Résumé :
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Communication n° 173 Duchenne muscular dystrophy (DMD) is a fatal neuromuscular recessive disease characterized by widespread muscle damage throughout the body. No cure is currently available for DMD. Our research group is pursuing a research program to develop a treatment based on myoblast transplantation (MT) obtained from an healthy donor. A sustained FK506 immunosuppression is currently required to prevent rejection of human transplanted allogeneic myoblasts. However, the major drawback of human MT is that the long-term use of immunosuppressive treatments has adverse effects: nephrotoxicity, increased cancer risk etc... The aim of this study is to avoid the adverse events associated with immunosuppression by inducing immunological tolerance to the transplanted myoblasts. During the last years, transplantation tolerance has been obtained by the development of stable donor-specific chimerism resulted from bone marrow cell transplantation (BMT). In our protocol, the host dystrophic mouse model, C57Bl10J mdx/mdx, was conditioned to develop tolerance for donor Balb/c MT as follow: mdx mice initially received a donor specific transfusion (DST), then a single cyclophosphamide and Treosulfan treatment and finally a donor Balb/c BMT. Thirty days after BMT, left tibialis anterior (TA) muscles of chimeric mice were grafted with donor myoblasts. One hundred days later, a second MT from the same donor strain has been performed in the right TA without any additional therapy. Results show that all treated mice developed permanent mixed chimerism for leukocyte and lymphocyte cell populations. Interestingly, long-lasting dystrophin positive fibers were present in both TAs of grafted chimeric mice in equivalent number to those observed in mdx mice treated with a FK506 sustained immunosuppression. Moreover, no infiltration was observed around dystrophin positive fibers. Thus, chimerism development with a mild conditioning regimen promotes donor specific stable tolerance avoiding the side effects of sustained immunosuppressive treatment and could be applied for the transplantation of myoblasts to DMD patients.
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