Inhibiting NFAT5 With KRN2 Mitigates Acute Allograft Rejection in a Murine Heart Transplantation Model

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.