A novel stem cell transplantation for refractory leukemia using HLA-haploidentical grafts

异基因干细胞移植需要HLA相同的同胞。然而，只有大约25%的需要异基因干细胞移植（SCT）的患者有这样的供体。因此，HLA-半相合（2-3抗原错配）供体被认为是替代供体。在未经操作的HLA半相合SCT中，严重的移植物抗宿主病（GVHD）是一个主要问题。围移植期炎性细胞因子的产生是GVHD发生的关键因素。我们计划通过降低预处理强度（非清髓性）或使用含有类固醇的强化GVHD预防来抑制细胞因子的产生，从而克服严重的GVHD。在使用HLA半相合供体的非清髓性SCT中，我们报道了96.2%的植入率和20%的严重GVHD发生率（Biol Blood Marrow Tr，2006; 12：1073）。此外，在使用含类固醇的强化GVHD预防的HLA半相合清髓性SCT中，我们获得了 ...更多信息 移植率为100%，严重GVHD发生率为36.7%（Exp Hematol，2008：36：1）。为了阐明HLA半相合造血干细胞移植中移植物抗宿主病（GVHD）的病理生理机制，我们建立了小鼠MHC不相合骨髓移植系统（B6 C3 F1（H-2^<B/k>）→ BDF 1（H-2^<B/d>））。在该系统中，受体小鼠发生或不发生致命的GVHD取决于全身照射剂量。我们分析了供体T细胞在次级淋巴器官（包括脾和淋巴结）以及GVHD靶器官（包括小肠和大肠、肝脏和皮肤）中的动力学和特征。结果，发现GVHD小鼠在所涉及的器官中具有大量侵入性供体T细胞，尽管GVHD和非GVHD小鼠之间次级淋巴器官中T细胞增殖的程度没有差异。因此，发现GVHD的发生取决于GVHD靶器官的炎症程度。少

Allogeneic stem cell transplantation requires an HLA-identical sibling. However, only about 25% of patients who need allogeneic stem cell transplantation (SCT) have such a donor. Thus, an HLA-haploidentical (2-3 antigen-mismatched) donor has been considered as an alternative donor. In unmanipulated HLA-haploidentical SCT, severe graft-versus-host disease (GVHD) is a major problem. Production of inflammatory cytokine in the peritransplantation period is a key factor for developing GVHD. We have planned to overcome severe GVHD through suppressing the production of cytokines by reducing intensity of conditioning treatment (nonmyeloablative), or by a use of intensified GVHD prophylaxis containing steroids.In nonmyeloablative SCT using an HLA-haploidentical donor, we reported a 96.2% engraftment rate and 20% incidence of severe GVHD (Biol Blood Marrow Tr, 2006; 12: 1073). Furthermore, In HLA-haploidentical myeloablative SCT using intensified GVHD prophylaxis containing steroids, we obtained … More a 100% engraftment rate and a 36.7% incidence of severe GVHD (Exp Hematol, 2008: 36: 1). These results indicated that unmanipulated HLA-haploidentical SCT was feasible.In order to clarify the pathophysiology of engraftment or GVHD in HLA-haploidentical SCT, we developed murine MHC-mismatched bone marrow transplantation system (B6C3F1(H-2^<b/k>)→BDF1(H-2^<b/d>)). In this system, recipient mice did or did not develop fatal GVHD depending on total body irradiation dose. We analyzed the kinetics of, and the characteristics of, donor T cells in secondary lymphoid organs, including spleen and lymph nodes as well as in GVHD-target organs, including small and large intestines, liver and skin. As a result, GVHD mice were found to have massive invasive donor T cells in involved organs, although there was no difference in the extent of proliferation of T cells in secondary lymphoid organs between GVHD and non-GVHD mice. Thus, GVHD was found to occur depending on the extent of inflammation of GVHD-target organs. Less