Intervention of MAdCAM-1 or fractalkine alleviates graft-versus-host reaction associated intestinal injury while preserving graft-versus-tumor effects
Intervention of MAdCAM-1 or fractalkine alleviates graft-versus-host reaction associated intestinal injury while preserving graft-versus-tumor effects
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DOI：
10.1189/jlb.0306231
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发表时间：
2007-01-01
影响因子：
5.5
通讯作者：
Matsushima, Kouji
中科院分区：
文献类型：
--
作者：
Ueha, Satoshi;Murai, Masako;Matsushima, Kouji
有益的移植物抗肿瘤(GVT)效应和有害的移植物抗宿主病(GVHD)的一致性仍然是同种异体骨髓移植(BMT)作为肿瘤免疫治疗广泛使用的主要障碍。在此，我们证明了在异基因反应供者CD8 T细胞扩增后给予MAdCAM-1(粘膜血管地址因子细胞黏附分子-1)或Fractalkine/CX(3)CL1的干预，选择性地抑制效应供者CD8 T细胞向肠道的募集，减轻移植物抗宿主反应(GVHR)相关的肠道损伤，而不削弱GVT的作用。在非照射的急性GVHD模型中，供者CD8 T细胞上调肠道归巢受体α4β7和趋化因子受体CXCR6和CX(3)CR1的表达，因为它们分化为效应细胞，随后渗透到肠道。应用抗MAdCAM-1抗体或抗Fractalkine抗体，即使在同种异体反应供体CD8 T细胞扩增后，也能选择性地减少肠道浸润性供体CD8 T细胞和肠腺细胞的凋亡，而不影响供体来源的抗宿主CTL的诱导或供体CD8 T细胞在肝肿瘤中的浸润。此外，在临床相关的清髓调节的GVHD模型中，这些抗体显著改善了存活率和体重减轻，而不损害有益的GVT效应。因此，在GVHD晚期阻断α4-β7-MAD-CAM-1或CX(3)CR1-Fractalkine的相互作用将是将GVT效应与GVHR相关性肠损伤分离的一种新的治疗方法。
Coincidence of the beneficial graft-vs.tumor (GVT) effects and the detrimental graft-vs.-host disease (GVHD) remains the major obstacle against the widespread use of allogeneic hone marrow transplantation (BMT) as tumor immunotherapy. We here demonstrate that intervention of MAdCAM-1 (mucosal vascular addressin cell adhesion molecule-1) or fractalkine/CX(3)CL1 after the expansion of allo-reactive donor CD8 T cells selectively inhibits the recruitment of effector donor CD8 T cells to the intestine and alleviates the graft vs.-host reaction (GVHR) associated intestinal injury without impairing GVT effects. In a nonirradiated acute GVHD model, donor CD8 T cells up-regulate the expression of intestinal homing receptor alpha 4 beta 7 and chemokine receptors CXCR6 and CX(3)CR1, as they differentiate into effector cells and subsequently infiltrate into the intestine. Administration of anti-MAdCAM-1 antibody or anti-fractalkine antibody, even after the expansion of alloreactive donor CD8 T cells, selectively reduced the intestine-infiltrating donor CD8 T cells and the intestinal crypt cell apoptosis without affecting the induction of donor derived anti-host CTL or the infiltration of donor CD8 T cells in the hepatic tumor. Moreover, in a clinically relevant GVHD model with myeloablative conditioning, these antibodies significantly improved the survival and loss of weight without impairing the beneficial GVT effects. Thus, interruption of alpha 4 beta 7-MAd-CAM-1 or CX(3)CR1-fractalkine interactions in the late phase of GVHD would be a novel therapeutic approach for the separation of GVT effects from GVHR-associated intestinal injury.