Basic analysis for the novel immunotherapy against the gastrointestinal tumor

异基因骨髓移植（allo-BMT）和供者淋巴细胞输注（DLI）的联合应用已成为治疗血液系统恶性肿瘤的潜在方法。抗白血病作用已得到临床证据的证实，大部分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）效应有关。移植物抗肿瘤（GVT）效应的可行性已在一些临床研究中得到证实，但其有效性和分子机制尚不清楚。在这里，我们修改了建立用于实验GVHD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，同种异体供者细胞输注联合辐射预处理可诱导肿瘤细胞凋亡，抑制肿瘤形成，TRAIL依赖的细胞毒系统与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，这构成了骨髓移植的危及生命的并发症。GVHD主要由供者来源的淋巴细胞活化引起，其中细胞因子级联起重要作用。由于p38 MAPK已被确定为细胞因子反应的调节剂，并提出作为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^<+/->供体移植物诱导了更多的急性GVHD相关死亡率和更严重的肠道损伤。总之，由于相关的肠道损伤，抑制p38 MARK可能不是GVHD的合适抗炎策略。

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.