Article

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: 10.1097/01.tp.0000233870.54297.9a
Source: PubMed

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 [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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    • "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. "
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