期刊
SCIENTIFIC REPORTS
卷 11, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41598-021-03115-z
关键词
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资金
- Projekt DEAL
- German Research Foundation (DFG) [HO2581/4-1]
- National Science Foundation of China (NSFC) [81760291]
- German Research Foundation DFG [RTG2504-401821119, CRC1181-261193037, DU548/5-1]
- Manfred Roth Stiftung
- IZKF Erlangen [A87, A80]
The study demonstrated that the combination of rapamycin and plerixafor in a fully-mismatched heart transplant model resulted in prolonged allograft survival, reduced fibrosis and myocyte lesions, and increased T-reg cell numbers, possibly through the regulation of pDCs. This pharmacological approach highlights the potential of pDCs as an attractive immunotherapeutic target along with plerixafor treatment.
Allograft-specific regulatory T cells (T-reg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive T-reg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific T-reg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for T-reg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3(+) T cell infiltrated, higher T-reg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated T-reg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase T-reg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment.
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