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Basic analysis for the novel immunotherapy against the gastrointestinal tumor

胃肠道肿瘤新型免疫疗法的基础分析

基本信息

批准号：
15590622
负责人：
SHIINA Shuichiro
金额：
$ 1.92万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

The combination of allogeneic bone marrow transplantation (allo-BMT) and donor lymphocyte infusion (DLI) has been potentially a curative therapy for patients with hematological malignancies. The anti-leukemic effect is substantiated by clinical evidence and much of the therapeutic potential relates to not only the high dose of chemoradiation but also the graft-versus-leukemia (GVL) effect. In a while, the feasibility of graft-versus-tumor (GVT) effect against solid cancers has been already suspected in some clinical studies, but the efficiency and molecular mechanisms remain unclear. Here we modified the mouse two-parent F1 model established for experimental GVHD analysis to investigate the GVT effect against solid tumor. In the subcutaneously transplanted colon cancer models, allogenic donor cell infusion combined with preconditioning by irradiation was effective for inhibiting tumor formation by inducing apoptosis of tumor cells, and TRAIL dependent cytotoxic system contributed to the anti-tumor effect cooperatively with FasL system.The gastrointestinal tract is a major target of graft-versus-host disease (GVHD), which constitutes a life-threatening complication of bone marrow transplantation. GVHD is mainly caused by the activation of donor-derived lymphocytes, in which cytokine cascades play essential roles. Since p38 MAPK has been identified as a regulator of cytokine reactions and proposed as a molecular target for anti-inflammatory therapy, we investigated the contribution of p38 to the severity of murine intestinal GVHD. Unexpectedly, p38α^<+/-> donor graft induced more acute GVHD-related mortality and more severe gut injury. In conclusion, the inhibition of p38 MARK may not be a suitable anti-inflammatory strategy for GVHD due to the associated intestinal injury.

同种异体骨髓移植（alloo - bmt）和供体淋巴细胞输注（DLI）的联合治疗已成为治疗恶性血液病患者的潜在疗法。临床证据证实了其抗白血病作用，其治疗潜力不仅与高剂量放化疗有关，还与移植物抗白血病（GVL）作用有关。一段时间以来，一些临床研究已经怀疑移植物抗肿瘤（GVT）治疗实体癌的可行性，但其有效性和分子机制尚不清楚。我们改良了用于GVHD实验分析的小鼠双亲F1模型，以研究GVT对实体瘤的作用。在结肠癌皮下移植模型中，同种异体供体细胞输注联合辐照预处理可通过诱导肿瘤细胞凋亡抑制肿瘤形成，TRAIL依赖性细胞毒系统与FasL系统协同发挥抗肿瘤作用。胃肠道是移植物抗宿主病（GVHD）的主要靶点，GVHD是骨髓移植中一种危及生命的并发症。GVHD主要由供体源性淋巴细胞激活引起，其中细胞因子级联反应起重要作用。由于p38 MAPK已被确定为细胞因子反应的调节因子，并被认为是抗炎治疗的分子靶点，我们研究了p38对小鼠肠道GVHD严重程度的贡献。出乎意料的是，p38α^<+/->供体移植引起了更严重的急性gvhd相关死亡率和更严重的肠道损伤。综上所述，由于GVHD相关的肠道损伤，抑制p38 MARK可能不是一种合适的抗炎策略。