Basic analysis for the novel immunotherapy against the gastrointestinal tumor

异基因骨髓移植(allo-BMT)与供者淋巴细胞输注(DLI)相结合已成为治疗恶性血液病的一种潜在的治疗方法。临床证据证实了其抗白血病作用，其治疗潜力不仅与大剂量放化疗有关，还与移植物抗白血病(GVL)作用有关。一段时间以来，移植物抗肿瘤(GVT)治疗实体瘤的可行性已经在一些临床研究中被怀疑，但其有效性和分子机制尚不清楚。在此，我们对建立的小鼠双亲F1模型进行了改进，用于实验性GVHD分析，以探讨GVT对实体瘤的作用。在皮下移植结肠癌模型中，异基因供体细胞输注联合辐射预适应可通过诱导肿瘤细胞凋亡而有效地抑制肿瘤形成，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，构成骨髓移植的严重并发症。移植物抗宿主病(GVHD)主要由供者来源的淋巴细胞活化引起，其中细胞因子级联反应起重要作用。由于p38MAPK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在小鼠肠道移植物抗宿主病严重程度中的作用。出乎意料的是，p38α^&lt；+/-&gt；供者移植物导致了更多与移植物抗宿主病相关的急性死亡和更严重的肠道损伤。综上所述，抑制p38Mark可能不是治疗GVHD的合适的抗炎策略，因为存在相关的肠道损伤。

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.