2. Academic Validation
  3. Combination of mesenchymal stem cells and FK506 prolongs heart allograft survival by inhibiting TBK1/IRF3-regulated-IFN-γ production

Combination of mesenchymal stem cells and FK506 prolongs heart allograft survival by inhibiting TBK1/IRF3-regulated-IFN-γ production

  • Immunol Lett. 2021 Oct;238:21-28. doi: 10.1016/j.imlet.2021.06.007.
Yingyu Chen 1,  Guoliang Yan 2,  Yunhan Ma 2,  Mengya Zhong 2,  Yan Yang 2,  Junjun Guo 3,  Chenxi Wang 3,  Weimin Han 3,  Liyi Zhang 2,  Shuangyue Xu 2,  Jinjin Huang 3,  Helong Dai 4,  Zhongquan Qi 5
Affiliations

Affiliations

  • 1 Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China; Organ Transplantation institute, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, China; School of Medicine, Xiamen University, Xiamen, Fujian, China.
  • 2 Organ Transplantation institute, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, China; School of Medicine, Xiamen University, Xiamen, Fujian, China.
  • 3 School of Medicine, Xiamen University, Xiamen, Fujian, China.
  • 4 Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China; Clinical Research Center for Organ Transplantation in Hunan Province, Changsha, China; Clinical Immunology Center, Central South University, Changsha, China. Electronic address: [email protected].
  • 5 Organ Transplantation institute, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, China; Medical College, Guangxi University, Nanning, Guangxi, China. Electronic address: [email protected].
PMID: 34228988 DOI: 10.1016/j.imlet.2021.06.007
Abstract

Lifelong immunosuppression use presents many serious side effects to transplant recipients. Previous studies have shown that mesenchymal stem cells (MSC) regulate the progress of inflammation and protect allograft function. However, the benefits of MSC combined with low-dose tacrolimus (FK506) has not been investigated in heart transplant recipients, and its mechanism deserves further investigation. SD Rat bone marrow-derived MSC were infused into recipient mouse (C57BL/6, B6) through the tail vein, followed by a BALB/c donor cervical ectopic heart transplantation on the next day of infusion. T-lymphocyte subsets and their functions were determined using flow cytometry, ELISA, and qPCR. Thereafter, in vitro and in vivo experiments were conducted to identify the mechanisms regarding MSC and FK506 combination (MF group) use in regulating IFN-γ signaling. MF group in the allogeneic heart transplantation mouse model inhibited acute rejection and prolonged mean survival time (MST) of grafts from 7 days (d) to 22d. Pathological examination of heart grafts suggested that inflammatory cell infiltration decreased, and tissue damage was significantly reduced in the MF group. IFN-γ mRNA expression levels in the grafts and recipients decreased, while IL-4 and TGF-β mRNA expression increased in the MF group. Phosphorylation of TBK1/IRF3 in recipient immune cells decreased under donor antigen stimulation. Combination use of MSC and FK506 can prolong graft survival, possibly by down-regulating TBK1/IRF3 phosphorylation, thus reducing IFN-γ production to prevent infiltration of inflammatory cells in the graft and extend graft survival. The findings provide a potential new approach to immunosuppression selection.

Keywords

FK506; IFN-γ; Mouse heart transplantation; TBK1/IRF3; mesenchymal stem cells.

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