Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA.
Transplantation. 2010 Dec 27;90(12):1607-15. doi: 10.1097/TP.0b013e3181ffbaff.
We have previously reported operational tolerance in patients receiving human leukocyte antigen-mismatched combined kidney and bone marrow transplantation (CKBMT). We now report on transient multilineage hematopoietic chimerism and lymphocyte recovery in five patients receiving a modified CKBMT protocol and evidence for early donor-specific unresponsiveness in one of these patients.
Five patients with end-stage renal disease received CKBMT from human leukocyte antigen-mismatched, haploidentical living-related donors after modified nonmyeloablative conditioning. Polychromatic flow cytometry was used to assess multilineage chimerism and lymphocyte recovery posttransplant. Limiting dilution analysis was used to assess helper T-lymphocyte reactivity to donor antigens.
Transient multilineage mixed chimerism was observed in all patients, but chimerism became undetectable by 2 weeks post-CKBMT. A marked decrease in T- and B-lymphocyte counts immediately after transplant was followed by gradual recovery. Initially, recovering T cells were depleted of CD45RA+/CD45RO(-) "naïve-like" cells, which have shown strong recovery in two patients, and CD4:CD8 ratios increased immediately after transplant but then declined markedly. Natural killer cells were enriched in the peripheral blood of all patients after transplant.For subject 2, a pretransplant limiting dilution assay revealed T helper cells recognizing both donor and third-party peripheral blood mononuclear cells. However, the antidonor response was undetectable by day 24, whereas third-party reactivity persisted.
These results characterize the transient multilineage mixed hematopoietic chimerism and recovery of lymphocyte subsets in patients receiving a modified CKBMT protocol. The observations are relevant to the mechanisms of donor-specific tolerance in this patient group.
我们之前报道过接受人白细胞抗原错配联合肾和骨髓移植（CKBMT）的患者出现了操作性耐受。我们现在报告了 5 例接受改良 CKBMT 方案的患者出现短暂的多谱系造血嵌合体和淋巴细胞恢复，并在其中 1 例患者中发现了早期的供者特异性无反应证据。
5 例终末期肾病患者接受人白细胞抗原错配、单倍体亲缘活体供者的改良非清髓性预处理后行 CKBMT。采用多色流式细胞术评估移植后多谱系嵌合体和淋巴细胞恢复情况。采用有限稀释分析评估辅助性 T 淋巴细胞对供者抗原的反应性。
所有患者均观察到短暂的多谱系混合嵌合体，但 CKBMT 后 2 周嵌合体检测不到。移植后 T 细胞和 B 细胞计数明显下降，随后逐渐恢复。最初，恢复的 T 细胞耗竭 CD45RA+/CD45RO(-)“幼稚样”细胞，其中 2 例患者显示出强烈的恢复，CD4:CD8 比值在移植后立即升高，但随后显著下降。所有患者移植后外周血自然杀伤细胞均增多。对于 2 号患者，移植前的有限稀释分析显示 T 辅助细胞可识别供者和第三方外周血单个核细胞。然而，在第 24 天前，供者反应检测不到，而第三方反应持续存在。
这些结果描述了接受改良 CKBMT 方案的患者短暂的多谱系混合造血嵌合体和淋巴细胞亚群恢复情况。这些观察结果与该患者群体中供者特异性耐受的机制相关。
