异基因骨髓移植具有移植物抗白血病（GVL）效应，对治愈恶性血液病至关重要。GVL和移植并发症-移植物抗宿主病（GVHD）均与供者T细胞相关联；上调GVL效应并分离GVHD，是本领域的研究热点。申请人最早发现蛋白酶体抑制剂硼替佐米在分离GVL与GVHD中的独特价值与不足；也曾报道移植不表达γ-干扰素受体（IFNγR）、但能正常释放γ-干扰素（IFNγ）的供者T细胞，可有效减轻GVHD，同时保留GVL效应，证实了IFNγR信号通路是分离GVL与GVHD的一个关键靶点。SAHA是一种抑制组蛋白去乙酰化酶的新型分子靶向药物，其作用机制被认为与阻断IFNγR信号通路相关联。申请人假设SAHA与低剂量硼替佐米两药合用对分离GVL/GVHD有协同调控作用，拟继续以相关小鼠移植模型为平台，探究上述二药合用对GVL/GVHD的影响，揭示其分离GVL/GVHD的免疫机制，为优化骨髓移植治疗策略提供理论依据。

Allogeneic bone marrow transplantation (allo-BMT) can induce graft-versus-leukemia (GVL) responses, which are crucial for the cure of hematological malignancies. Graft-versus-host disease (GVHD) which is a major complication in BMT, and GVL are both closely related to donor graft T cells; and up-regulating GVL responses while separating GVHD is one of the research highlights in the field of BMT. The applicant first discovered the unique value and shortcomings of proteasome inhibitor bortezomib in separating GVL and GVHD, and demonstrated that transplantation of donor T cells that release interferon-gamma (IFNγ) but do not express interferon-gamma receptor (IFNγR) are able to effectively reduce the pathological damage of GVHD while preserving GVL responses, which confirmed that IFNγR signal pathway is a key target of separation of GVL and GVHD. Suberoylanilide hydroxamic acid (SAHA, vorinostat) is a novel kind of molecular-targeted drug that inhibits histone deacetylases, and studies indicated that its mechanism of action is correlated with the inhibition of IFNγR signal pathway. In this proposal we hypothesize that SAHA and low-dose bortezomib exert a synergistic effect on separating GVL and GVHD. We are going to continue the investigations on the platform of related mouse BMT models to study the synergistic effect of the combination of SAHA and bortezomib on GVL and GVHD, and reveal the immune mechanism of separating GVL and GVHD, so as to provide theoretical evidence for improvement of BMT treatment strategies.