Induction of Indefinite Survival of Fully Mismatched Cardiac Allografts and Generation of Regulatory Cells by Sarpogrelate Hydrochloride
ABSTRACT 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.
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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 , selective cyclooxygenase 2 inhibitor , sarpogrelate hydrochloride , ranitidine , eicosapentaenoic acid , ursodeoxycholic acid , and danazol . Our recent studies have shown that oral administrations of commonly used Japanese Herbal Medicine, Sairei-to (TJ-114)  and Tokishakuyakusan (TJ-23)  could significantly prolong survivals of allogeneic cardiac grafts and generate regulatory cells in mice. "
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.Evidence-based Complementary and Alternative Medicine 07/2012; 2012:689810. DOI:10.1155/2012/689810 · 1.88 Impact Factor
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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 HDLNeural Networks, 2002. IJCNN '02. Proceedings of the 2002 International Joint Conference on; 02/2002
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ABSTRACT: The micromagnetic simulations for perpendicular recording media with incoherent magnetization rotation was performed by dividing a grain into subgrains in the direction of film thickness. When intra-grain exchange coupling was smaller, incoherent magnetization rotation occurred, leading to a stronger thermal fluctuation effect and lower coercive force H<sub>c</sub>. It was found that the critical thickness δ<sub>c</sub> exists, beyond which the incoherent magnetization rotation occurs. δ<sub>c</sub> is approximately proportional to 2.5<sup>*</sup>(A/K<sub>u</sub>)<sup>1</sup>2/, where A is the intra-grain exchange stiffness constant and K<sub>u</sub> is the uniaxial perpendicular anisotropy energy. In the incoherent magnetization rotation, the decreasing rate of H<sub>c</sub> by logarithmic time (in thermal viscosity slopes) was larger than that for coherent rotation. The calculations were in good agreement with the experimental coercive forces and thermal viscosity slopes.IEEE Transactions on Magnetics 10/2003; 39(5-39):2303 - 2305. DOI:10.1109/TMAG.2003.816279 · 1.21 Impact Factor