Amélioration de la transplantation de myoblastes un traitement possible de la dystrophie musculaire de Duchenne : utilisation de la forme active de la vitamine D3 et obtention d'une tolérance immunologique par l'administration de drogues cytoréductrices
|Abstract:||Duchenne muscular dystrophy is a fatal neuromuscular recessive disease characterized by widespread muscle damage throughout the body. No cure is currently available this disease. Myoblast transplantation (MT) is an interesting approach to enhance the life quality and life expectancy of patients. This therapy consists in harvesting myoblasts of a non-dystrophic donor and in transplanting them in dystrophic muscles. This approach involves many drawbacks and predominantly the loss of the grafted cells in post-transplantation period. Firstly, an important part of injected myoblasts quickly dies following their injection. Thus, the graft success relies on the survival of a little proportion of grafted cells. The pathways involved in this important death of cells are not well established. However, following a muscle injury, the muscular regeneration depends on the proliferation and the differentiation of myoblasts. In a first study, we propose an administration of the activated form of vitamin D3 on human myoblasts to compensate the early loss of injected cells. Actually, some previous studies demonstrated that this vitamin acted directly on myoblasts, regulating their proliferation and fusion. We have confirmed these effects and demonstrated that the administration of the vitamin D3 enhances the success of human MT. The second part of this thesis broaches the specific immune rejection associated with the allogeneic MT. Currently, Duchenne patients are treated with chronic immunosuppression for MT. However, the problem in humans is that the long-term use of immunosuppressive treatments has adverse effects: nephrotoxicity, increased cancer risk etc... Mixed-haematopoietic chimerism is a promising approach to circumvent sustained immunosuppression but most of proposed protocols need antibodies treatment or host irradiation. The second study of this thesis shows that we have developed a protocol based on a short term administration of two cytoreductive drugs, both approved for clinical use. The mixed-chimerism development obtained with our conditioning regimen promotes donor specific stable tolerance. Taken together, this thesis gives two solutions to circumvent the early and late destruction of transplanted myoblasts. These approaches could be further included in the clinical essay developed for the Duchenne muscular dystrophy by promoting the efficiency and decrease the clinical risk related to the MT.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||13 April 2018|
|Collection:||Thèses et mémoires|
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