Department of Complementary and Alternative Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Transpl Immunol. 2012 Mar;26(2-3):163-70. doi: 10.1016/j.trim.2011.12.005. Epub 2011 Dec 14.
In small bowel transplantation (SBTx), inhibition of both graft-versus-host disease (GVHD) and allograft rejection is necessary.
We investigated the potency of a new sphingosine-1-phosphate receptor agonist, W-061, for these two immune responses in SBTx. W-061 has a completely different molecular structure from FTY720. Heterotopic SBTx was performed from Wistar-Furth (WF) into (WF×ACI) F1 rats as a GVHD model or F1 to WF rats as a rejection model. Recipients were orally given 3 mg/kg/day W-061 for 14 days after SBTx. Recipient survival, body weight, histopathology, lymphocyte subpopulations, and the cytokine profile were evaluated.
W-061 treatment significantly prolonged graft survival over 100 days in four out of six recipients in the GVHD group and over 60 days in three out of six recipients in the rejection group. W-061 strongly inhibited GVHD and rejection as seen histopathologically in comparison with untreated control rats. W-061 caused a significant reduction in donor-derived T cells in target organs and infiltrating T cells in allografts by promoting these cells to home into the secondary lymphoid tissues and sequestrating those cells there. W-061 significantly decreased production of interferon-γ in target organs and allografts.
Therefore, these data suggest that W-061 has considerable potential as a new therapeutic immunosuppressant in patients with SBTx.
在小肠移植（SBTx）中，需要抑制移植物抗宿主病（GVHD）和同种异体排斥反应。
我们研究了新型鞘氨醇-1-磷酸受体激动剂 W-061 对 SBTx 中这两种免疫反应的作用。W-061 与 FTY720 具有完全不同的分子结构。将 Wistar-Furth（WF）到（WF×ACI）F1 大鼠的异位 SBTx 作为 GVHD 模型，或 F1 到 WF 大鼠的 SBTx 作为排斥反应模型。在 SBTx 后，受体每天口服给予 3mg/kg 的 W-061，持续 14 天。评估受体存活率、体重、组织病理学、淋巴细胞亚群和细胞因子谱。
在 GVHD 组的六只受体中有四只，在排斥组的六只受体中有三只，W-061 治疗显著延长了移植物的存活时间，超过 100 天和 60 天。与未治疗的对照大鼠相比，W-061 在组织病理学上强烈抑制了 GVHD 和排斥反应。W-061 通过促进这些细胞归巢到次级淋巴组织并将这些细胞隔离在那里，导致靶器官和同种异体移植物中的供体衍生 T 细胞和浸润 T 细胞显著减少。W-061 显著降低了靶器官和同种异体移植物中干扰素-γ的产生。
因此，这些数据表明，W-061 作为 SBTx 患者的新型治疗性免疫抑制剂具有相当大的潜力。
