Alzheimer's disease (AD) is the most prevalent form of progressive dementia and is characterized by the accumulation of amyloid beta (Aß) peptide in the brain and in the cerebral vessels forming cerebral amyloid angiopathy (CAA). As previously reported, an active immunization strategy of mice with Aß1-42 peptide results in decreased Th1 and increased Th2 cytokine responses as well as an effectively clearance of CNS Aß. This approach has also yielded favorable results for many patients, unfortunately, a small percentage of these study participants developed severe aseptic meningoencephalitis likely secondary to CNS invasion of activated T-cells. We have previously demonstrated that disruption of CD40-40L pathway reduces Aß plaque load, promotes Th2 response, and rescues from cognitive impairments. However, direct blockage of the CD40 pathway by passive vaccination with anti-CD40L antibody leads to immunosupression. Therefore, in its current form this therapeutic strategy poses an unacceptable risk to the recipient of treatment, aged individual. For those reasons, the identification and characterization of alternative modulators/inhibitors of CD40 signaling may be necessary for the development of safe and effective AD immunotherapy. This proposal introduces novel immunomodulatory therapies that are based on previous vaccination strategies or cell based therapies across medial field. We showed that transcutaneous vaccination can both be efficacious and safe, thus clearly demonstrating that the right combination of the antigens, adjuvants, and the routes of administration are crucial for the right vaccine. Furthermore, we demonstrated that the effects of current Aß vaccine strategies could be enhanced by a simultaneous blockade of CD40-40L signaling. As an alternative approach, we explored the possibility of cell-based therapies and showed that human umbilical cord blood cells, which are currently used as a treatment for systemic lupus erythematosus and leukemia, and currently investigated against stroke, amyotropic lateral sclerosis, age-related macular degeneration, multiple sclerosis, and Parkinson's disease, and showed that not just they improved the AD like pathology in transgenic animals but altered both the brain and peripheral inflammation levels. Lastly, we discussed the involvement of microglia, one of the key players in both AD pathogenesis and Aß clearance and suggesed that microglia in actuality has a continuum of physiological activation states that contribute to proinflammation, antiinflammation, and phagocytosis.

Der Ligand TRAIL wurde 1997 aufgrund seiner hohen Sequenzhomolgie ge-genüber dem TNFL CD95L entdeckt (28 %). Allerdings besitzt TRAIL, anders als die Liganden CD95L und TNF, die bemerkenswerte Eigenschaft vor allem in veränderten Zellen Apoptose zu induzieren, während gesunde Zellen davor bewahrt werden. Die TRAIL-induzierte Apoptose wird durch die apoptoseinduzierenden Todesrezeptoren TRAILR1 und TRAILR2 vermittelt. Allerdings bindet und aktiviert lösliches TRAIL hauptsächlich den Todesrezeptor TRAILR1, während membrangebundes TRAIL sowohl TRAILR1 als auch TRAILR2 gut aktiviert. In den letzten Jahren wurden verschiedene Methoden entwickelt, um die Bioaktivität löslicher TNFL zu steigern. Hierzu zählen z.B.: Stabilisierung der trimeren Molekülanordnung über die TNC-Domäne, Oligomerisierung des Flag-getaggten Liganden mithilfe des monoklonalen Antikörpers M2, sowie Generierung einer artifiziellen, antigenabhängigen Membranständigkeit. In dieser Arbeit wurde der Oberflächenrezeptor CD40 zur Immobilisierung des generierten Fusionsproteins scFv:CD40-Flag-TNC-TRAIL genutzt. In verschieden Experimenten konnten mit scFv:CD40-Flag-TNC-TRAIL in CD40-exprimierenden Zellen starke Apoptoseinduktion ermittelt werden. Charakteris-tische Kennzeichen und Spaltprodukte der Apoptose konnten ausschließlich in CD40-positiven Tumorzellen detektiert werden. Dabei wurde in allen Versuchen die für die Apoptoseinduktion benötigte Konzentration des Konstrukts mithilfe des Proteinsyntheseinhibitors CHX um das 10- bis 100-fache verringert. Es konnte auch gezeigt werden, dass in CD40-positiven Zellen, nach Stimulation mit scFv:CD40-Flag-TNC-TRAIL, nicht-apoptotische Signalwege verstärkt aktiviert werden. Dies war auf die agonistische Aktivität des monoklonalen Antikörperfragments scFv:CD40 zurückzuführen. Die Antikörperdomäne war folglich nicht nur zur effizienten Aktivierung der TRAIL-Todesrezeptoren mittels Immobilisierung fähig, sondern konnte zusätzlich zur Stimulation des Immunsystems genutzt werden. Zusammenfassend konnte gezeigt werden, dass der lösliche, schwach aktive Ligand TRAIL mittels Oberflächenimmobilisierung über Antigen-Antikörper-Wechselwirkungen in einen hochaktiven Liganden mit lokal begrenzter Toxizität überführt werden kann. Mithilfe dieses Fusionsproteins ist es somit möglich die selektive Toxizität von TRAIL durch Steigerung seiner Aktivität effizient zu nutzen. Zusätzlich kann durch die Antigenbindung der Wirkungsbereich weiter eingegrenzt werden (CD40-positive Tumoren), wodurch unerwünschte Nebenwirkungen reduziert oder sogar ausgeschaltet werden können. Das in Tumoren oft heruntergefahrene Immunsystem kann CD40-abhängig stimuliert werden, um somit auch Tumorzellen in apoptoseresistenten Stadien zu eliminieren. Basierend auf diesen Ergebnissen können in der Zukunft weitere Studien zur Therapie von TRAIL-resistenten, CD40-exprimierenden Tumoren fortgeführt werden. / TRAIL has been characterized in 1997 based on its high sequence homology towards the TNFL CD95L (28 %). Differing from the ligands CD95L and TNF, TRAIL has the remarkable quality to induce apoptosis in tumor cells, while healthy cells are protected from apoptosis. In this case apoptosis is accomplished by the death receptors TRAILR1 and TRAILR2. However soluble TRAIL binds and activates primarily the death receptor TRAILR1, while membrane-bound TRAIL activates well both TRAILR1 and TRAILR2. In recent years different methods have been generated to raise the bioactivity of soluble TRAIL. To these belong for example: stabilization of the trimeric molecule structure with the TNC-domain, oligomerization of the ligand with the monoclonal antibody M2, generation of an artificial antigen-restricted membrane-bound form. In this work we made use of the surface receptor CD40 for immobilization of the generated fusion protein scFv:CD40-Flag-TNC-TRAIL. With the aid of this fusion protein it is thus possible to use the selective toxicity of TRAIL efficiently by an increase of its activity. Additionally the field of action could be localized further by antigen binding (CD40-positive tumors). As a consequence undesirable side effects can be reduced or even deactivated. The shut down immune system in tumors can be stimulated CD40-dependant, so that tumor cells resistant to apoptosis are also wiped out. Based on these results future studies may be conducted to treat TRAIL-resistant, CD40-expriming tumors.

Graves¡¦ disease (GD), an organ specific autoimmune disease, requires two signals to activate the T cells. In addition to the specific binding of T cell receptor to the antigenic peptide-MHC complex, an antigen-independent costimulatory pathway reportedly require generate subsequent cytokines and cell surface molecules. This regulation of T-cell response is a highly-organized multiple step program. T cell costimulatory signals is found to regulate the magnitude and duration of various type of autoimmune diseases. This study is to test whether genetic polymorphism of these costimulatory genes is related with the disease susceptibility or progression. We anticipated that the candidate genetic makers are beneficial for importing GD management. We recruited 262 GD patients from the Outpatient Department of Endocrine and 200 healthy controls from the Health Screening Center of Chang Gung Memorial Hospital in Kaohsiung.The GD patients were divided into three groups: recurred within 9 months (n=91), between 10-36 months (n=65), and more than 36 months (n=106). Clinical and laboratory attributes included: the genotypes of CTLA-4, CD28, ICOS, PD-1 and CD40; serum levels of T4, T3 and TSH; goiter size and TSH-receptor antibodies at the beginning and end of treatment. Genomic DNA was extracted from peripheral blood leucocytes by kit. The single nuclotide polymorphisms of the candidate genes were genotyped by polymerase chain reaction- restriction fragment length polymorphism and TaqMan® SNP Genotyping Assays with specific primers. Linkage disequilibuium between pairs of polymorphism was estimated by Haploview software. Haplotype analyses were performed using the Hap-Clustering program. Variance and correlation of data was statistically analyzed by Chi-square, general liner model, multiple logistic regression analysis and Kaplan-Meier plot. A p value <0.01 was considered significant. The results showed:(1) Genetic polymorphism within the costimulatory molecules affected the susceptibility and progression of GD; (2) GD patients carried more risk alleles than the controls; (3) Within the GD group, patients harboring more risk alleles wound relapse earlier after drug withdrawal; (4) Number of risk alleles, goiter size and TBII levels at end of treatment were independent predictors of disease relapse; (5) A risk score calculation based on odds ratio of risk alleles correlated with patients¡¦ relapse time after drug withdrawal. We concluded that patients¡¦ genetic makers of costimulatory molecules may be helpful in choosing appropriate treatment for GD.

Thesis (Ph. D.)--University of Missouri--Columbia, 2000. / "December 2000." Typescript. Vita. Includes bibliographical references (leaves 177-206). Also available on the Internet.

Dendritic cells (DCs) are a migratory group of bone-marrow-derived leukocytes specialized for uptake, transport, processing and presentation of antigens to T cells. Exposure of DCs to bacterial pathogens can induce DC maturation characterized by cytokine production, up-regulation of co-stimulatory molecules and an increased ability to activate T cells. DCs have the ability to restrict growth of L. pneumophila (Lp), an intracellular Gram-negative bacillus that causes a severe form of pneumonia known as Legionnaires' disease, in murine ER-derived organelles (121) but replicate in human DCs (145). Even in human cells, however, lysis of the DCs does not occur for at least 24 hours which may allow DCs time to participate in the transition from innate to adaptive immunity (145). The primary polyphenol in green tea extract is the catechin (-)-epigallocatechin-3-gallate (EGCG) which accounts for most of the numerous reported biological effects of green tea catechins, including anti-bacterial, anti-tumor, and neuroprotective effects. Primary murine bone marrow derived DCs from BALB/c mice were treated in vitro with Lp, or stimulated for comparison with Escherichia coli lipopolysaccharide (LPS). CD11c, considered an important marker of mouse DCs, and surface expression of co-stimulatory molecules CD40, CD80, CD86, as well as class I/ II MHC molecules was determined by flow cytometry. Treatment of the cells with EGCG inhibited the microbial antigen induced up-regulation of CD11c, CD40, CD80, CD86 and MHC I/ II molecules. EGCG also inhibited, in a dose dependent manner, induced production of the Th1 helper cell activating cytokine, IL-12, and the chemokines RANTES, MIP1a, and MCP-1. However, EGCG upregulated TNFa production. In addition, EGCG inhibited both Lp and LPS induced expression of both TLR2 and TLR4 as well as LPS-induced NF-kB activation; all of which are important mediators of DC maturation. The modulation of phenotype and function of DCs by EGCG has implications for host interaction with microbial pathogens like Lp, which involve TLR interaction.

CD20 est une phosphoprotéine transmembranaire exprimée spécifiquement à la surface des lymphocytes B. Malgré les nombreuses études qui ont montré son implication dans le flux calcique, son rôle physiologique est assez mal connu. Cependant, des études récentes ont démontré que CD20 peut jouer un rôle important dans la mort cellulaire. D’ailleurs, le rituximab, un anticorps monoclonal chimérique dirigé contre CD20 humain, a montré son efficacité dans le traitement de nombreuses maladies auto-immunes. Cet anticorps est capable d’induire une profonde déplétion des lymphocytes B, qui va également interférer avec la coopération T et la sécrétion de cytokines. En plus, l’engagement du CD20 à la surface des cellules induit la mort cellulaire, alors que la partie cytoplasmique de cette molécule ne possède pas un motif de mort. Donc, il est possible que cette réponse soit médiée par des molécules qui semblent être associées au CD20 comme CD40. En effet, CD40, une glycoprotéine transmembranaire de type I, est un composant majeur du système immunitaire, dont l’engagement pourrait moduler la fonction cellulaire et même conduire à la mort rapide des cellules B. Le travail présenté dans ce mémoire porte sur l’étude de la mort cellulaire induite par un anti-CD20, le rituximab, ainsi que l’étude du rôle de l’association CD20/CD40 dans la mort cellulaire médiée par cet anticorps. Nos résultats montrent que la mort cellulaire induite par le rituximab varie en fonction du type cellulaire et du niveau d’expression du CD20, et que la présence du CD40 à la surface des cellules augmente l’activité de la mort cellulaire induite par le rituximab. En plus, CD20 et CD40 sont associés à la surface cellulaire, et la partie cytoplasmique n’est pas impliquée dans cette association mais semble être importante dans la mort cellulaire induite via CD20. / CD20 is a transmembrane phosphoprotein specifically expressed at the surface of B cells. Despite the many studies that have shown its involvement in calcium flux, its physiological role is poorly understood. However, recent studies have shown that CD20 can play an important role in cell death. Moreover, rituximab, a chimeric monoclonal antibody directed against human CD20, has shown efficacy in the treatment of many autoimmune diseases. Indeed, this antibody is able to induce a profound depletion of B cells and interfere in T cooperation and secretion of cytokines. In addition, the engagement of CD20 at the cell surface induces cell death, while the cytoplasmic portion of this molecule has no death domain. So, it is possible that this response is mediated by molecules that could be associated with CD20, like CD40. In fact, CD40, a type I transmembrane glycoprotein, is a major component of the immune system. The engagement of CD40 can modulate cellular function and may even lead to rapid B cell death. The work presented in this thesis will focus on the study of cell death induced by an anti-CD20, rituximab, and on the role of the association of CD40 with CD20 at the cell surface in susceptibility to cell death mediated by this antibody. Our results show that cell death induced by rituximab depends on cell type and on the levels of expression of CD20, and that the presence of CD40 at the cell surface increases cell death induced by rituximab. In addition, CD20 and CD40 are associated at the cell surface, and the cytoplasmic portion is not involved in this association but seems to be important in induction of cell death by CD20.

Le CD40 est un membre de la famille des récepteurs du facteur de nécrose tumorale ("Tumour necrosis factor", TNF), initialement identifié sur des cellules de carcinome de la vessie. L'interaction du CD40 avec son ligand (CD40L) est d'une importance cruciale pour le développement des cellules B et de la commutation d'isotype au cours de la réponse immunitaire acquise. L'expression du complexe CD40/CD40L était initialement cru d'être limiter aux cellules du système immunitaire, mais aujourd'hui il est bien connu que ce complexe est également exprimé sur les cellules du système circulatoire et vasculaire, et est impliqué dans diverses réactions inflammatoires; de sorte que le CD40L est maintenant considéré comme une molécule thrombo-inflammatoire prédictive des événements cardiovasculaires. Les plaquettes expriment constitutivement le CD40, alors que le CD40L n'est exprimé que suite à leur l'activation. Il est ensuite clivé en sa forme soluble (sCD40L) qui représente la majorité du sCD40L en circulation. Il fut démontré que le sCD40L influence l'activation plaquettaire mais son effet exact sur la fonction plaquettaire, ainsi que les mécanismes cellulaires et moléculaires sous-jacents à son action demeurent inconnus. Ainsi, ce projet a été entrepris dans le but d’adresser les objectifs spécifiques suivants: 1) évaluer les effets in vitro du sCD40L sur l'activation et l'agrégation plaquettaire; 2) identifier les récepteurs plaquettaires impliqués dans l’action du sCD40L; 3) élucider les voies signalétiques intracellulaires induits par le sCD40L; 4) évaluer les effets du sCD40L sur la formation de thrombus in vivo. Nous avons trouvé que le sCD40L augmente fortement l'activation et l'agrégation des plaquettes en réponse à de faibles concentrations d'agonistes. Les plaquettes humaines traitées avec une forme mutante du sCD40L qui n'interagit pas avec le CD40, et les plaquettes de souris déficientes en CD40 ne furent pas en mesure d'induire de telles réponses, indiquant que le récepteur principal du sCD40L au niveau des plaquettes est le CD40. En plus, nous avons identifié la présence de plusieurs membres de la famille du facteur associé du récepteur du TNF ("TNF receptor-associated factor", TRAF) dans les plaquettes et nous avons montré que seulement le TRAF2 s'associe avec le CD40 suite à la stimulation par le sCD40L. Nos résultats indiquent aussi que le sCD40L agisse sur les plaquettes au repos par l'entremise de deux voies signalétiques distinctes. La première voie implique l'activation de la petite GTPase Rac1 et de sa cible en aval, soit la protéine kinase p38 activée par le mitogène ("p38 mitogen-activated protein kinase", p38 MAPK ), menant au changement de forme plaquettaire et à la polymérisation de l'actine; alors que la deuxième voie implique l'activation de la cascade signalétique du NF-kB. Par ailleurs, à la suite d'une lésion artérielle induite par le chlorure de fer, le sCD40L exacerbe la formation de thrombus et l'infiltration leucocytaire au sein du thrombus dans les souris du type sauvage, mais pas chez les souris déficientes en CD40. En conclusion, ce projet a permis d'identifier pour la première fois deux voies signalétiques distinctes en aval du CD40 plaquettaire et a permis d'établir leur implication dans l'activation et l'agrégation plaquettaire en réponse au sCD40L. De manière plus importante, ce projet nous a permis d'établir un lien direct entre les niveaux élevés du sCD40L circulant et la formation de thrombus in vivo, tout en soulignant l'importance du CD40 dans ce processus. Par conséquent, l'axe CD40/CD40L joue un rôle important dans l'activation des plaquettes, les prédisposant à une thrombose accrue en réponse à une lésion vasculaire. Ces résultats peuvent expliquer en partie la corrélation entre les taux circulants élevés du sCD40L et l'incidence des maladies cardiovasculaires. / CD40 is a member of the tumour necrosis factor (TNF) receptor family, originally identified on human bladder carcinoma cells. Interaction of CD40 with its ligand (CD40L) is of crucial importance for B cell development and immunoglobulin isotype switching during the adaptive immune response. Expression of the CD40/CD40L dyad was initially thought to be restricted to cells of the immune system, but today it is known to be also expressed on cells of the circulatory and vascular systems, and have important implications in various inflammatory reactions, such that CD40L is now regarded as a thrombo-inflammatory molecule and a reliable predictor of cardiovascular events. Platelets constitutively express CD40, whereas CD40L is expressed upon activation and subsequently cleaved into its soluble form (sCD40L), accounting for the majority of circulating sCD40L. Soluble CD40L has been shown to influence platelet activation but its precise effect on platelet function, and the underlying cellular and molecular mechanisms remain undefined; hence the purpose of this project. The specific aims of this study are: 1) to evaluate the in vitro effects of sCD40L on platelet activation and aggregation; 2) to determine the receptor(s) on platelets involved in the action of sCD40L; 3) to elucidate the intracellular signalling pathways induced by sCD40L; and 4) to evaluate the in vivo effects of sCD40L on thrombus formation. We have showed that sCD40L strongly enhances activation and aggregation of washed human platelets in response to sub-threshold concentrations of agonists. Human platelets treated with a mutated form of sCD40L that lacks CD40 binding, and platelets from CD40 deficient mice failed to elicit such responses, indicating that CD40 is the major platelet receptor for sCD40L. Moreover, we identified the presence of multiple members of the TNF receptor-associated factor (TRAF) in platelets and showed that only TRAF2 associates with CD40 after sCD40L stimulation. Interestingly, sCD40L primes resting platelets through two distinct signalling pathways. The first pathway involves activation of the small GTPase Rac1 and its downstream target p38 mitogen-activated protein kinase, leading to platelet shape change and actin polymerization; whereas the second pathway involves activation of the NF-κB signalling cascade. Furthermore, sCD40L exacerbates thrombus formation and leukocyte infiltration within the thrombus mass in wild-type mice but not in CD40 deficient mice following ferric chloride-induced arterial injury. In conclusion, we have identified for the first time two distinct signalling pathways downstream of platelet CD40, and established their implication in platelet activation and aggregation in response to sCD40L. Noticeably, we established a direct link between elevated levels of sCD40L and in vivo thrombus formation, while emphasizing the requirement of CD40 in this process. Therefore, the CD40/CD40L dyad plays an important role in platelet priming that predisposes platelets to enhanced thrombus formation in response to vascular injury. These results may partly explain the correlation between elevated circulating levels of sCD40L and the incidence of cardiovascular diseases.

CD40 (TNFRSF5) és una glicoproteïna de membrana que pertany a la família de receptors del factor de necrosi tumoral (TNF-R). La interacció amb el seu lligand fisiològic (CD40L o CD154) regula una àmplia varietat de funcions biològiques, des de l'activació del sistema immune, tant humoral com cel·lular, a diferents aspectes de la resposta inflamatòria. Els 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.

Thèse (M.Sc.)--Université Laval, 2008. / Titre de l'écran-titre (visionné le 12 janvier 2009). Bibliogr.

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [82]-102).