No description available.

The use of organs from donors after circulatory death (DCD) has been recommended as one strategy to enlarge the donor pool and raise the transplant rate. However, DCD allografts had higher incidence of early post-transplant dysfunction. The general aim of this research project was to develop clinical and experimental strategies to reduce the incidence of early post-transplant dysfunction of kidney and liver allografts from DCD. First the ability of a clinical scoring system based on donor data for identifying DCD kidneys with high-risk of post-transplant dysfunction was evaluated using the Oxford and the UK National DCD kidney transplant cohorts. This works suggest that stratification of DCD kidneys before transplantation might allow early identification of kidneys in which lower graft function and survival could be expected if any additional therapeutic intervention is implemented. Second, as it has been suggested that hypothermic machine perfusion (HMP) may protect DCD kidneys from additional preservation injury and improve their outcome after transplantation, this work explored the benefit of HMP as preservation technique fo DCD kidneys in Oxford and discusses the potential of this technique for reducing the incidence of post-transplant dysfunction in DCD kidneys. The Oxford. Liver Group has provided evidence of the benefit of preservation with normothermic machine perfusion (NMP) on post-transplant function and survival of DCD liver allografts. In this work, the molecular mechanisms associated with this benefit were characterized using micro array technology. This analysis suggests that the beneficial effect ofNMP may be associated with the induction of the ischaemic preconditioning phenomenon and highlights a group of genes with potential for gene therapy. Finally, this works provides the "proof-of-concept" that the use of a non-mammalian viral vector for gene transfer of kidneys and livers during conventional cold preservation is feasible and is not associated with additional tissue injury.

Although the short-term outcomes of solid allograft survival have improved substantially over the last few decades, there has been no significant improvement in long-term survival of solid allografts. This thesis presents the initial characterisation of alloantibody mediated rejection in a murine heart transplant model, with particular focus on the impact of the different phases of the humoral alloimmune response (follicular or germinal centre) on graft rejection.

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Le système immunitaire nous protège contre les infections et les cancers. Cependant, des réponses immunitaires excessives ou incontrôlées peuvent causer des pathologies potentiellement mortelles comme le choc endotoxinique, des maladies auto-immunes, ou le rejet d’allogreffe. Une compréhension claire des mécanismes de régulation des réponses immunes permettrait d’envisager de nouvelles thérapeutiques plus ciblées. Dans ce travail réalisé chez la souris, la modulation de la réponse inflammatoire à une toxine bactérienne, le lipopolysaccharide (LPS), a été utilisée comme archétype de la régulation immunitaire. Ceci nous a permis de démontrer que la régulation de la prolifération homéostatique de lymphocytes T CD4+CD25- par des lymphocytes T régulateurs naturels tempère la réponse inflammatoire au LPS. Cet effet est notamment dépendant d’une diminution de la sécrétion d’IFN-γ par les lymphocytes activés par la prolifération induite par la lymphopénie. Nous avons aussi observé, que la désensibilisation du système immunitaire inné vis-à-vis du LPS, suite à des injections répétées d’endotoxine, induit le développement de cellules myéloïdes suppressives (myeloïd-derived suppressor cells MDSC) capables de réguler des réponses lymphocytaires T in vitro et in vivo. Nous avons pu mettre en évidence que l’effet suppresseur des MDSC est dépendant de leur expression de l’enzyme hème oxygénase-1 et de leur production d’IL-10. Le dialogue constant entre les cellules de l’immunité innée et de l’immunité acquise assure donc à la fois l’activation et la régulation du système immunitaire. Dans la majorité des cas, ceci permet aux réponses immunitaires d’être efficaces sans être excessives. La mise en évidence de ces processus identifie les lymphocytes T régulateurs et les cellules myéloïdes suppressives comme des éléments clefs de la régulation d’un processus inflammatoire. Les traitements immunosuppresseurs, les thérapies cellulaires et les greffes de moelle ont des effets variables et mal connu sur ces populations de cellules régulatrices. Tenir compte de ces interférences thérapeutiques avec les processus naturels de régulation de notre système immunitaire permettra certainement d’optimaliser l’utilisation de ce type de traitements. D’autre part, l’utilisation thérapeutique de ces deux types de cellules régulatrices pourrait être envisagé dans de nouvelles stratégies d’immuno-modulation plus « physiologique ».

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No description available.

Universiẗat, Diss.--Bochum, 2007. / Literaturverz. S. XIII - XXVII.

Stem cell-based therapies are promising in regenerative medicine. However, the success of cell therapy is greatly limited by the low engraftment rate to the target tissues. The present study demonstrated that human mesenchymal stem cells (hMSCs) were subjected to a self selection process via microencapsulation in collagen barrier when they were induced to migrate out from this barrier. While retaining the immuophenotype and self renewal capacity, the selected hMSCs showed a significantly better in vitro migratory response of than those cultured in traditional monolayer. The migratory response could be controlled by varying the fabrication parameters of the collagen barrier, including initial collagen concentration and cells seeding density. Affinity to adhere on endothelial cells layer is another engraftment related property. Significant difference was observed between these selected hMSCs and hMSCs in monolayer culture. In order to investigate the engraftment potential of the selected hMSCs, an animal model was performed. The selected hMSCs were transplanted intravenously into NOD/SCID mice under partial hepatectomy. Presence of human cells in the residual liver was determined by the presence of human HLA-ABC using flow cytometry after 48 hours, 1 week and 1 month. Engraftment of the selected hMSCs was significantly higher than that of monolayer cultured hMSCs in time point of 1 month. It demonstrated that the selected hMSCs favor the engraftment to the injured liver. Further investigation is required to determine the fate of the engrafted hMSCs in order to truly confirm their therapeutic potential. The current work demonstrated that collagen-hMSCs microsphere could act as a barrier to select hMSCs with enhanced in vitro migratory response and in vivo engraftment properties. These findings may contribute towards the development of better stem cell therapies. / published_or_final_version / Mechanical Engineering / Master / Master of Philosophy

published_or_final_version / Medicine / Master / Doctor of Medicine