Induction of Indefinite Survival of Fully Mismatched Cardiac Allografts and Generation of Regulatory Cells by Sarpogrelate Hydrochloride

Department of Surgery, Keio University, Edo, Tōkyō, Japan
Transplantation (Impact Factor: 3.83). 10/2006; 82(8):1051-9. DOI: 10.1097/
Source: PubMed


At initiation of the immunologic response, platelets rapidly release chemical mediators such as serotonin (5-hydroxytryptamine, [5-HT]) and cytokines. Sarpogrelate hydrochloride (SH), a selective 5-HT2-receptor antagonist, is used to treat patients with peripheral arterial disease. We investigated the effect of SH on the alloimmune response in a murine cardiac transplantation model.
CBA mice underwent transplantation of a C57BL/10 heart and received a short course of SH treatment. Survival of the allograft was recorded. An adoptive transfer study was performed to determine whether regulatory cells were generated. Immunohistochemistry studies of intercellular adhesion molecule 1 (ICAM-1), histological, cell-proliferation, and cytokine assessments were performed.
Untreated CBA mice rejected C57BL/10 cardiac grafts acutely (median survival time [MST], 8 days). In mice given 10 mg/kg of SH, all allografts survived indefinitely (MST, >100 days); these mice also had significantly prolonged survival of donor-specific skin grafts but acute rejection of third-party skin grafts. Secondary CBA recipients given not only whole but also CD4 splenocytes from primary SH-treated CBA recipients with C57BL/10 cardiac allograft had indefinite survival of C57BL/10 hearts (MST, >100 days). SH inhibited upregulation of ICAM-1 on endothelial cells in the allografts. Graft acceptance and hyporesponsiveness were confirmed by the histological and cell-proliferation studies, respectively. Production of interleukin-4 and interleukin-10 from splenocytes of SH-treated transplant recipients increased compared to that from splenocytes of untreated recipients.
SH induced indefinite survival of fully allogeneic cardiac allografts, generated CD4 regulatory cells, inhibited ICAM-1 expression in the allografts, and upregulated IL-4 and IL-10 production.

5 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "However , the role of 5-HT 2A receptors in inflammatory processes is unclear, with only a very few published and inconsistent reports. Some studies report that blockade of 5-HT 2A receptor function with the selective antagonist sarpogrelate can decrease expression of proinflammatory markers (Marconi et al., 2003; Akiyoshi et al., 2006), whereas others indicate that sarpogrelate can increase expression of proinflammatory markers (Ito et al., 2000). Cloëz-Tayarani et al. (2003) have alleged that the 5-HT 2 receptor-specific agonist 1-(2,5-dime- thoxy-4-iodophenyl)-2-aminopropane (DOI) represses interleukin (IL)-1 expression and production of tumor necrosis factor-(TNF-) through 5-HT 2A receptor activation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The G protein-coupled serotonin 5-hydroxytryptamine (5-HT)(2A) receptor is primarily recognized for its role in brain neurotransmission, where it mediates a wide variety of functions, including certain aspects of cognition. However, there is significant expression of this receptor in peripheral tissues, where its importance is largely unknown. We have now discovered that activation of 5-HT(2A) receptors in primary aortic smooth muscle cells provides a previously unknown and extremely potent inhibition of tumor necrosis factor (TNF)-alpha-mediated inflammation. 5-HT(2A) receptor stimulation with the agonist (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(R)-DOI] rapidly inhibits a variety of TNF-alpha-mediated proinflammatory markers, including intracellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin (IL)-6 gene expression, nitric-oxide synthase activity, and nuclear translocation of nuclear factor kappaB, with IC(50) values of only 10 to 20 pM. It is significant that proinflammatory markers can also be inhibited by (R)-DOI hours after treatment with TNF-alpha. With the exception of a few natural toxins, no current drugs or small molecule therapeutics demonstrate a comparable potency for any physiological effect. TNF-alpha-mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, rheumatoid arthritis, psoriasis, type II diabetes, depression, schizophrenia, and Alzheimer's disease. Our results indicate that activation of 5-HT(2A) receptors represents a novel, and extraordinarily potent, potential therapeutic avenue for the treatment of disorders involving TNF-alpha-mediated inflammation. Note that because (R)-DOI can significantly inhibit the effects of TNF-alpha many hours after the administration of TNF-alpha, potential therapies could be aimed not only at preventing inflammation but also treating inflammatory injury that has already occurred or is ongoing.
    Full-text · Article · Sep 2008 · Journal of Pharmacology and Experimental Therapeutics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We researched simplified multi-layer neural networks to equip them in one-chip FPGA. We reexamined neuron functions, bits number of connection-weights, and learning methods; and proposed a "and/or"-neural network, which is derived from the disjunctive-normal-form in the binary logic; however it can be expanded to the multi-valued. We designed the network by using HDL
    Full-text · Conference Paper · Feb 2002
Show more