Abstract
We investigated Inchingorei-san (TJ-117), a 6-component Japanese herbal medicine, on alloimmune responses in murine cardiac allograft transplantation. CBA mice underwent transplantation of a C57BL/6 (B6) heart and received oral administration of TJ-117 or each component of TJ-117 from the day of transplantation until 7 days afterward. Naive CBA mice rejected B6 cardiac grafts acutely (median survival time (MST), 7 days). CBA recipients given 1 g/kg/day of TJ-117 had prolonged B6 allograft survival (MST, 37 days). Moreover, given 1 g/kg/day of Artemisiae Capillaris Herba (ACH), one component of TJ-117, indefinitely prolonged B6 allograft survival (MST, >100 days). However, other five components of TJ-117 were less effective than TJ-117 and ACH. Secondary CBA recipients given whole splenocytes, CD4+, and CD4+CD25+ cells from primary ACH-treated CBA recipients with B6 cardiac allografts 30 days after grafting had prolonged survival of B6 hearts (MSTs, 57, >100, and >100 days, resp.). Flow cytometry studies showed that the CD4+CD25+Foxp3+ regulatory cell population was increased in transplant recipients given ACH. Cell proliferation, interleukin-2, and interferon-γ were suppressed in ACH-treated mice, whereas interleukin-4 and interleukin-10 were upregulated. In conclusion, ACH, one component of TJ-117, as well as TJ-117 induced hyporesponsiveness to fully allogeneic cardiac allografts and may generate CD4+CD25+Foxp3+ regulatory cells.
Highlights
Transplantation is the ultimate treatment for patients with total loss of function of a life-sustaining organ
Extensive studies have demonstrated that mutation of forkhead box P3 (Foxp3) or downregulation of Foxp3 expression in T regulatory (Treg) cells leads to reduction of Treg cell numbers and loss of Treg suppressive activity and induces immune dysregulation [7,8,9], strongly suggesting that Foxp3 plays a dominant role in the development and function of Treg cells
Survival of Cardiac Allografts in Mice Treated with TJ-117 and Each Component
Summary
Transplantation is the ultimate treatment for patients with total loss of function of a life-sustaining organ. The mechanisms of peripheral tolerance include anergy, deletion, ignorance and active immune suppression [3]. Among the mechanisms of peripheral tolerance, active suppression by regulatory T cells is likely to have a crucial role in maintaining tolerance to transplants because other mechanisms may not suppress newly generated alloreactive lymphocytes [3]. Extensive studies have demonstrated that mutation of Foxp or downregulation of Foxp expression in Treg cells leads to reduction of Treg cell numbers and loss of Treg suppressive activity and induces immune dysregulation [7,8,9], strongly suggesting that Foxp plays a dominant role in the development and function of Treg cells. Once donorspecific regulatory cells have been induced and survived in the recipient of a graft, it may be possible to modify the life-long use of nonspecific immunosuppressive agents. Identification of agents that promote induction and maintenance of regulatory cells may have implications for the development of new tolerogenic strategies in transplantation
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