Donor Peripheral Blood Stem Cell Infusion and Apoptosis in Lymphocytes Induces Immunological Tolerance of Kidney Allografts in Rhesus Monkeys

供体外周血干细胞输注和淋巴细胞凋亡诱导恒河猴肾同种异体移植物的免疫耐受

• 批准号: 13470245
• 负责人: KIMIKAWA Masaaki
• 金额: $ 8.9万
• 依托单位: Tokyo Women's Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470245/
• 关键词: Transplantation; tolerance; apoptosis in lymphocytes; kidney transplantation; FTY720; peripheral blood stem cell transplantation

(Background) We previously demonstrated that a nonmyeloablative, T-cell depleting preparative regimen including whole-body irradiation, thymic irradiation and donor bone marrow infusion induced mixed chimerism and allograft tolerance. Although tolerance has been successfully induced in the majority of recipients treated with this approach, broad clinical application requires simplifying the therapeutic regimen.(Methods) Male rhesus monkeys weighing 4-7 kg were used. T-cell depletion was planned using a combination of cyclophosphamide (CY) and the novel agent, FTY720 without irradiation. A second modification was allotransplantation of granulocyte-colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs), which has been increasingly used clinically as an alternative to allogeneic bone marrow transplantation.(Results) In 3 of 5 recipients in full protocol, renal function remained stable with no evidence of rejection more than 300 days after discontinuing immunosuppressive therapy. Donor-specific hyporesponsiveness was confirmed by sequential in vitro mixed lymphocyte reactions as well as skin transplantation from the original kidney donor in 1 recipient. The donor skin was accepted, while third party skin was rejected.(Conclusions) The mechanisms involved in the long-term immunosuppression-free allograft survival observed here remain to be elucidated. Nevertheless, these encouraging preliminary observations suggest that this approach to tolerance induction is particularly applicable to clinical protocols because of the non-toxic, relatively uncomplicated conditioning regimen required.

（背景）我们以前证明了一种非清髓性、T细胞耗竭的准备方案，包括全身照射、胸腺照射和供体骨髓输注，诱导了混合嵌合体和同种异体移植耐受。虽然在大多数接受这种方法治疗的患者中成功诱导了耐受性，但广泛的临床应用需要简化治疗方案。（方法）雄性恒河猴，体重4-7 kg。计划使用环磷酰胺（CY）和新试剂FTY 720的组合进行T细胞耗竭，而不进行照射。第二个修改是同种异体移植粒细胞集落刺激因子（G-CSF）动员的外周血干细胞（PBSC），这已越来越多地用于临床作为替代异基因骨髓移植。（结果）5例完全接受免疫抑制治疗的受者中，3例在停止免疫抑制治疗后300天以上肾功能保持稳定，无排斥反应发生。供体特异性低反应性通过体外混合淋巴细胞反应以及1例受者的原肾供体皮肤移植证实。供体皮肤被接受，而第三方皮肤被拒绝。（结论）这里观察到的无免疫抑制的同种异体移植物长期存活的机制仍有待阐明。然而，这些令人鼓舞的初步观察结果表明，这种方法的耐受性诱导是特别适用于临床方案，因为无毒，相对简单的调理方案所需的。