A metalloproteinase inhibitor prevents acute graft-versus-host disease while preserving graft-versus-leukemia effect of allogeneic bone marrow transplantation

金属蛋白酶抑制剂可预防急性移植物抗宿主病，同时保留同种异体骨髓移植的移植物抗白血病作用

• 批准号: 11670457
• 负责人: MIYAJIMA Hiroaki
• 金额: $ 2.24万
• 依托单位: JUNTENDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670457/
• 关键词: GVHD; TNF-α; Fas; FasL; MPI; HVGD; IL-4; メタロプロテナーゼインヒビター

We here examined the effect. of a hydroxamic acid-based matrix metalloproteinase inhibitor (KB-R7785), which we previously demonstrated a potent ameliorating effect on acute graft-versus-host disease (GVHD), on graft-versus-leukemia (GVL) effect of allogeneic bone marrow transplantation (BMT), KB-R7785 was administrated into (C57BL/6 x BALB/c) Fl (CBF1) mice, that had been inoculated with IgE-producing B53 hybridoma cells of BALB/c origin as a model tumor, along with or without transplantation of C57BL/6 (B6) bone marrow cells and spleen cells (BMS). Administration of KB-R7785 without BMS significantly prolonged the survival of B53-inoculated CBF1 mice by inhibiting the infiltration of B53 cells into the liver and spleen. Transplantation o fB6 BMS without KB-R7785 resulted in the death of most recipients due to acute GVHD while efficiently eliminating B53 cells. Administration of KB-R7785 along with B6 BMS resulted in 50% survival of B53-inoculated CBF1 mice over 50 days without histological manifestations of acute GVHD or residual B53 cells. These results indicate beneficial effects of KB-R7785 that inhibit tumor infiltration and prevent acute GVHD while preserving the GVL effect of allogeneic BMT.

我们在这里检查了效果。异羟肟酸基质金属蛋白酶抑制剂为了研究KB-R7785对同种异体骨髓移植（BMT）的移植物抗白血病（GVL）效应的有效改善作用，将KB-R7785施用到（C57 BL/6 x BALB/c）F1（CBF 1）小鼠，其已接种BALB/c来源的IgE产生性B53杂交瘤细胞作为模型肿瘤，沿着移植或不移植C57 BL/6（B6）骨髓细胞和脾细胞（BMS）。不含BMS的KB-R7785给药通过抑制B53细胞浸润到肝脏和脾脏中而显著延长了B53接种的CBF 1小鼠的存活。无KB-R7785的fB 6 BMS的移植导致大多数受体由于急性GVHD而死亡，同时有效地消除了B53细胞。沿着给予KB-R7785和B6 BMS导致接种B53的CBF 1小鼠在50天内存活50%，没有急性GVHD或残留B53细胞的组织学表现。这些结果表明KB-R7785抑制肿瘤浸润和预防急性GVHD同时保持同种异体BMT的GVL效应的有益作用。

项目成果

Sakurai, J: "Blockade of CTLA-4 signals inhibits Th2-mediated murine chronic graft-versus-host disease by an enhanced expansion of regulatory"J.Immunol. 164 : 2. 664-669 (2000)

Sakurai, J：“阻断 CTLA-4 信号可通过增强调节性扩展来抑制 Th2 介导的小鼠慢性移植物抗宿主病”J.Immunol。

Nozawa, K.: "Preferential blocade of CD8+T cell responses by administration of anti-CD137 ligand moclonal antibody result in differential effect on development of murine acute and chronic graft-versus-host disease"J.Immunol. 167.9. 4981-4986 (2001)

Nozawa, K.：“通过施用抗 CD137 配体单克隆抗体优先产生 CD8 T 细胞反应，对小鼠急性和慢性移植物抗宿主病的发展产生不同的影响”J.Immunol。

Sakurai, J.Ohata, J.Saito, K.Miyajima, H.Hirano, T.Kohsaka, T.Enomoto, S.Okumura, K.and Azuma, M.: "Blockade of CTLA-4 signals inhibits Th2-mediated murine chronic graft- versus-host disease by an enhanced expansion of regulatory CD8+ T cells."J. lmmunol.

Sakurai, J.Ohata, J.Saito, K.Miyajima, H.Hirano, T.Kohsaka, T.Enomoto, S.Okumura, K. and Azuma, M.：“阻断 CTLA-4 信号可抑制 Th2 介导的小鼠

Nozawa, K.Ohata, J Sakurai, J.Hashimoto, H.Miyajima, H.Yagita, H.Okumura, K.and Azuma, M.: "Preferential blockade of CD8(+) T cell responses by administration of anti-CD137 ligand monoclonal antibody results in differntial effect on development of murine

Nozawa, K.Ohata, J Sakurai, J.Hashimoto, H.Miyajima, H.Yagita, H.Okumura, K. 和 Azuma, M.：“通过施用抗 CD137 配体优先阻断 CD8( ) T 细胞反应

Sakurai, J: "Blockade of CTLA-4 signals inhibits Th2-mediated murine chronic graft-versus-host disease by an enhanced expansion of regulatory"J.Immunol. 164:2. 664-669 (2000)

Sakurai, J：“阻断 CTLA-4 信号可通过增强调节性扩展来抑制 Th2 介导的小鼠慢性移植物抗宿主病”J.Immunol。