2004 Fiscal Year Final Research Report Summary
Basic analysis for the novel immunotherapy against the gastrointestinal tumor
| Project/Area Number |
15590622
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
SHIINA Shuichiro The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 助手 (70251238)
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| Co-Investigator(Kenkyū-buntansha) |
TATEISHI Keisuke The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手
KAWAKAMI Takayuki The University of Tokyo, Faculty of Medicine, Medical Staff, 医学部附属病院, 医員 (60376457)
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| Project Period (FY) |
2003 – 2004
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| Keywords | GVT / GVHD / Gastrointestinal tumor |
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| Research Abstract |
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.
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