 10ug/kg e 100ug/kg de anticorpo antiCD40 administrado por via intracerebroventricular. Foram acompanhados por 10 dias para curva de sobrevivência e testes comportamentais. Em outro experimento, animais foram mortos em 12, 24 e 48 horas após CLP para avaliar expressão de CD40 e CD40L por Western Blotting e 24 horas após para avaliação de dano oxidativo em lipídios (TBARS), dano às proteínas por carbonilação protéica, concentração de nitrito/nitrato (ON), mieloperoxidase (MPO), quebra da barreira hematoencefálica (BHE) e níveis de citocinas. Dados foram avaliados por teste t e análise de variância de uma via e teste post hoc Tukey. Teste de Kaplan-Meier e log-rank foram utilizados para sobrevivência e teste de Man Whitney para análise comportamental todos com significância p<0,05. Os resultados mostram que o tratamento com anti-CD40 não é capaz de interferir na sobrevivência de animais submetidos a sepse, por outro lado, apresentam melhoras na memória e aprendizado. Os resultados também apresentam aumento nos níveis de CD40 e CD40L em hipocampo, mostram que a dose de 100 ug/kg foi mais efetiva na redução da permeabilidade da BHE, níveis de citocinas e MPO. A dose de 10 e 100 ug/kg foram efetivas na diminuição de TBARS e doses de 1 e 10 e 100 ug/kg foram efetivas apenas na redução de ON. Carbonil não mostrou resultado significativo em nenhuma dose. Conclui-se que o tratamento com anti-CD40 é eficaz na redução de dano cognitivo e parâmetros inflamatórios em sobreviventes de sepse.
Sepsis and multiple organ dysfunction syndrome represent a clinical problem of high relevance, mainly due to its high incidence in critically ill patients and their high mortality rates. Although therapeutic measures have been able to reduce the mortality, it is known that many survivors of sepsis are not able to resume their usual activities. Encephalopathy associated with sepsis (EAS) is often the first organ dysfunction to manifest. The presence of the EAS is associated with higher mortality and worse prognosis, many patients have cognitive impairment in the medium and long term that may be irreversible. Associated mechanisms station around the increase of proinflammatory cytokines, changes in the permeability of the blood brain barrier (BBB), microglial activation with potentiation of the release of cytokines and oxidative stress resulting in neuronal damage. Therefore, such events can be leveraged through the participation of molecules that when activated perpetuate the inflammatory response and breakdown of the BBB. Thus it is possible to postulate that the CD40 molecule may be involved in the inflammatory process. The aim of this study was to investigate the interaction between the CD40 - CD40L molecules in neuroinflammatory and behavioral parameters in rats submitted to sepsis model. Male Wistar rats were subjected to cecal ligation and puncture (CLP) to induce sepsis. The animals were divided into sham, CLP, CLP + 1ug/kg, 10ug/kg and 100ug/kg antibody anti-CD40 administered by intracerebroventricular route. Were followed for 10 days for survival curve and behavioral testing. In another experiment, the animals were killed at 12, 24 and 48 hours after CLP to evaluate expression of CD40 and CD40L by Western blotting, 24 hours for assessment of oxidative damage to lipids (TBARS), damage to proteins by protein carbonylation, concentration of nitrite/nitrate (NO), myeloperoxidase (MPO), breakdown of the blood brain barrier (BBB) and cytokine levels. Data were analyzed by t test and analysis of variance and Tukey post hoc test. Kaplan-Meier and log-rank test were used for survival and Man Whitney test for behavioral analysis with all significant at p< 0.05. The results show that treatment with anti-CD40 antibody is not able to affect the survival of animals with sepsis, on the other hand, show improvements in learning and memory. The results also showed increased levels of CD40 and CD40L in the hippocampus, show that dose of 100 ug/kg was more effective in reducing the permeability of the BBB, levels of cytokines and myeloperoxidase. The dose of 10 and 100 ug/kg were effective in lowering TBARS and doses of 1 and 10 and 100 ug/kg were effective only in the reduction of NO. Carbonyl not showed significant result in any dose. Thus concluding that treatment with anti-CD40 antibody is effective in reducing cognitive impairment and inflammatory parameters in survivors of sepsis.
Liljenfeldt, Lina. « CD40L Gene Therapy for Solid Tumors ». Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-222705.
Texte intégralInwald, David Philip. « The role of platelet CD40L in inflammation ». Thesis, University College London (University of London), 2004. http://discovery.ucl.ac.uk/1446614/.
Texte intégralHenrique, Rocha Agnellini Andrielly. « The role of nitric oxide in cancer immunotherapy ». Doctoral thesis, Università degli studi di Padova, 2016. http://hdl.handle.net/11577/3424452.
Texte intégralL’immunoterapia cellulare adottiva (indicata di seguito con l’acronimo inglese ACT) oggi rappresenta una promettente strategia per il trattamento di pazienti affetti da cancro. Quest’approccio clinico consiste nel trasferimento adottivo di linfociti T CD8+, specifici per gli antigeni tumorali. L’efficacia dell’ACT è limitata da alcuni eventi fondamentali come il richiamo delle cellule trasferite nel sito tumorale e l’ambiente molto immunosoppressivo in cui si sviluppa il cancro. I tumori sono delle lesioni complesse e dinamiche, nelle quali le cellule neoplastiche interagiscono con le cellule del sistema immunitario dell’ospite. Nel tumore, l’immunosoppressione è mediata da alcune popolazioni cellulari come le cellule mieloidi e i macrofagi associati al tumore, noti per sopprimere la proliferazione delle cellule T in diversi modi. Uno di questi è la sovraespressione e l’attività coordinata di due enzimi: l’arginasi (ARG1) e l’ossido nitrico sintasi 2 (NOS2 o iNOS). Nel sito tumorale ARG1 induce la deplezione dell’aminoacido L-arginina, necessaria per l’attivazione e la proliferazione delle cellule T. NOS2 è responsabile della sintesi dell’ossido nitrico e altre specie reattive dell’azoto. Questi radicali liberi sono noti bloccare le funzioni delle cellule T nel tumore. Inoltre, il nostro gruppo recentemente ha descritto un nuovo meccanismo d’immunosoppressione associato al tumore basato sulle modifiche post- traduzionali indotte dalle specie reattive dell’azoto sulle chemochine. L’ossido nitrico ha un duplice ruolo nella biologia del cancro poiché può promuovere come inibire la progressione tumorale. L’ossido nitrico induce la progressione tumorale e le metastasi agendo direttamente sulla proliferazione e migrazione delle cellule tumorali e indirettamente attraverso l’espressione di fattori angiogenici e linfoangiogenici. Tuttavia, una elevata concentrazione di ossido nitrico può causare effetti citotossici che possono condurre alla regressione tumorale e l’inibizione delle metastasi. Questa dicotomia dipende principalmente dalla quantità, dalla localizzazione e dalla cinetica di generazione dell’ossido nitrico e soprattutto dalla sensibilità cellulare all’esposizione di questo radicale. L’obiettivo primario di questo studio è stato di delucidare il ruolo di NOS2 e del suo principale prodotto (ossido nitrico) nel microambiente tumorale, in particolare nell’approccio clinico dell’ immunoterapia cellulare adottiva. Abbiamo svolto esperimenti di trasferimento adottivo sia nel modello animale wild type che nel modello Nos2 knock-out, nei quali si è indotto lo sviluppo di tumori mediante l' inoculo di una linea tumorale esprimente l’antigene ovalbumina (OVA). Allo scopo di chiarire il ruolo dell’ossido nitrico nell’immunoterapia cellulare adottiva, si è rivelato fondamentale la messa a punto di valide metodiche per monitorare il rilascio di questo radicale in tempo reale attraverso la microscopia confocale, che è stata condotta su “fettine” vitali di tumore in seguito all’interazione con le cellule T e l’isolamento tramite delle cellule responsabili dell’induzione di ossido nitrico dopo l’immunoterapia cellulare adottiva. Il nostro lavoro introduce un approccio innovativo per lo studio delle dinamiche dell’NO nel microambiente tumorale. Tale approccio è stato fondamentale per l’identificazione, per la prima volta nei tumori, di una nuova sottopopolazione mieloide, denominata “cellule dendritiche TNF/iNOS producenti” (Tip-DCs), caratterizzate da attività antitumorale che è mediata da NOS2 e conseguente produzione di ossido nitrico. Principalmente il nostro studio porta la consapevolezza che la NOS2 è fondamentale per l’efficacia dell’ACT, aprendo nuove prospettive per il miglioramento dell’immunoterapia del cancro basata sulla modulazione di NOS2 e dell’ossido nitrico nei tumori.
Capobianco, Marcela Petrolini [UNESP]. « Polimorfismos dos Genes CD40, CD40L e BLYS, associados na co-estimulação dos Linfócitos B, em indivíduos naturalmente infectados pelo Plasmodium vivax na Amazônia Brasileira ». Universidade Estadual Paulista (UNESP), 2013. http://hdl.handle.net/11449/92537.
Texte intégralPlasmodium vivax é a espécie mais prevalente de malária no Brasil. O processo co-evolutivo parasita-hospedeiro pode ser visto como uma ferramenta, na qual trocas genéticas adaptativas podem influenciar na diversidade da população. Objetivo: Investigar polimorfismos de genes envolvidos na resposta imune humoral visando identificar possíveis associações com a malária. Material e Métodos: a amostra foi constiuída por 103 pacientes com malária vivax não complicada e como grupo controle 97 indíviduos não-maláricos. A identificação dos SNPs –726T>C no gene CD40L, -1 C>T no gene CD40 e -871C>T no gene BLYS foram efetuadas pelo método de PCR-RFLP. As frequências genotípicas, alélicas e de indivíduos portadores de cada alelo foram estimadas por contagem direta. Também foram comparadas as frequências genotípicas observadas com as esperadas segundo o teorema de Hardy e Weinberg. Resultados: As freqüências genotípicas e alélicas para esses SNPs não diferiram estatisticamente entre pacientes e indivíduos do grupo controle. A combinação dos genótipos entre os genes CD40 e BLYS e entre CD40L e BLYS não revelou interação gênica na população estudada. Não foi observada associação entre resposta imune humoral e parasitemia nos indivíduos maláricos com os polimorfismos dos genes investigados. Ambos os genes se encontram em equilíbrio de Hardy e Weinberg. Conclusões: Os resultados deste estudo sugerem que as variantes genéticas analisadas nos genes CD40, CD40L e BLYS não afetam a funcionalidade das moléculas de modo que possa interferir na susceptibilidade a doença, mas estas variantes podem influenciar o curso clínico em vez de simplesmente aumentar ou diminuir a susceptibilidade
Plasmodium vivax is the most prevalent malaria species in Brazil. The parasite-host coevolutionary process can be viewed as an ‘arms race’, in which adaptive genetic changes in one are eventually matched by alterations in the other. Objectives: following the candidate gene approach we analyzed the CD40, CD40L and BLYS genes that participate in B-cell co-stimulation, for associations with P. vivax malaria. Methods: the study sample included 97 patients and 103 controls. We extracted DNA using the extraction and purification commercial kit and identified the following SNPs: -1C>T in the CD40 gene, –726T>C in the CD40L gene and the -871C>T in the BLyS gene using PCR-RFLP. We analyzed the genotype and allele frequencies by direct counting. We also compared the observed with the expected genotype frequencies using the Hardy-Weinberg Equilibrium. Results: The allele and genotype frequencies for these SNPs did not differ statistically between patient and control groups. Gene-gene interactions were not observed between the CD40 and BLYS and between the CD40L and BLYS genes. Overall, the genes were in Hardy-Weinberg Equilibrium. Significant differences were not observed among the frequencies of antibody responses against P. vivax sporozoite and erythrocytic antigens and the CD40 and BLYS genotypes Conclusions: the results of this study show that, although the investigated CD40, CD40L and BLYS alleles differ functionally, this variation does not alter the functionality of the molecules in a way that would interfere in susceptibility to the disease. Significance: The variants of these genes may influence the clinical course rather than simply increase or decrease susceptibility
Capobianco, Marcela Petrolini. « Polimorfismos dos Genes CD40, CD40L e BLYS, associados na co-estimulação dos Linfócitos B, em indivíduos naturalmente infectados pelo Plasmodium vivax na Amazônia Brasileira / ». São José do Rio Preto, 2013. http://hdl.handle.net/11449/92537.
Texte intégralBanca: Ana Elizabete Silva
Banca: Karin Kirchgatter
Resumo: Plasmodium vivax é a espécie mais prevalente de malária no Brasil. O processo co-evolutivo parasita-hospedeiro pode ser visto como uma "ferramenta", na qual trocas genéticas adaptativas podem influenciar na diversidade da população. Objetivo: Investigar polimorfismos de genes envolvidos na resposta imune humoral visando identificar possíveis associações com a malária. Material e Métodos: a amostra foi constiuída por 103 pacientes com malária vivax não complicada e como grupo controle 97 indíviduos não-maláricos. A identificação dos SNPs -726T>C no gene CD40L, -1 C>T no gene CD40 e -871C>T no gene BLYS foram efetuadas pelo método de PCR-RFLP. As frequências genotípicas, alélicas e de indivíduos portadores de cada alelo foram estimadas por contagem direta. Também foram comparadas as frequências genotípicas observadas com as esperadas segundo o teorema de Hardy e Weinberg. Resultados: As freqüências genotípicas e alélicas para esses SNPs não diferiram estatisticamente entre pacientes e indivíduos do grupo controle. A combinação dos genótipos entre os genes CD40 e BLYS e entre CD40L e BLYS não revelou interação gênica na população estudada. Não foi observada associação entre resposta imune humoral e parasitemia nos indivíduos maláricos com os polimorfismos dos genes investigados. Ambos os genes se encontram em equilíbrio de Hardy e Weinberg. Conclusões: Os resultados deste estudo sugerem que as variantes genéticas analisadas nos genes CD40, CD40L e BLYS não afetam a funcionalidade das moléculas de modo que possa interferir na susceptibilidade a doença, mas estas variantes podem influenciar o curso clínico em vez de simplesmente aumentar ou diminuir a susceptibilidade
Abstract: Plasmodium vivax is the most prevalent malaria species in Brazil. The parasite-host coevolutionary process can be viewed as an 'arms race', in which adaptive genetic changes in one are eventually matched by alterations in the other. Objectives: following the candidate gene approach we analyzed the CD40, CD40L and BLYS genes that participate in B-cell co-stimulation, for associations with P. vivax malaria. Methods: the study sample included 97 patients and 103 controls. We extracted DNA using the extraction and purification commercial kit and identified the following SNPs: -1C>T in the CD40 gene, -726T>C in the CD40L gene and the -871C>T in the BLyS gene using PCR-RFLP. We analyzed the genotype and allele frequencies by direct counting. We also compared the observed with the expected genotype frequencies using the Hardy-Weinberg Equilibrium. Results: The allele and genotype frequencies for these SNPs did not differ statistically between patient and control groups. Gene-gene interactions were not observed between the CD40 and BLYS and between the CD40L and BLYS genes. Overall, the genes were in Hardy-Weinberg Equilibrium. Significant differences were not observed among the frequencies of antibody responses against P. vivax sporozoite and erythrocytic antigens and the CD40 and BLYS genotypes Conclusions: the results of this study show that, although the investigated CD40, CD40L and BLYS alleles differ functionally, this variation does not alter the functionality of the molecules in a way that would interfere in susceptibility to the disease. Significance: The variants of these genes may influence the clinical course rather than simply increase or decrease susceptibility
Mestre
Rousseau, Raphaël. « Application du transfert de gène à l'immunothérapie antitumorale : du développement préclinique aux essais cliniques de phase I dans les leucémies et les neuroblastomes de haut risque ». Paris 7, 2002. http://www.theses.fr/2002PA077168.
Texte intégralMarques, Otávio Cabral. « Alterações genético-moleculares em pacientes deficientes de CD40L ». Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-19112008-162056/.
Texte intégralCD40-Ligand (CD40L) deficiency or X linked Hyper-IgM syndrome (X-HIGM) is considered a T and B cell combined primary immunodeficiency. CD40L is expressed on the cell surface of activated T lymphocytes and interacts with CD40, expressed on the surface of B lymphocytes, macrophages, dendritic cells, endothelial cells, and neutrophils. The CD40L-CD40 interaction induces activation, differentiation, and cell proliferation. Our aim was to analyze the molecular-genetic alterations of CD40L molecule affecting individuals of 5 brazilian families, leading to X-HIGM. We genotyped 25 individuals, whom 6 were X-HIGM patients, 13 were heterozygote related patients, and 6 were healthy homozygotes. Within the patients with X-HIGM, two of them were of caucasoid origin and four were mestiços. The patients age ranged from 2 to 20 years and their recurrent infections started in average during their first 4 months of life. The main recurrent infections were pneumonia and otitis. The patient TB presented blastomycosis, a unique observation in this immunodeficiency. The molecular-genetic analysis revealed heterogeneity. TB patient presented a splicing defect causing a deletion of exon 3 (r.345_402del) of CD40L gene (CD40LG). Patient FS presented a new missense mutation g.11856 G>C (c.476 G>C, pW140C). Patient KC presented a nonsense substitution g.11855 G>A (c.475G>A, p. W140X). Patients CH, VIC, and FE presented a deletion g. 3074_3077delTAGA, causing an alteration on RNA processing. The leukocytes fenotyping demonstrated that T helper lymphocytes (CD3+CD4+), T cytotoxic lymphocytes (CD3+CD8+), B lymphocytes (CD19+CD40+), and T activated (CD3+CD69+) cell counts of patients were similar to healthy controls. However it was observed a significant reduction of CD40L expression on cell surface patients CD3+ and CD4+ lymphocytes. The T lymphocyte confocal microscopy analysis revealed that homozygotes with residual expression of CD40L in their surface also presented a reduction on the density of CD3 molecule expression, suggesting the need of molecular integrity of CD40L for normal CD3 expression. We conclude that mutations on CD40L leading to X-HIGM syndrome are heterogeneous and the molecular-genetic analysis allowed a precise diagnosis making possible the genetic counseling and newborn screening of the involved families.
Grosdidier, Charlotte. « Anti-plaquettaires et risque hémorragique : rôle du CD40L ». Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5063/document.
Texte intégralAspirin and thienopyridine are the therapy for patients with percutaneous coronary intervention after ACS. The level of platelet inhibition by thienopyridine varies between patients, this variability, multifactorial, is associated with adverse clinical outcomes. Treatment efficacy was evaluated mainly on the association between poor thienopyridine response and thrombotic events but less on the principal side effect: bleeding complications. Platelet play a key role in atherosclerosis and thrombosis, notably via CD40L.I studied platelet factors that influence the bleeding risk in these patients and brought a new highlight on platelet function less known such as inflammation.P450 cytochrome genetic variants (2C19*2 and 2C19*17) influence platelet response to thienopyridines. There is a relation between platelet reactivity and bleeding events. A very low on-treatment platelet reactivity (VASP<10 %) is a predictor of bleeding and is mainly observed with prasugrel treatment. We then focussed on a marker of platelet inflammatory status, CD40L. Its release by platelets depends on P2Y12 signalling, whereas its surface expression is less dependent on this signalling pathway. A low platelet-CD40L surface expression is associated with bleeding events in these patients We show that genetic background on thienopyridine treatment efficacy is related to bleeding risk and that other platelet parameters influence the bleeding risk independently of platelet aggregation inhibition. Thus, a molecule of inflammation, CD40L, would be a link between inflammation and bleeding/thrombosis equilibrium
Angin, Mathieu. « Induction de tolérance en transplantation par blocage de la voie CD40/CD40L : caractérisation des cellules tolérogènes induites chez le rat et évaluation chez le primate ». Nantes, 2008. https://archive.bu.univ-nantes.fr/pollux/show/show?id=e840c663-196c-4edc-9608-019f57b0bd82.
Texte intégralInhibition of the CD40/CD40L costimulation pathway using an adenovirus coding for CD40Ig can generate CD8+CD45RClo T regulatory cells that induce indefinite graft tolerance in a rat cardiac allograft model. A gene expression study of tolerogenic cells by DNA microarray allowed us to explore the mechanisms involved. As expected, IFNg seems to be a key player and might induce the expression of the immuno-regulatory protein Fgl2. MHC-II molecules seem to be important too. Other molecules observed in other Treg microarray analyses are also over-expressed. Other hypothesis are also discussed. This tolerance induction strategy was evaluated in primates using recombinant AAV coding for the human CD40Ig molecule and/or sc28AT, an inhibitor of the CD28/B7 costimulation pathway. These molecules were functional in vitro. The AAV injection led to a prolonged expression of CD40Ig whereas sc28AT molecule was produced transiently, as it seemed to be immunogenic. Unlike CD40Ig, sc28AT appeared to be efficient in vivo. The animal receiving both transgenes had delayed graft rejection, and other experiments are now scheduled. The expression of therapeutic molecules through viral vectors to evaluate the tolerance induction efficiency in primates is feasible. However the efficiency of the CD40Ig and sc28AT molecules in our model is still debatable and raises the issue of the relevance of rodent models compared to primate pre-clinical strategies
Becker, Hans Jiro [Verfasser]. « Einfluss der Hypoxie auf den Immunphänotyp sowie auf die mRNA- und miRNA-Expressionsprofile CD40-aktivierter B-Zellen (CD40Bs) / Hans Jiro Becker ». Köln : Deutsche Zentralbibliothek für Medizin, 2016. http://d-nb.info/1104192764/34.
Texte intégralRehklau, Jutta. « Untersuchung der Einflüsse auf die Regulation des Zelloberflächenmoleküles CD40L ». Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-10558.
Texte intégralWolf, Dennis [Verfasser], et Andreas [Akademischer Betreuer] Zirlik. « Deskriptive und funktionelle Charakterisierung der CD40L/Mac-1 Interaktion ». Freiburg : Universität, 2012. http://d-nb.info/112347009X/34.
Texte intégralMühle, Kerstin. « Interaction of CD8+CD40L+ T cells with B cells ». Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19127.
Texte intégralCTLs are important for the elimination of infected and degenerated cells by inducing apoptosis of the target cells. Recently our group identified a sub-population of CD8+ T cells expressing CD40L instead of common CTL markers. To that date, transient CD40L expression on T cells has been only described as a function of activated CD4+ T cells, which displays this key molecule for CD4+ T cell mediated help by binding to the CD40 receptor on other immune cells. Particularly, CD40L signaling provided by CD4+ T cells is indispensable for T cell dependent B cell activation and GC responses, which generate B cells secreting high affinity antibodies that protect the host from invading pathogens. Due to its associated helper functions, this thesis aimed to dissect whether CD40L positive CD8+ T cells are restricted to cytotoxic killing or if this sub-population possesses similar properties as CD4+ T cells when interacting with B cells. In vitro co-culture experiments showed that 50% of murine antigen specific CD8+ T cells up-regulated CD40L upon activation by antigen presenting B cells. When compared to CD40L deficient CD8+ T cells, the interaction of CD8+ CD40L+ T cells induced remarkable changes in B cells on the RNA and protein level and triggered a B cell phenotype resembling that of B cells primed by CD4+ T cells. By the infection of mice with the B cell trophic virus MHV-68, it was found that E8IcrexCD40Lflox transgenic mice lacking CD40L only on matured CD8+ T cells, exhibited a significant decrease of GC B cells in superficial cervical lymph nodes at the acute state of infection compared to WT mice. A closer look into the memory B cell repertoire revealed a preferred usage of the murine IGHJ3 gene family that modifies the CDR3 and thus the recognition groove of the B cell antibody in E8IcrexCD40Lflox mice. In summary, this work provides sufficient evidence that CD8+ CD40L+ T cells adopt helper-like functions by supporting B cell activation and subsequent GC formation.
Loyal, Lucie. « The molecular regulation of CD40L in CD8+ T cells ». Doctoral thesis, Humboldt-Universität zu Berlin, 2019. http://dx.doi.org/10.18452/20158.
Texte intégralThe T cell compartment consists of two major subsets with diverse assignments. CD4+ T cells express CD40L upon activation, a central co-stimulatory receptor to induce B cell mediated humoral immunity, activate APCs and prime efficient effector CD8+ T cell development (“helper function”). In contrast, cytotoxic CD8+ T cells are predetermined to kill infected or malignant cells directly. However, a fraction of CD8+ T cells expressing CD40L upon activation was identified. So far, it is not understood in CD8+ T cells a) how CD40L expression is regulated, b) when and how the ability of CD40L expression is implemented and c) what are the implications for the immune system. In this thesis, we found that CD40L expression is regulated by DNA-methylation of regulatory regions of the CD40LG locus in CD4+ as well as CD8+ T cells. The de-methylation of central elements is implemented in the thymus and increases with T cell maturation reflected by enhanced stability of CD40L expression. Elevated CD5 and NUR77 expression of CD40L+ CD8+ SP thymocytes suggests that high affine detection of self-peptides during positive selection in the thymus implements CD40L expression ability and predetermines the fate of the CD40L imprinted CD8+ T cells. CD40L+ naïve CD8+ T cells differ in their TCR repertoire from their CD40L- counterparts and preferentially mature into memory cell subsets with cytokine and chemokine receptor profiles of Tc2, Tc17 and Tc22 cells. With their non-cytotoxic phenotype and gene expression signatures, the CD40L+ memory CD8+ T cell subsets Tc2, Tc17 and Tc22 widely resemble helper CD4+ T cells and can be distinguished from classical cytotoxic Tc1 and Tc17+1 cells by their IL-6R and absent SLAMF7 expression and their skin migratory phenotype. Altogether, we demonstrate that from the earliest developmental stages in thymus onwards naive CD8+ T cells are not homogenous and the abilites to provide “CD40L based help” or “cytotoxicity mediated killing” are independent of the CD4+ or CD8+ T cell status. Cells with helper-type CD8+ T cell cytokine and gene-expression signatures were found at barrier sites (skin, lung) by us and others where they contribute to multiple autoinflammatory diseases. Therefore, this work insinuates the need to revisite CD8+ T cell capablities and function in immune responses.
Tariket, Sofiane. « Investigation de la pathogenèse du syndrome de détresse respiratoire aiguë post-transfusionnel (TRALI) dans un modèle murin ». Thesis, Lyon, 2017. http://www.theses.fr/2017LYSES059/document.
Texte intégralBlood transfusion saves lives and reduces morbidity for many diseases and clinical conditions, but it is not without complications. A transfusion-related adverse event, also known as the Adverse Reaction (AR), is an incident occurring in a patient during or after a blood transfusion. Among them, TRALI is considered as one of the most critical inflammatory reactions. This pathology usually occurs within 6 hours after transfusion. Two types are recognized: immune TRALI and non-immune TRALI. In France, the first is almost completely prevented by a blood product safety policy, while the frequency of the second increases. The pathophysiology of TRALI remains poorly understood. While some scientists give an important function of patient blood platelets, others consider them dispensable. The aim of this thesis was, first, to investigate the inflammatory potential of blood platelets stored in platelet concentrates and its impact on the general vascular endothelium. Next, the role of patient blood platelets, including their secretory products, in the pathogenesis of this transfusion complication will be evaluated. For it, an ALI (mimicking a TRALI) was triggered, in an in vivo model, by an injection of anti-MHC I antibody in mice previously stimulated with LPS. Our results confirm the inflammatory potential of blood platelets in platelet concentrates, which can probably assume the entire responsibility for triggering a non-immune TRALI, and a secondary role for patient blood platelets in the amplification of the severity of this pathology. This thesis is the continuity of studies conducted in the laboratory GIMAP-EA3064, investigating the function of blood platelets in inflammation, thus opening up new perspectives in transfusion safety
Bukosza, Eva Nora [Verfasser], et Andreas [Akademischer Betreuer] Zirlik. « Contribution of CD40L/Mac-1 pathway to the metabolic syndrome ». Freiburg : Universität, 2018. http://d-nb.info/1156532655/34.
Texte intégralWieckowski, Sébastien. « Synthetic CD40L mimetics : Biological effects and potential applications in immunotherapy ». Université Louis Pasteur (Strasbourg) (1971-2008), 2007. https://publication-theses.unistra.fr/public/theses_doctorat/2007/WIECKOWSKI_Sebastien_2007.pdf.
Texte intégralThe CD40–CD40L interaction plays a central role in development of both humoral and cellular immune responses. CD40 belongs to the tumor necrosis factor receptor (TNF-R) family, and is constitutively expressed on B lymphocytes, dendritic cells and monocytes/macrophages. CD40L belongs to the TNF family, and is mainly expressed transiently on activated T lymphocytes. Proteins from the TNF-R/TNF superfamily assemble in a C3 symmetry, forming hexavalent complexes that are important for transduction of intracellular cell signaling. Many groups have used antibodies directed against CD40 and CD40L as therapeutics, to either inhibit or activate the immune system. Research on synthetic multivalent molecules that could act as ligands in complex biological systems is an innovating field in medicinal chemistry. On the basis of crystallographic data and directed mutagenesis experiments, we have developed synthetic molecules (mini-CD40Ls) built on synthetic C3 platforms linked to the residues essential for interaction with CD40 via spacer arms. The results obtained with mini-CD40Ls in various molecular and cellular systems suggested for the first time that small synthetic molecules could act as functional CD40L mimetics. A complete structure–activity study was performed on mini-CD40Ls to get detailed informations on their mechanisms of action and to optimize them. In particular, we found an interesting mini-CD40L mutant that has lost its cooperative effect in the interaction with CD40. Our data suggested that CD40 binding properties are important for effector functions. We then used mini-CD40Ls as valuable tool to dissect complex signaling pathways activated by CD40 in different cell systems. Finally, we demonstrated that mini-CD40Ls induce an efficient T immune response during experimental infection with Trypanosoma cruzi in mice
Wieckowski, Sébastien Fournel Sylvie Guichard Gilles. « Synthetic CD40L mimetics Biological effects and potential applications in immunotherapy / ». Strasbourg : Université Louis Pasteur, 2008. http://eprints-scd-ulp.u-strasbg.fr:8080/903/01/WIECKOWSKI_Sébastien_2007.pdf.
Texte intégralThèse soutenue sur un ensemble de travaux. Titre provenant de l'écran-titre. Notes bibliogr.
Duran, Amparo. « Investigation of a Trimeric Hemagglutinin Stem Domain from Influenza B for a Universal Vaccine ». Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/38200.
Texte intégralField, Ann Elizabeth. « The development and characterization of transgenic Leishmania major expressing murine CD40L ». College Park, Md. : University of Maryland, 2007. http://hdl.handle.net/1903/7006.
Texte intégralThesis research directed by: Cell Biology & Molecular Genetics. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
Abduh, Maisa. « Follicular CD4 T Cells Tutor CD8 Early Memory Precursors : an Initiatory Journey to the Frontier of B Cell Territory ». Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS371.
Texte intégralAntigen-specific CD8 T cells are involved in the adaptive immune response and play a critical role in protecting the host from infection by intracellular pathogens. This long-lasting protection depends on the generation of memory CD8+ T cell responses, which are highly functional in terms of frequency and functionality, after secondary infection.Following antigen activation, a naive CD8 T cell undergoes strong clonal expansion, generating a heterogeneous population of activated cells that is dominated, at the peak of expansion, by short-lived CD8 effectors (SLECs). This expansion is followed by a phase of drastic contraction through massive apoptosis. A few cells survive this contraction phase and eventually become highly competent memory cells. Precisely when and how these memory precursors (MPECs) are generated is largely unknown, and so are the subsequent steps of their maturation into fully functional memory cells. Help signals from CD4+ T cells are clearly required throughout the MPEC maturation process.Our team has previously shown that FoxP3+ regulatory CD4+ T cells (Tregs) favor MPECs maturation by limiting exposure to IL-2 and by providing inhibitory signals, but this is probably only one facet of the complex and multifaceted help provided by CD4+ T cells to MPEC, and Tregs act on pre-existing MPECs.B-cell memory and CD8+ T cell memory share some common features, such as the expression of the transcription factor Bcl-6. Tfh are major producers of the cytokine IL-21. The mechanisms by which Tfh induces Bcl-6 in B-cells need to be clarified, they might include IL-21 and CD40-CD40L.In this PhD project, we have investigated the potential role of Tfh on the initiation of CD8 memory differentiation, in transgenic mice models, allowing transient and selective depletion of Tfh cells, infected by recombinant Listeria monocytogenes-OVA.We have shown that as early as 2 days after infection, very early memory precursors can be identified by their expression of the chemokine receptor CXCR5. These early precursors, which have an effector phenotype, expand and temporarily migrate to the junction of T-cell and B-cell zones, where they interact with follicular CD4 T cells (Tfh) then lose their CXCR5 expression.Remarkably, this interaction with Tfh, hitherto considered as exclusive B-cell helpers, is required for memory precursors to become competent memory cells responsive to IL-21 and capable of mounting efficient cytotoxic secondary effector responses.This study thus unveils critical early steps in the generation of CD8 memory, identifies CXCR5 as the earliest known marker of CD8 memory precursors, reveals a major helper role for Tfh, and points to possible coordination, through Tfh, between the pathways of CD8 and B-cell memory generation. These findings may have implications for vaccine and immunotherapy design
Pietravalle, Fabienne. « Identification, caractérisation, et étude de l'activité biologique des formes solubles du CD40L ». Toulouse 3, 1996. http://www.theses.fr/1996TOU30321.
Texte intégralWagner, Nikki J. Vilen Barbara J. « In vivo regulation of autoreactive B cells by IL-6, CD40L and TNF[alpha] ». Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,2132.
Texte intégralTitle from electronic title page (viewed Feb. 17, 2009). "... in partial fulfillment of the requirements for the degree of Masters in Science in the Department of Microbiology and Immunology." Discipline: Microbiology and Immunology; Department/School: Medicine. On title page, [alpha] appears as Greek character.
Schubert, Lisa Ann. « Characterization of the transcriptional regulation of the human CD40L gene in CD4 T cells / ». Thesis, Connect to this title online ; UW restricted, 1998. http://hdl.handle.net/1773/8325.
Texte intégralLee, Sheritha P. Parise Leslie V. « Chronic inflammation in sickle cell disease potential role of platelets and the inflammatory mediator CD40L / ». Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2006. http://dc.lib.unc.edu/u?/etd,497.
Texte intégralTitle from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillments of the requirements for the degree of Doctor of Philosophy in the Department of Pharmacology." Discipline: Pharmacology; Department/School: Medicine.
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.
Texte intégralHASEGAWA, YOSHINORI, KAZUYOSHI IMAIZUMI, NAOZUMI HASHIMOTO, MIYOKO MATSUSHIMA et TSUTOMU KAWABE. « CD40/CD40 LIGAND INTERACTIONS IN IMMUNE RESPONSES AND PULMONARY IMMUNITY ». Nagoya University School of Medicine, 2011. http://hdl.handle.net/2237/15350.
Texte intégralDias, Junior Pedro Paulo 1986. « Avaliação das proteínas inflamatórias CD40L e light nas propriedades adesivas dos neutrófilos e outros tipos celulares ». [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311497.
Texte intégralDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-21T11:46:04Z (GMT). No. of bitstreams: 1 DiasJunior_PedroPaulo_M.pdf: 932681 bytes, checksum: a8ceae0940e26759a4abe344de43b8f4 (MD5) Previous issue date: 2012
Resumo: A resposta vascular inflamatória envolve a interação complexa entre células. A adesão dos neutrófilos aos sítios inflamatórios é constituído de várias etapas que envolvem a interação das moléculas de adesão com os neutrófilos, intermediado pela L-selectina (CD62L) e pelas integrinas ?2, LFA-1 e Mac-1 (CD11a/CD18 e CD11b/CD18) com ligantes sobre o endotélio. Os eritrócitos podem aderir ao endotélio vascular usando as moléculas de adesão CD 36 e integrina VLA-4 entre outras moléculas de adesão. O mecanismo de adesão das plaquetas envolve o sequestro celular no local da lesão tecidual através da interação de quatro receptores sinérgicos: a glicoproteína GPIb/IX (CD42b/CD42a), a integrina ?2?1 (GPIa/IIa; CD49b/CD41a), a integrina ?IIb?3 (GPIIb/IIIa; CD41a/CD61), e a integrina ?5?1 (GPIc/IIIa; CD51/CD61). Em doenças associadas com a inflamação vascular, tais como a doença falciforme e aterosclerose, alterações na adesão de leucócitos à parede vascular desempenham um papel central na fisiopatologia da doença. O CD40L e o LIGHT são proteínas citocinas pertencente ao fator de necrose tumoral (TNF), tendo como receptores o CD40L, LTBR e o HVEM, respectivamente. Diante disso, este estudo objetivou avaliar os efeitos das proteínas inflamatórias CD40L e LIGHT nas propriedades adesivas dos neutrófilos, hemácias e plaquetas. Os neutrófilos, hemácias e plaquetas foram separados do sangue periférico e foram realizados ensaios de adesão estática e citometria de fluxo após estimulo destas células com as proteínas recombinantes, CD40L e LIGHT. Após incubação com CD40L ou LIGHT, os neutrófilos e hemácias da circulação periférica apresentaram alterações quanto às propriedades adesivas em relação aos neutrófilos e hemácias não estimulados. As plaquetas estimuladas com as citocinas não demonstraram alteração nas propriedades adesivas. Neutrófilos incubados com anticorpos bloqueadores das integrinas Mac-1 e LFA-1 apresentaram uma reversão no aumento das propriedades adesivas após estimulo com CD40L ou LIGHT. Os neutrófilos estimulados com as citocinas apresentaram uma diminuição na expressão proteíca de CD62L, característica de ativação celular. Nao foi observado nenhuma diferença quanto a expressão das integrinas Mac-1 e LFA-1 nos neutrófilos após estímulo com as citocinas. Esses resultados sugerem que essas proteínas inflamatórias podem aumentar as propriedades adesivas de neutrofilos (intermediado por um aumento na afinidade das integrinas) e hemácias. A presença de altas concentrações destas citocinas na circulação, como encontrados em algumas patologias caracterizadas por inflamação vascular, pode resultar em conseqüências importantes, como a indução da adesão dos leucócitos e hemácias à parede vascular
Abstract: The vascular inflammatory response involves a complex interaction between cells. The adhesion of neutrophils to inflammatory sites is composed of several stages involving the interaction of adhesion molecules on neutrophils and on the endothelium. These interactions are mediated by Lselectin (CD62L) and the ?2 integrins, LFA-1 and Mac-1 (CD11a/CD18 and CD11b / CD18, respectively) with ligands on the endothelium. The red cells may adhere to vascular endothelial adhesion molecules using CD 36 and the VLA-4 integrin and other adhesion molecules. The mechanism of adhesion of platelets involves the adhesion of these cells at the site of tissue injury through the interaction of four synergistic receptors: glycoprotein GPIb/IX (CD42b/CD42a), integrin ?2?1 (GPIa/IIa; CD49b/CD41a), integrin ?IIb?3 (GPIIb / IIIa, CD41a/CD61), and integrin ?5?1 (GPIC/ IIIa; CD51/CD61). In diseases associated with vascular inflammation, such as sickle cell disease and atherosclerosis, changes in leukocyte adhesion to the vascular wall plays a central role in the pathophysiology of the disease. The CD40L and LIGHT cytokines are proteins belonging to the tumor necrosis factor (TNF) family, and interact with the receptors, CD40L, LTBR and HVEM, respectively. Thus, this study aimed to evaluate the effects of the inflammatory proteins, CD40L and LIGHT, on the adhesive properties of neutrophils, erythrocytes and platelets. Neutrophils, erythrocytes and platelets were separated from peripheral blood and static adhesion assays and flow cytometry were performed after stimulation of these cells with the recombinant proteins, CD40L and LIGHT. After incubation with CD40L or LIGHT, neutrophils and red blood cells from the peripheral circulation showed alterations in adhesive properties compared to unstimulated neutrophils and erythrocytes. Platelets stimulated with cytokines showed no changes in adhesive properties. Neutrophils incubated with antibodies that block the functions of integrins Mac-1 and LFA-1 reversed the increase in adhesive properties after stimulation with CD40L or LIGHT. Neutrophils stimulated with cytokines showed a decrease in the protein expression of CD62L, a characteristic of cellular activation. No difference was observed in the expression of the integrins Mac-1 and LFA-1 on neutrophils after stimulation with cytokines. These results suggest that these inflammatory proteins can increase the adhesive properties of neutrophils (mediated by an increase in the affinity of the integrin) and erythrocytes. The presence of high concentrations of these cytokines in the circulation, as found in certain vascular diseases characterized by inflammation, can result in important consequences, such as the induction of the adhesion of leukocytes and red blood cells to the vascular wall
Mestrado
Ciencias Biomedicas
Mestre em Ciências Médicas
Oliveira, Fabrícia Alvisi de. « Participação do CD40L solúvel e da metaloproteinase de matriz -9 na resposta imune na leishmaniose visceral humana ». Universidade Federal de Sergipe, 2016. https://ri.ufs.br/handle/riufs/3621.
Texte intégralIn the present study, the sera levels of soluble CD40 ligand (sCD40L) and matrix metalloproteinase-9 (MMP-9) were quantified by Luminex assay in Visceral leishmaniasis patients before and during treatment follow-up and after regular antimony treatment and also in individuals exposed to infection, living in endemic areas. Different from the other molecules present in sera from classic VL patients, sCD40L and MMP-9 are fairly increased, and increase over time during the follow-up of VL patients undergoing antimony treatment. sCD40L and MMP-9 sera levels were also high in individuals living in endemic settings at high risk of infection (endemic controls). On the other hand, sCD40L and MMP-9 were not observed in sera from non-endemic controls, which are not exposed of infection. Additionally, negative correlations were found between spleen sizes and MMP-9 before treatment and sCD40L at day 15 of treatment. Negative correlations were also found between parasite load with both sCD40L and MMP-9. These findings indicate that both molecules can be used in monitoring therapeutic efficacy in VL. Furthermore, these data suggest a protective effect of these molecules, since the individuals exposed to infection without the symptoms of disease have high sera levels of sCD40L and MMP-9. These data were published in BMC Infectious diseases journal [1]. To confirm the protective effect of sCD40L present in sera of VL patients and determine if this molecule had biological activity, the ability of sera from patients containing high levels of this molecule sCD40L to control infection in vitro in Leishmania infantum infected macrophages, and the ability to induce cytokines production. Thereby, macrophages from of healthy donor were infected with Leishmnia infantum, and later incubated in presence of sera from individuals exposed to infection in presence of anti-CD40L. The infection was evaluated by counting of the number of infected macrophages/100 and the number of intracellular amastigotes/100 macrophages. The data showed that serum sCD40L decrease the number of infected macrophages and the number of intracellular amastigotes. The blockage of sCD40L activity with specific antibody, increase the infection. Moreover, the analysis of cytokines in supernatant of these macrophage cultures by Luminex assay demonstrated that sCD40L induces the IL-12, IL-23, IL-27, IL-15 e IL-1 production. The levels of these cytokines is inversely correlated with infection rate and the number of intracellular parasites from infected macrophages. A second manuscript with these data were published in PLOS One [2] . These results demonstrated that serum sCD40L from individuals exposed to VL improve the microbicide effect and the inflammatory cytokine production, suggesting its potential use in VL immunotherapy. Nevertheless, there is still a long way to be approached in future experimental and clinical studies.
No presente estudo, os níveis séricos dos marcadores inflamatórios CD40 ligante solúvel (sCD40L) e da metaloproteinase de matrix-9 (MMP-9) foram quantificados por Luminex nos pacientes com leishmaniose visceral antes, durante e após o tratamento com antimonial, e em indivíduos controles expostos à infecção, residindo em áreas endêmicas. Ao contrário das outras moléculas inflamatórias presentes nos soros de pacientes com LV, as moléculas sCD40L e MMP-9 apresentaram elevação moderada, havendo um aumento significativo de ambas no decorrer do tratamento com antimonial. Níveis séricos elevados de sCD40L e MMP-9 também foram encontrados nos indivíduos controles sem doença, provenientes de áreas endêmicas e expostos a infecção. Entretanto, o sCD40L e a MMP-9 não foram detectados nos soros de indivíduos de áreas não endêmicas, os quais não estão expostos a infecção. Adicionalmente, correlações negativas entre o tamanho do baço com a MMP-9 antes do tratamento e com o sCD40L 15 dias após o início do tratamento foram observadas, bem como correlações negativas entre ambas as moléculas com a carga parasitaria dos pacientes. Estes resultados indicam que estas moléculas podem ser utilizadas no monitoramento da eficácia terapêutica na leishmaniose visceral. Além disso, estes dados nos sugerem um efeito protetor dessas moléculas contra a doença, desde que os indivíduos expostos e sem a doença apresentaram concentrações elevadas dessas moléculas. Estes dados foram publicados no BMC Infectious diseases [1]. Para confirmar o efeito protetor do sCD40L e investigar se a molécula presente nos soros dos pacientes com LV tinha atividade biológica, foi avaliado se o sCD40L presente no soro dos indivíduos infectados teria ação na resposta leishmanicida e na produção de citocinas por macrófagos infectados por Leishmania infantum. Dessa forma, macrófagos de doadores normais foram infectados com L. infantum e posteriormente incubados com soro de indivíduos expostos a infecção na presença de anti-CD40L. A avaliação da infecção através da contagem de células infectadas e do número de parasitas intracelulares demonstrou que a presença do sCD40L sérico diminui o número de macrófagos infectados e o número de amastigotas intracelulares. O bloqueio da atividade do sCD40L com anticorpo específico reverteu este efeito, aumentando a infecção. Além disso, a análise de citocinas no sobrenadante das culturas de macrófagos por Luminex mostrou que a adição de sCD40L induziu a produção de IL-12, IL- 23, IL-27, IL-15 e IL-1. As concentrações destas citocinas correlacionaram-se inversamente com as taxas de infecção e com o número de parasitas intracelulares nos macrófagos infectados. Um segundo artigo com estes resultados foi publicado na PLOS One [2]. Estes resultados demonstram que o sCD40L sérico dos indivíduos expostos à LV melhora a capacidade microbicida e a produção de citocinas inflamatórias, sugerindo seu potencial uso na imunoterapia na LV humana, embora este seja um longo caminho a ser abordado em estudos futuros experimentais e clínicos.
Garrido, Vanessa Tonin 1985. « Avaliação do papel das citocinas inflamatórias, LIGHT e CD40L, na inflamação mediada por plaquetas na anemia falciforme ». [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312445.
Texte intégralTexto em português e inglês
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-24T19:18:22Z (GMT). No. of bitstreams: 1 Garrido_VanessaTonin_D.pdf: 6610754 bytes, checksum: 9b799d90821835bae6ac5d806b1d2f1c (MD5) Previous issue date: 2014
Resumo: A anemia falciforme (AF) é uma hemoglobinopatia hereditária resultante de uma mutação no gene que codifica a subunidade ?-globina, levando à produção da hemoglobina S (HbS) nos eritrócitos. Com a polimerização da HbS, durante a desoxigenação, ocorre a deformação e fragilização das células vermelhas, resultando em anemia hemolítica e eventos vaso-oclusivos. As crises vaso-oclusivas são a principal causa de morbidade nos pacientes com anemia falciforme e as plaquetas parecem ter um papel importante nesse processo, pois uma vez ativadas elas secretam e expressam mediadores que induzem uma resposta inflamatória tanto em leucócitos como em células endoteliais. A proposta deste trabalho foi investigar a produção e expressão dos mediadores inflamatórios derivados de plaquetas, LIGHT e CD40L, em controles (indivíduos saudáveis; CON), pacientes com anemia falciforme (AF) e pacientes com anemia falciforme em terapia com hidroxiureia (AFHU). Também avaliamos o envolvimento das plaquetas e seus mediadores na ativação de leucócitos e células endoteliais. Os níveis plasmáticos de ambas citocinas foram significativamente maiores em indivíduos AF e AFHU do que nos indivíduos controle e, curiosamente, apesar da hidroxiureia ser capaz de diminuir a concentração plasmática de algumas citocinas inflamatórias, a terapia com essa droga não foi associada com qualquer alteração nos níveis de LIGHT ou CD40L. Foi observada uma correlação expressiva da concentração de LIGHT com níveis plasmáticos de CD40L, IL-8, ICAM-1, Trombospondina-1 e TNF-?, enquanto que a concentração plasmática de CD40L correlacionou-se com os níveis de TNF-? e principalmente com Trombospondina-1, indicando que tanto LIGHT como CD40L podem estar participando ou então refletindo a inflamação crônica presente na anemia falciforme. A expressão proteica de LIGHT foi significativamente maior na superfície de plaquetas de indivíduos AF e AFHU em comparação com plaquetas CON e apresentou uma correlação com marcadores de ativação plaquetária. A secreção de LIGHT pelas plaquetas foi determinada por ELISA e concentrações significativas dessa citocina puderam ser detectadas no sobrenadante de plaquetas CON e AF, sugerindo que essas células podem ser uma fonte importante de LIGHT na circulação. Apesar da expressão de CD40L não ter sido detectada na superfície das plaquetas de pacientes e controles, as plaquetas de pacientes AF secretaram uma quantidade maior de CD40L em comparação aos controles e foi observada uma correlação significativa entre a liberação de LIGHT e CD40L em plaquetas de pacientes AF, indicando que pode existir uma associação na secreção dessas duas citocinas. A expressão dos receptores de LIGHT (HVEM e LT?R) e de CD40L (CD40) foi avaliada por citometria de fluxo em plaquetas, neutrófilos, linfócitos e monócitos. Foi observado que o receptor HVEM estava mais expresso em plaquetas e linfócitos de pacientes com anemia falciforme, enquanto que a expressão do receptor CD40 estava elevada nas plaquetas, nos neutrófilos, nos linfócitos e nos monócitos de pacientes, comparando com o grupo controle. Esses dados mostram que a via de sinalização de LIGHT e CD40L pode estar alterada na anemia falciforme, contribuindo com a ativação dos leucócitos. Quando avaliamos a participação das plaquetas na ativação dos leucócitos, observamos que as plaquetas de indivíduos com anemia falciforme foram eficientes em aumentar a expressão do marcador de ativação, CD69, nos linfócitos e também em induzir o fenótipo pró-inflamatório nos monócitos. Enquanto que a co-cultura de HUVECs com plaquetas demonstrou que as plaquetas de pacientes com anemia falciforme possuem uma capacidade maior de induzir a expressão de ICAM-1 em células endoteliais do que as plaquetas de indivíduos controle. Na presença de anticorpos anti-CD40L observamos uma redução drástica no aumento da expressão de ICAM-1 pelas plaquetas e apesar dessa expressão também ter sido reduzida na presença de anticorpos anti-LIGHT, esses resultados não foram estatísticamente significativos. Interessantemente, altas concentrações plasmáticas de LIGHT estavam associadas com a elevada velocidade de regurgitação tricúspide, um indicativo de hipertensão pulmonar na anemia falciforme e uma associação significativa também foi encontrada entre níveis elevados de CD40L e pacientes com histórico de Síndrome Torácica Aguda. Essas evidências sugerem que LIGHT e CD40L parecem estar contribuindo com a ativação dos leucócitos e do endotélio, exercendo um papel importante na fisiopatogenia da anemia falciforme e aparentemente nas manifestações clínicas desta doença. Os resultados encontrados neste estudo evidenciam a importância que as plaquetas e seus mediadores inflamatórios, LIGHT e CD40L, podem ter na propagação da inflamação vascular presente na anemia falciforme, se tornando possíveis alvos para novas abordagens terapêuticas
Abstract: Sickle cell disease results from a single amino acid substitution in the gene encoding the ?-globin subunit, leading to hemoglobin S production in red blood cells. Polymerization of deoxygenated sickle hemoglobin leads to decreased deformability of red blood cells, resulting in hemolytic anemia and vaso-occlusive events. Platelets appear to play an important role in the vaso-occlusive process, as following their activation they express and secrete mediators that induce an inflammatory response in endothelial cells and leukocytes. The purpose of this study was to investigate the production and expression of LIGHT and CD40L on platelets, the presence of this protein in the plasma of controls (healthy subjects; CON), sickle cell anemia patients (AF) and sickle cell anemia patients on hydroxyurea therapy (AFHU). In addition, this study evaluated the involvement of platelets and their mediators, LIGHT and CD40L, in the activation of leukocytes and endothelial cells. Plasma levels of both cytokines were significantly higher in AF and AFHU individuals than in control individuals and interestingly, HU therapy was not associated with a reduction in these levels. A significant correlation was observed between levels of LIGHT with plasma levels of CD40L, IL-8, ICAM-1, Thrombospondin-1 and TNF-?, whereas the plasma concentration of CD40L correlated with levels of TNF-? and especially with plasma Thrombospondin-1. LIGHT expression was significantly higher on the surface of platelets from AF and AFHU subjects, compared with CON individuals and this expression demonstrated a correlation with markers of platelet activation. LIGHT secretion was determined by ELISA and significant concentrations of this cytokine could be detected in the supernatant of platelets from CON and AF individuals, indicating that platelets may be an important source of LIGHT. Although CD40L expression was not detected on the platelet surface in patients or controls, sickle platelets secreted an increased amount of CD40L, compared to controls. A significant correlation was observed between CD40L and LIGHT release in sickle cell patients, indicating that the production of these two proteins may be tightly coupled. The expression of LIGHT (HVEM and LT?R) and CD40L (CD40) receptors was evaluated by flow cytometry on the surface of platelets, neutrophils, lymphocytes and monocytes. An increased HVEM receptor expression was observed on the platelets and lymphocytes of sickle cell patients, whereas the expression of the CD40 receptor was elevated on platelets, neutrophils, lymphocytes and monocytes from sickle cell patients, compared to control subjects. Evaluating the contribution of platelets to leukocyte activation, we observed that platelets from sickle cell anemia individuals increased the expression of the activation marker, CD69, on lymphocytes and also induced a pro-inflammatory phenotype on monocytes. Co-culture of HUVEC with platelets demonstrated that sickle cell platelets have an increased ability to induce ICAM-1 expression on endothelial cells than platelets from control subjects. Furthermore, in the presence of anti-CD40L antibodies, a drastic reduction was observed in this increase. Although the expression of endothelial ICAM -1 was also reduced in the presence of anti-LIGHT antibodies, these results were not statistically significant. Interestingly, high plasma concentrations of LIGHT were associated with elevated tricuspid regurgitant velocity, indicative of pulmonary hypertension in sickle cell anemia. A significant association was also found between high levels of CD40L and patients with a lifetime history of acute chest syndrome. LIGHT and CD40L appear to contribute to leukocyte and endothelial activation, playing an important role in the pathophysiology of sickle cell anemia and apparently in the clinical manifestations of this disease. These results highlight the important role that platelets and their inflammatory mediators may play in the vascular inflammation that is known to occur in sickle cell anemia
Doutorado
Fisiopatologia Médica
Doutora em Ciências
Merlotti, Guido. « Role of lymphocyte co-stimulation pathways and extracellular vesicles in cardiovascular damage of chronic uremic patients and new therapeutic strategies ». Doctoral thesis, Università del Piemonte Orientale, 2021. http://hdl.handle.net/11579/127932.
Texte intégralBlankenbach, Hermann [Verfasser], et Dennis [Akademischer Betreuer] Wolf. « Generierung und Charakterisierung eines neuen Liganden- und Aktivitäts-spezifischen Antikörpers zur selektiven Hemmung der CD40L/Mac-1 Interaktion ». Freiburg : Universität, 2016. http://d-nb.info/112264731X/34.
Texte intégralBrittain, George C. IV. « A Novel Role for the TRAFs as Co-Activators and Co-Repressors of Transcriptional Activity ». Scholarly Repository, 2009. http://scholarlyrepository.miami.edu/oa_dissertations/451.
Texte intégralBungenstock, Anne. « Endothelzellmigration ». Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2003. http://dx.doi.org/10.18452/14935.
Texte intégralAngiogenesis, the formation of new blood vessels from the preexisting vasculature, is a process involved in physiologic conditions, such as embryonic development and woundhealing, as well as in pathologic conditions, such as diabetic retinopathy and growth and spreading of solid tumors. Chronic inflammation such as atherosclerosis and rheumatoid arthritis is also associated with angiogenic processes. Angiogenesis is a tightly regulated process that requires migration, proliferation and differentiation of endothelial cells. Cell migration is a very important biologic function of the endothelial cell. The aim of this study was therefore to investigate the impact of various cytokines on endothelial cell migration and to characterize the chemotactic signal transduction pathways involved in this process. Leptin, the product of the ob-gene, proved to be a potent stimulus of endothelial cell migration. The actvation of the protein kinases ERK-MAPK and Akt is critical for endothelial cell migration, and their pharmacological inhibition caused a significant down-regulation of the migratory response towards migration factors such as Leptin and VEGF. The antidiabetic thiazolidinediones Troglitazone and Ciglitazone inhibited the leptin-induced endothelial cell migration by interfering with the cytosolic protein kinase Akt. They did not exert any influence on the activation of the ERK-MAPK. These findings prove the existence of two different, independent ways of signal transduction involved in endothelial cell migration: The ERK-MAPK and the protein kinase Akt. The activation of either kinase is necessary, but not sufficient to induce a migratory response in human endothelial cells. The proinflammatory mediators TNF alpha and CD40L caused a significant inhibition of endothelial cell migration in response to VEGF, when they were added to the culture medium for 24 h. TNF alpha did not stimulate the migration of endothelial cells, even when administered during a comparable short period of 5 h. This observation is in contrast with the postulated association of inflammatory and angiogenic proceses. In conclusion, the results of this study show for the first time a direct inhibition of leptin-induced endothelial cell migration by antidiabetic drugs belonging to the PPAR gamma-ligand-family through their inhibitory effect on Akt. This possibly broadens the spectrum of therapeutic applications of the antidiabetic thiazolidinediones in patients suffering from NIDDM and secondary complications such as diabetic retinopathy.
Tahir, Sibgha [Verfasser], et Markus [Akademischer Betreuer] Hecker. « CD40L-dependent von Willebrand factor-platelet string formation in the mouse microcirculation in vivo / Sibgha Tahir ; Betreuer : Markus Hecker ». Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177691280/34.
Texte intégralMühle, Kerstin [Verfasser], Hans-Dieter [Gutachter] Volk, Andreas [Gutachter] Thiel et Ulf [Gutachter] Wagner. « Interaction of CD8+CD40L+ T cells with B cells / Kerstin Mühle ; Gutachter : Hans-Dieter Volk, Andreas Thiel, Ulf Wagner ». Berlin : Humboldt-Universität zu Berlin, 2018. http://d-nb.info/1185495924/34.
Texte intégralLoyal, Lucie [Verfasser], Andreas [Gutachter] Thiel, Chiara [Gutachter] Romagnani et Hans-Dieter [Gutachter] Volk. « The molecular regulation of CD40L in CD8+ T cells / Lucie Loyal ; Gutachter : Andreas Thiel, Chiara Romagnani, Hans-Dieter Volk ». Berlin : Humboldt-Universität zu Berlin, 2019. http://d-nb.info/1190641046/34.
Texte intégral