Induction of Regulatory T Cells and Prolongation of Fully Allogeneic Cardiac Grafts by Herbal Medicine, Shohangekabukuryo-to

Abstract

Objective: Shohangekabukuryo-to (Tsumura Japan [TJ]-21) is well known as an herbal medicine with few side effects to treat vomiting, nausea, acute and chronic gastritis, and hyperemesis of pregnancy in Japan. In this study, we performed fully allogeneic cardiac grafts in mice to investigate the effect of TJ-21 on alloimmune responses.Methods: CBA (H2 k ) mice underwent transplantation of a C57BL/6 (H2 b ) heart and received oral administration of 0.02, 0.2 and 2 g/kg per day of TJ-21 from the day of operation until 7 days afterward. Adoptive transfer study was performed to determine whether regulatory cells were generated. Histologic and cell proliferation studies, flow cytometry analyses and cytokine measurements were also performed.Results: Compared to untreated CBA mice rejected C57BL/6 hearts acutely (median survival time [MST], 8 days), MST of allografts from TJ-21-treated mice was prolonged (MST, 77 days). Moreover, adoptive transfer of whole splenocytes from TJ-21-treated allograft CBA recipients had prolongation of allograft survival in secondary recipients (MST, 53 days). Flow cytometry study showed TJ-21-treated mice had an increased CD4 + CD25 + Foxp3 + cell population. Cell proliferation showed that interleukin-2 (IL-2) and interferon-γ were inhibited in TJ-21-treated mice, whereas IL-4 and IL-10 were increased. Conclusions:In summary, TJ-21 could induce hyporesponsiveness of fully MHC-mismatched cardiac allografts and generate regulatory cells.