Renal cancer treatment with low levels of mixed chimerism induced by nonmyeloablative regimen using cyclophosphamide in mice
Renal cancer treatment with low levels of mixed chimerism induced by nonmyeloablative regimen using cyclophosphamide in mice
复制标题
DOI：
10.1158/0008-5472.can-05-0457
复制
发表时间：
2005-11-01
期刊：
影响因子：
11.2
通讯作者：
Naito, S
中科院分区：
文献类型：
--
作者：
Harano, M;Eto, M;Naito, S
近年来，非清髓性异基因造血干细胞移植治疗转移性肾癌备受关注。成熟供体T细胞引起移植物抗宿主病（GVHD），尽管它们也是与这种治疗相关的有益的移植物抗肿瘤活性的主要介质。因此，从GVHD中分离移植物抗肿瘤活性是管理临床治疗过程的重要挑战。我们曾报道了一系列关于异基因脾细胞（含骨髓细胞）和环磷酰胺诱导小鼠同种异体移植耐受的研究。在这里，我们展示了一种改良的环磷酰胺诱导的耐受系统，用于治疗小鼠肾细胞癌，RENCA，通过转移移植物抗宿主和宿主抗移植物反应之间的平衡，向移植物抗宿主反应与供体淋巴细胞输注。我们的研究结果清楚地表明，抗RENCA的抗肿瘤活性，只有低水平的混合嵌合体在外周和体内和体外获得性免疫RENCA，即使当混合嵌合体几乎检测不到。由于混合嵌合体的消除降低了GVHD的风险，因此在我们的模型中，抗肿瘤活性与初始GVHD依次分离。我们相信这是第一个独特的非清髓性异基因造血细胞移植治疗肾癌的模型系统。
Recently, much attention has been paid to nonmyeloablative allogeneic stem cell transplantation for the treatment of metastatic renal cancer. Mature donor T cells cause graft-versus-host disease (GVHD) although they are also the main mediators of the beneficial graft-versus-tumor activity associated with this treatment. Hence, the segregation of the graft-versus-tumor activity from GVHD is an important challenge in managing the clinical course of treatment. We previously reported a series of studies regarding the allograft tolerance induced by allogeneic spleen cells (with bone marrow cells) and cyclophosphamide in mice. Here, we show a modified cyclophosphamide-induced tolerance system for the treatment of murine renal cell carcinoma, RENCA, by shifting the equal balance between graft-versus-host and host-versus-graft reactions toward graft-versus-host reaction with donor lymphocyte infusion. Our results clearly show the antitumor activity against RENCA with only low levels of mixed chimerism in the periphery and the in vivo and in vitro acquired immunity against RENCA even when mixed chimerism is almost undetectable. Because the withdrawal of mixed chimerism reduces the risk of GVHD, the antitumor activity is thus sequentially segregated from the initial GVHD in our model. We believe that this is the first unique model system of nonmyeloablative allogeneic hemopoietic cell transplantation to ever be reported for the treatment of renal cancer.