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

使用 HLA-半相合移植物进行新型干细胞移植治疗难治性白血病

基本信息

批准号：
18591090
负责人：
OGAWA Hiroyasu
金额：
$ 2.57万
依托单位：
Hyogo College of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591090/
关键词：
transplantation graft-versus-host disease

项目摘要

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

同种异体干细胞移植需要 HLA 相同的同胞，然而，只有大约 25% 需要异体干细胞移植 (SCT) 的患者拥有这样的供体，因此，HLA 单倍体（2-3 抗原不匹配）供体已成为可能。在未操作的 HLA 单倍体 SCT 中，严重的移植物抗宿主病 (GVHD) 是产生炎症细胞因子的主要问题。围移植期是发生 GVHD 的关键因素。我们计划通过降低调理治疗（非清髓性）强度或使用含有类固醇的强化 GVHD 预防来抑制细胞因子的产生。在使用 HLA 的非清髓性 SCT 中。 -半相合供体，我们报道了 96.2% 的植入率和 20% 的严重 GVHD 发生率（Biol 骨髓Tr，2006；12：1073）此外，在使用含有类固醇的强化 GVHD 预防的 HLA 半相合清髓性 SCT 中，我们获得了 100% 的植入率和 36.7% 的严重 GVHD 发生率（Exp Hematol，2008：36：1）。）这些表明未操作的 HLA-单倍体的结果。 SCT是可行的。为了阐明HLA半相合SCT移植或GVHD的病理生理学，我们开发了小鼠MHC错配骨髓移植系统（B6C3F1（H-2^<b/k>）→BDF1（H-2^） <b/d>))。在该系统中，受体小鼠是否发生致命的 GVHD，取决于全身辐射剂量。以及次级淋巴器官（包括脾脏和淋巴结）以及 GVHD 靶器官（包括小肠和大肠、肝脏和皮肤）中供体 T 细胞的特征，结果发现 GVHD 小鼠具有大量侵入性供体。受累器官中的T细胞，尽管GVHD小鼠和非GVHD小鼠的次级淋巴器官中的T细胞增殖程度没有差异，因此发现GVHD的发生取决于GVHD靶标的炎症程度。器官较少。