High dose of antithrombin III induces indefinite survival of fully allogeneic cardiac grafts and generates regulatory cells

Department of Surgery, Keio University, Edo, Tōkyō, Japan
Transplantation (Impact Factor: 3.83). 01/2003; 75(2):217-20. DOI: 10.1097/01.TP.0000041781.94679.A1
Source: PubMed


The authors investigated whether antithrombin III (AT-III) could induce unresponsiveness to alloantigens.
CBA mice were given intravenous injection of 50 or 500 U/kg AT-III or control plasma the same day as transplantation of a heart from a C57BL/6 mouse. An adoptive transfer study and mixed leukocyte culture analysis were also performed.
Naive CBA mice rejected C57BL/6 cardiac grafts acutely (median survival time [MST], 9 days). The 50-U/kg dose of AT-III induced a moderate increase in graft survival (MST, 25 days), whereas control mice rejected their graft acutely (MST, 7 days). With the 500-U/kg dose of AT-III, all grafts survived indefinitely (>100 days) and regulatory cells were generated. In vitro, AT-III suppressed proliferation of mixed leukocyte responses and generation of interleukin-2.
AT-III can be not only an antithrombotic agent but also a strong immunomodulating agent when used at high dose.

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    • "Since Japanese government health officials officially recognized the therapeutic effects of Japanese herbal medicines about 30 years ago, these agents have been widely used as alternative therapy for several diseases. We previously demonstrated the efficacy of several commonly employed agents in inducing donor-specific regulatory cells and prolonging allograft survival in mice [15-21]. Li and Weir [22] showed that Radix Tripterygium wilfordii, a Chinese herbal medicine, has immunosuppressive effects in human blood mononuclear cells in vitro. "
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    ABSTRACT: Background Herbal medicines have unique odors, and the act of smelling may have modulatory effects on the immune system. We investigated the effect of olfactory exposure to Tokishakuyaku-san (TJ-23), a Japanese herbal medicine, on alloimmune responses in a murine model of cardiac allograft transplantation. Methods Naïve or olfactory-dysfunctional CBA mice underwent transplantation of a C57BL/6 heart and were exposed to the odor of TJ-23 until rejection. Some naïve CBA recipients of an allograft were given olfactory exposure to Sairei-to (TJ-114), trimethylthiazoline (TMT), individual components of TJ-23, or a TJ-23 preparation lacking one component. Adoptive transfer studies were performed to determine whether regulatory cells were generated. Results Untreated CBA mice rejected their C57BL/6 allografts acutely, as did olfactory-dysfunctional CBA mice exposed to the odor of TJ-23. CBA recipients of a C57BL/6 heart given olfactory exposure to TJ-23 had significantly prolonged allograft survival, whereas those exposed to the odor of TJ-114, TMT, one component of TJ-23, or TJ-23 lacking a component did not. Secondary allograft recipients that were given, at 30 days after transplantation, either whole splenocytes, CD4+ cells, or CD4+CD25+ cells from primary recipients exposed to the odor of TJ-23 had indefinitely prolonged allograft survival. Conclusions Prolonged survival of cardiac allografts and generation of regulatory cells was associated with exposure to the odor of TJ-23 in our model. The olfactory area of the brain may have a role in the modulation of immune responses.
    Full-text · Article · May 2014 · Journal of Cardiothoracic Surgery
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    • "Therefore, identification of agents that promote induction and maintenance of regulatory cells may have implications for the development of new tolerogenic strategies in trans- plantation. In a murine model, we previously demonstrated the efficacy of the following commonly used agents in inducing donor-specific regulatory cells and prolonging allograft survival: antithrombin III [10], selective cyclooxygenase 2 inhibitor [11], sarpogrelate hydrochloride [12], ranitidine [13], eicosapentaenoic acid [14], ursodeoxycholic acid [15], and danazol [16]. Our recent studies have shown that oral administrations of commonly used Japanese Herbal Medicine, Sairei-to (TJ-114) [17] and Tokishakuyakusan (TJ-23) [18] could significantly prolong survivals of allogeneic cardiac grafts and generate regulatory cells in mice. "
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    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.
    Full-text · Article · Jul 2012 · Evidence-based Complementary and Alternative Medicine
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