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Cell Journal، جلد ۱۵، شماره Suppl ۱، صفحات ۴۷-۴۷
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عنوان انگلیسی Ps-60: Peripheral Tolerance Allows Transdifferentiation of Allogenic Bone Marrow Cells into Liver Parenchyma/Mesenchyma Cells for Phenotype Correction of Hemophilia A Mouse
چکیده انگلیسی مقاله Objective: Earlier, we have shown that the severity of bleeding disorder can be ameliorated by transplanting uncommitted bone marrow (BM) cells in perturbed liver of hemophilia A (HA) mouse. Since hemophilia is an X-chromosome-linked recessive bleeding disorder, the same can not be treated using autologous BM cells. Transplantation of allogenic cells leads to graft rejection and in worst situation may cause host disease. These immune reactions are commonly suppressed by using immunosuppressive drugs. There are numerous side effects on recipient for using immunosuppressive drugs, the most significant are opportunistic infections and transplant- related malignancies. Therefore, it is necessary to develop an alternate method for immune-suppression, which has no or less side effect on the host. Here, we present an immunological method for development of donor MHC-specific peripheral tolerance that allows engraftment and transdifferentiation of allogenic cells in hemophilic mouse liver. Materials and Methods: Uncommitted (Lin-) eGFPexpressing BM cells of FVB/J mouse (H2Kq) were cotransplanted with allo-antigen sensitised recipient HA mouse (H2Kb) T-regulatory (Treg) cells. The mice were sacrificed at different times of transplantation for examining effectors CD4+ T cells and CD4+CD25+Foxp3+ Treg cells population in the spleen and delayed-type hypersensitivity (DTH) reactions in the liver. The presence of donor specific cells in the recipient liver and their phenotypes were examined by immuno-histochemical analyses. The phenotype correction of HA mice was assessed by quantifying the clotting factor in plasma and tail-clip challenge experiment. Results: The results suggest that allo-antigen specific Treg cells were able to control the immune reaction by suppressing CD4+ T cells, which was correlated with the pathology of the liver tissue. We have also evaluated different cellular sources of FVIII synthesis to find out a potential candidate for treatment of hemophilia A. The results suggest that in addition to hepatocytes, BM-derived sinusoidal endothelial and Kuffer cells expressed FVIII. The transplanted HA mice showed FVIII activity in plasma and survived tail-clip challenge experiment. Conclusion: The allogenic BM-derived hepatocytes, endothelial and Kuffer cells can synthesize FVIII in liver and involved in correcting bleeding phenotype of HA mice. This conversion is possible by inducing peripheral tolerance against allo-antigen.
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نشانی اینترنتی http://celljournal.org/journal/article/abstract/864
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