Donor CD4 T Cells Are Critical in Allogeneic Stem Cell Transplantation against Murine Solid Tumor
Donor CD4 T Cells Are Critical in Allogeneic Stem Cell Transplantation against Murine Solid Tumor
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DOI：
10.1158/0008-5472.can-08-2517
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发表时间：
2009-06-15
期刊：
影响因子：
11.2
通讯作者：
Yoshikai, Yasunobu
中科院分区：
文献类型：
--
作者：
Kamiryo, Yoriyuki;Eto, Masatoshi;Yoshikai, Yasunobu
非清髓性异基因干细胞移植(SCT)已被用于各种恶性肿瘤，但具体的抗肿瘤作用机制尚不清楚。结果表明，非清髓性同种异体SCT方案对已建立的小鼠膀胱肿瘤MBT-2具有抗肿瘤作用，该方案由供体脾和骨髓细胞注射、环磷酰胺治疗和供体淋巴细胞输注(DLI)诱导的混合嵌合体组成。在DLI后不久，检测到供者CD4T细胞的扩张，伴随着短暂但强烈的干扰素-γ的产生。体内中和干扰素-γ或去除DLI中的CD4T细胞可消除其抗肿瘤作用，提示供者产生干扰素-γ的CD4T细胞起着不可或缺的作用。供者和宿主的CD8T细胞随着时间的推移在肿瘤区域聚集。重要的是，去除DLI中的CD8T细胞并不能逆转对肿瘤生长的抑制，这表明CD4T细胞在介导早期抗肿瘤作用中发挥了更重要的作用。此外，还提示宿主CD8T细胞对肿瘤的特异性反应。这些结果不仅为非清髓性同种异体SCT治疗膀胱癌提供了第一个证据，而且也阐明了DLI抗肿瘤作用的详细机制。[癌症资源2009；69(12)：5151-8]
Nonmyeloablative allogeneic stem cell transplantation (SCT) has been used for various malignancies, although detailed mechanisms of antitumor effects remain unclear. We showed that a nonmyeloablative allogeneic SCT regimen, which consists of mixed chimerism induced by an injection of donor spleen and bone marrow cells followed by cyclophosphamide treatment and a donor lymphocyte infusion (DLI), exerted antitumor effects on established murine bladder tumor, MBT-2. An expansion of donor CD4 T cells accompanied by transient but vigorous IFN-gamma production was detected shortly after DLI. In vivo neutralization of IFN-gamma or depletion of CD4 T cells from DLI abolished the antitumor effects, indicating an indispensable role of donor CD4 T cells producing IFN-gamma. Donor as well as host CD8 T cells accumulated in the tumor region with time. Importantly, depletion of CD8 T cells from DLI did not reverse the suppression of tumor growth, indicating that CD4 T cells play a more essential role in mediating early antitumor effects. Furthermore, tumor-specific response of host CD8 T cells was suggested. These results not only provide the first evidence of nonmyeloablative allogeneic SCT for the treatment of bladder tumor but also elucidate detailed mechanisms of antitumor effects provoked by DLI. [Cancer Res 2009;69(12):5151-8]