Treatment of autoimmune diseases by portal venous bone marrow transplantation

门静脉骨髓移植治疗自身免疫性疾病

• 批准号: 12670219
• 负责人: INABA Muneo
• 金额: $ 2.18万
• 依托单位: Kansai Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670219/
• 关键词: Bone marrow transplantation; Portal vein; donor-derived cell; hemopoietic progenitor cells; stromal cells

A new bone marrow transplantation (BMT) method for treating severe autoimmune diseases in MRL/lpr mice without using immunosuppressants has been established. The method consists of fractionated irradiation (5.5 Gy x 2) followed by the portal venous (PV) injection of whole bone marrow cells (BMCs) from allogeneic normal C57BL/6 (B6) mice and intravenous (IV) injection of whole B6 BMCs 5 days after the PV injection. Al recipients survived more than 1 year after this treatment. Abnormal T cells (B220+/Thy1.2+/CD3+/CD4-/CD8-) present in untreated MRL/lpr mice disappeared. In the mice thus treated, the number of donor-derived cells possessing the mature lineage (Lin) markers rapidly increased in the bone marrow, spleen, and liver, indicating that hematolymphoid cells are completely reconstituted with donor-derived cells. The number of donor-derived hemopoietic progenitor cells (c-kit+Lin- cells) increased in the BMCs, hepatic mononuclear cells, and spleen cells. Simultaneously, homopoietic foci adjoining donor-derived stromal cells were observed in the liver when injected via PV, but not IV. Furthermore, donor-derived stromal cells were detected in the BMCs after the culture. This indicates that the donor-derived stromal cells are not only trapped in the liver but also migrate into the bone marrow where they construct the hemopoietic environment.These findings suggest that not only donor hemopoietic stem cells (HSCs) but also donor stromal cells administered via the PV were trapped in the liver, resulting in the early engraftment of donor HSCs in cooperation with donor-derived stromal cells.

建立了一种不使用免疫抑制剂的骨髓移植治疗MRL/lpr小鼠严重自身免疫性疾病的新方法。方法为分次照射（5.5 Gy × 2）后，门静脉注射异基因正常C57BL/6 （B6）小鼠全骨髓细胞（BMCs），静脉注射B6全骨髓细胞5天后静脉注射B6骨髓细胞（IV）。所有受者在治疗后存活超过1年。MRL/lpr小鼠中存在的异常T细胞（B220+/Thy1.2+/CD3+/CD4-/CD8-）消失。在这样处理的小鼠中，骨髓、脾脏和肝脏中具有成熟谱系（Lin）标记的供体来源细胞的数量迅速增加，表明血淋巴细胞完全被供体来源细胞重建。供体来源的造血祖细胞（c-kit+Lin-细胞）在骨髓、肝单核细胞和脾细胞中数量增加。同时，通过PV注射，在肝脏中观察到邻近供体来源的基质细胞的同型灶，而不是IV。此外，在培养后的bmc中检测到供体来源的基质细胞。这表明供体来源的基质细胞不仅被困在肝脏中，而且还迁移到骨髓中，在那里它们构建了造血环境。这些发现表明，不仅供体造血干细胞（hsc），通过PV给药的供体间质细胞也被困在肝脏中，导致供体造血干细胞与供体来源的间质细胞合作早期移植。

项目成果

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