Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cardiovascular Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China; and.
J Cardiovasc Pharmacol. 2023 Mar 1;81(3):212-220. doi: 10.1097/FJC.0000000000001392.
Despite advancements in immunosuppressive therapy, acute allograft rejection remains an important challenge for heart transplantation patients. Nuclear factor of activated T-cells 5 (NFAT5), a member of the family of Rel homology domain-containing factors that plays an important role in regulating immune responses of T lymphocytes, may be closely associated with cardiac rejection. KRN2, as a specific inhibitor of NFAT5, is injected intraperitoneally daily starting from day 0 after murine heart transplantation. When compared with saline treatment, KRN2 treatment can improve allograft survival. Histologic examination revealed that the KRN2 treatment group experienced less-severe rejection, and enzyme-linked immunosorbent assay revealed lower levels of inflammatory cytokines in circulating serum. The proportion and number of T-cell subpopulations in the spleens were analyzed by flow cytometry. We found that KRN2 treatment reduced the proportions of CD4 + IFN-γ + , CD4 + IL-17A + , and CD4 + IL-4 + Th cells, whereas increasing CD4 + Foxp3 + Treg cells compared with the control group. These findings suggest that KRN2 attenuates acute allograft rejection by regulating CD4 + T lymphocyte responses. NFAT5 could be a promising therapeutic target for preventing acute allograft rejection.
尽管免疫抑制治疗取得了进展，但急性同种异体移植排斥仍然是心脏移植患者面临的重要挑战。活化 T 细胞核因子 5（NFAT5）是 Rel 同源结构域包含因子家族的成员，在调节 T 淋巴细胞的免疫反应中起着重要作用，可能与心脏排斥密切相关。KRN2 是 NFAT5 的特异性抑制剂，从鼠心脏移植后第 0 天开始每天经腹腔注射。与生理盐水治疗相比，KRN2 治疗可提高移植物存活率。组织学检查显示，KRN2 治疗组的排斥反应较轻，循环血清中的炎症细胞因子水平较低。通过流式细胞术分析脾脏中 T 细胞亚群的比例和数量。我们发现，与对照组相比，KRN2 治疗降低了 CD4 + IFN-γ + 、CD4 + IL-17A + 和 CD4 + IL-4 + Th 细胞的比例，而增加了 CD4 + Foxp3 + Treg 细胞。这些发现表明，KRN2 通过调节 CD4 + T 淋巴细胞反应来减轻急性同种异体移植排斥。NFAT5 可能是预防急性同种异体移植排斥的有前途的治疗靶点。
