期刊
JOURNAL OF TRANSLATIONAL MEDICINE
卷 13, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12967-015-0638-2
关键词
Gene transfer; Transcription factor forkhead box p3; Mesenchymal stem cells; Tolerance; Regulatory T cells
资金
- National Natural Science Foundation of China [81102241]
- Specialized Research Fund for the Doctoral Program of Higher Education in China [20110162120016]
Background: The transcription factor forkhead box P3 (Foxp3) is a master regulatory gene necessary for the development and function of CD4(+) CD25(+) regulatory T cells (Tregs). Mesenchymal stem cells (MSC) have recently emerged as promising candidates for cell-based immunosuppression/tolerance induction protocols. Thus, we hypothesized that MSC-based Foxp3 gene therapy would improve immunosuppressive capacity of MSC and induce donor-specific allograft tolerance in rat's liver allograft model. Methods: The present study utilized a lentivirus vector to overexpress the therapeutic gene Foxp3 on MSC. In vivo, Injections of 2 x 10(6) MSC, FUGW-MSC or Foxp3-MSC into the portal vein were carried out immediately after liver transplantation. Results: Successful gene transfer of Foxp3 in MSC was achieved by lentivirus carrying Foxp3 and Foxp3-MSC engraftment in liver allograft was confirmed by fluorescence microscopy. Foxp3-MSC treatment significantly inhibited the proliferation of allogeneic ACI CD4(+) T cells to splenocytes (SC) from the same donor strain or third-party BN rat compared with MSC. Foxp3-MSC suppressive effect on the proliferation of CD4+ T cells is contact dependent and associated with Programmed death ligand 1(PD-L1) upregulation in MSC. Co-culture of CD4+ T cells with Foxp3-MSC results in a shift towards a Tregs phenotype. More importantly, Foxp3-MSC monotherapy achieved donor-specific liver allograft tolerance and generated a state of CD4(+) CD25(+) Foxp3(+) Tregs-dependent tolerance. Conclusion: Foxp3-engineered MSC therapy seems to be a promising and attractive cell therapy approach for inducing immunosuppression or transplant tolerance.
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