同一供者来源亲属活体肾移植联合造血干细胞移植诱导免疫耐受

Renal transplantationplus hematopoietic stem cell transplantation as Induction therapy: a single-center 10-year experience

目的探讨肾移植联合造血干细胞移植(HSCT)诱导免疫耐受的效果,并总结其长期随访结果。方法11例同一供者来源的亲属活体肾移植联合HSCT,其中2例供、受者HLA抗原全相配,其余为半相合。肾移植术前5 d使用粒细胞集落刺激因子动员供者造血干细胞,术前1 d采集供者造血干细胞。术前连续3 d受者接受全身照射,肾移植术中给予抗胸腺细胞球蛋白诱导,术后第2、4、6天输注供者造血干细胞。术后检测调节性T淋巴细胞、嵌合体、B淋巴细胞活化因子和混合淋巴细胞培养等指标,并长期随访。结果与移植前比较,移植后受者外周血中调节性T淋巴细胞(Treg细胞)比例明显增加,且主要是活化性Treg细胞。1例HLA全相合受者诱导出30~50%的嵌合体,半年后消失,其余受者未诱导混合嵌合体。术后1年内受者BAFF水平明显增加。混合淋巴细胞培养提示免疫耐受诱导受者对供者特异性低反应。随访717~3612 d,第1例受者出现移植肾功能丧失,其余10例受者移植肾功能稳定。11例受者均未出现骨髓抑制和移植物抗宿主病。经移植肾活检证实,1例受者出现轻度急性排斥反应,其余10例受者未发生排斥发生。5例减少了免疫抑制剂的用量。结论肾移植时联合HSCT诱导免疫耐受的方案是安全的,嵌合体对诱导免疫耐受至关重要。

Objective To explore the efficacy of renal transplantation plus hematopoietic stem cell transplantation on inducing immune tolerance and summarize its long-term follow-up outcomes. Methods From 2009 to 2018, a total of 11 cases of living related donor kidney transplantation plus hematopoietic stem cell transplantation were performed. Two of them were HLA-matched and the remainder were mismatched for one HLA haplotype. The donor hematopoietic stem cells were mobilized using granulocyte colony-stimulating factor at 5 days pre-transplantation and collected at 1 day pre-operation. The recipients received total lymphoid irradiation for 3 days pre-transplantation and received anti-thymocyte globulin induction during transplantation. The donor hematopoietic stem cells were infused at 2, 4 and 6 postoperative day. Postoperative regulatory T cells, chimerism, B cell activating factor and mixed lymphocyte culture and other parameters were detected and long-term follow-up outcomes tracked. Results The immune tolerance-inducible recipients had a significant increase in activated Treg. One HLA-matched recipient achieved 30%-50% of chimerism and lost after 6 months. However, other recipients did not achieve mixed chimerism. The BAFF of recipient spiked sharply after transplantation. Mixed lymphocyte culture indicated that a donor-specific low response was induced. The recipients were followed up for 717 to 3612 days. The first recipient lost renal function and another ten recipients had stable renal function. None of the recipients had myelosuppression or graft-versus-host disease. Allograft biopsy confirmed only one case of mild acute rejection. The dose of immunosuppressive agents was lowered in 5 patients. Conclusions Hematopoietic stem cell transplantation for inducing tolerance is safe during renal transplantation. And chimerism is essential for inducing immune tolerance.