<b>A Japanese Herbal Medicine, Shigyakusan, Induces Prolonged Survival of Fully MHC-Mismatched Murine Cardiac A</b><b>llografts</b> / 日本東洋医学雑誌

<p><b>Background </b>: Shigyakusan, a 4-component Japanese herbal medicine (Paeoniae radix, Aurantii fructus immaturus, Glycyrrhizae radix and Bupleuri radix), is used not only for cholecystitis and gastritis as an antiinflammatory agent, but also for anxiety neurosis and insomnia as an anti-anxiety agent.<br><b>Methods </b>: We investigated the effects of shigyakusan on alloimmune responses in fully MHC-mismatched murine cardiac allograft transplantation. CBA mice underwent transplantation of a C57BL/6 heart and received shigyakusan or one component of shigyakusan administered orally from the day of transplantation until 7 days afterward. Histologic studies, cytokine measurements, and flow cytometry assessments were performed.<br><b>Results </b>: Untreated CBA recipients acutely rejected C57BL/6 cardiac grafts (median survival times [MST], 7 days). On the other hand, CBA transplant recipients given shigyakusan had significantly prolonged C57BL/6 allograft survival (MST, 22.5 days). MSTs for C57BL/6 transplant recipients given Paeoniae radix, Aurantii fructus immaturus, Glycyrrhizae radix and Bupleuri radix were 11, 9.5, 18.5 and 8 days, respectively. Additionally, flow cytometry studies showed that the percentage of CD25+Foxp3+ cell populations in CD4+ cells was increased in transplant recipients given shigyakusan.<br><b>Conclusion </b>: Shigyakusan induced hyporesponsiveness to fully MHC-mismatched allogeneic cardiac allografts and may generate CD4+CD25+Foxp3+ cells in our model.</p>

Tokishakuyakusan Induces Prolonged Survival of Fully Mismatched Cardiac Allografts and Generates Regulatory Cells in Mice / 日本東洋医学雑誌

Tokishakuyakusan is a Japanese herbal medicine which is extracts from six herbal materials. The author investigated the effects of oral administration of Tokishakuyakusan in a murine model of cardiac transplantation with fully mismatched allografts. CBA mice (H 2k) underwent transplantation of C 57 BL/6 (H 2b) hearts and received oral administration of Tokishakuyakusan from day 0 to day 7 after grafting. Untreated CBA mice rejected C 57 BL/6 cardiac grafts acutely (median survival time [MST], 7 days). Mice given 2 g/kg/day of Tokishakuyakusan accepted their grafts (MST, 60 days). However, each herbal material alone and 0.2, 0.02 g/kg/day of Tokishakuyakusan did not prolong the allografts survival. Splenocytes from Tokishakuyakusan-treated recipients showed alloproliferative hyporesponsiveness and down-regulation of IFN-γ in mixed leukocyte culture with C 57 BL/6 stimulators. Secondary CBA recipients (naive) given whole splenocytes from primary Tokishakuyakusan-treated CBA recipients with C 57 BL/6 cardiac allografts 30 days after grafting had prolonged survival of C 57 BL/6 hearts (MST, 100 days) compared to that in the secondary recipients with adoptive transfer of naive splenocytes (MST, 12 days). In flow cytometry experiment, the population of CD 4+CD 25+cells, CD 4+FOXP 3+cells and CD 25+FOXP 3+cells were increased in the spleens of Tokishakuyaku-san-treated CBA recipients. Treatment with Tokishakuyakusan induced unresponsiveness to fully allogeneic cardiac allograft and generated regulatory cells. Traditional knowledge of Japanese herbal medicine may contribute to immunomodulation after modern transplantation surgery.

Saireito Induced Prolonged Survival of Fully Mismatched Cardiac Allografts in Mice / 日本東洋医学雑誌

Saireito, a 12-component Japanese herbal medicine, is used to treat immune-related diseases. We investigated the effects of oral administration of Saireito extract in a murine model of cardiac transplantation with fully mismatched allografts. Untreated recipients and those given water rejected their cardiac allografts acutely (median survival time [MST], 7 and 8 days, respectively), as did those treated with either 0.02 or 0.002 g/kg/day of Saireito extract (MST, 7 days in both groups). Recipients given 0.2 g/kg/day of Saireito extract had only moderate prolongation of allograft survival (MST, 41 days). However, all transplant recipients given 2 g/kg/day of Saireito extract had significant prolongation of allograft survival (MST>100 days). None of the single crude drug extracts of Saireito prolonged allograft survival, suggesting that its effects require administration of the combination agent. In mixed leukocyte cultures, proliferation of splenocytes from Saireito-treated CBA recipients was markedly suppressed compared with that of splenocytes from untreated mice, and interferon-γ production was significantly reduced. In flow cytometry experiment, the population of CD 4+CD 25+FOXP 3+cells was increased in the spleens of Saireito-treated CBA recipients compared with the spleens of naïve CBA mice or untreated CBA recipients. Thus, in our model, Saireito treatment induced hyporesponsiveness to cardiac allografts in a dose-dependent manner, and the combination of the components is essential for this effect.