Saireito (Tsumura Japan [TJ]-114) could induce long-term cardiac allograft survival through the generation of CD4+CD25+Foxp3+ cells (regulatory T cells, Tregs). However, little is known regarding the effects of TJ-114 on the suppression of donor-specific antibody (DSA). Therefore, we aimed to further investigate the suppressive properties of TJ-114 and its effects on DSA production in a murine cardiac allograft model. CBA mice underwent transplantation of C57BL/6 hearts and were subsequently administered TJ-114 (2g/kg/d) from the day of transplantation until 7 days afterward. TJ-114-treated recipients demonstrated upregulation of splenic Tregs and suppressed DSA production at postoperative day 10 relative to untreated controls. This effect was sustained at postoperative day 20 even when TJ-114 administration was stopped at day 7. To then investigate the involvement of Tregs in the suppression of DSA production, anti-interleukin-2 receptor alpha antibody (PC-61) was administered to deplete Treg populations in TJ-114-treated CBA recipients on postoperative days 0, 3, 6, and 9 or 20, 23, and 26. At day 10, CBA recipients that received PC-61 with TJ-114 demonstrated suppression of DSA production similar to those receiving only TJ-114. Nonetheless, when mice were treated with PC-61 at days 20, 23, and 26, DSA levels gradually increased to levels comparable to those of untreated mice by day 29, suggesting that Tregs are necessary to sustain the suppression of DSA once the effects of TJ-114 have subsided. Taken together, TJ-114 may be a promising therapeutic strategy to prolong allograft survival through its combined immunosuppressive effects in inducing Tregs and suppressing DSA production.
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