Basic analysis for the novel immunotherapy against the gastrointestinal tumor

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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.