Am J Transl Res 8(8):3603-3613 

BATF inhibition prevent acute allograft rejection after cardiac transplantation

Zhishui Chen


摘要:

Acute allograft rejection is a serious and life-threatening complication of organ transplantation. Th17 cells induced inflammation has been described to play an important role in allograft rejection. Since there is a plenty of evidence indicating that transcriptional factor BATF regulates the differentiation of Th17 and follicular T helper cells both in vitro and in vivo, we investigated whether is BATF involved in acute rejection and allograft survival by injecting lentivirus containing BATF shRNA through tail vein before the cardiac transplantation operation. We found that the allograft survival time of the mice treated with BATF shRNA was significantly prolonged compared with that of negative shRNA treated group and the control group. Further pathological analysis revealed that the BATF shRNA treatment group had significantly lower rejection degree than the negative shRNA group, while there was no significant difference between the negative shRNA group and the control group. Furthermore, flow cytometry analysis and quantitative polymerase chain reaction and enzyme-linked immuno sorbent assay were used to determine the proportion of T helper cells, the expression of specific transcription factor and the inflammatory cytokines respectively. Data showed that BATF regulated Th17 and Treg responses during allograft rejection. And BATF inhibition led to reduction of the expression level of Rorγ-t and enhancement of the Foxp-3. In addition, cytokines IL-17A and IL-4 were found decreased. This may indicate BATF as a novel therapy target for treatment of acute allograft rejection.This study was approved by the Institutional Animal Care and Use Committee of Tongji Medical College. Male BALB/C (H2d) and C57BL/6 (B6, H2b) mice at age of 4-8 weeks were maintained at the Animal Facility of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, under controlled conditions (specific pathogen-free, 22°C, 55% humidity and 12 h day/night).We successfully performed the acute rejection model of heterotopic cardiac transplantation in mice (Supplementary Figure 1), the histological analysis of cardiac grafts harvested on POD 7 after allogeneic cardiac transplantation revealed severe pathological feature of acute rejection by comparing with those mice treated with syngeneic transplantation and untreated. The cardiac grafts in the rejection group showed rigorous infiltration of inflammatory cells and allograft destruction (Figure 1A-C). The BATF mRNA levels were significantly higher in the rejection group compared with other groups (Supplementary Figure 2). Furthermore, the proportion of IL-17A secreting cells from splenocytes of recipients was analyzed by flow cytometry. We found that CD4+IL-17A+ cells in the recipients of rejection group increased significantly as compared with those mice in negative control and control group (Figure 1D), which was in accordance with our previous report [10].This study was supported by grants from the National Natural Science Foundation of China (No. 81370581, 81470936) and the Natural Science Foundation of Hubei Province of China (No. 2015CFB573).
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