混合嵌合体、淋巴细胞恢复以及接受联合肾和骨髓移植以诱导耐受的患者中早期供者特异性无反应的证据。
Mixed chimerism, lymphocyte recovery, and evidence for early donor-specific unresponsiveness in patients receiving combined kidney and bone marrow transplantation to induce tolerance.
机构信息
Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA.
出版信息
Transplantation. 2010 Dec 27;90(12):1607-15. doi: 10.1097/TP.0b013e3181ffbaff.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
背景
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。
方法
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。
结果
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。
结论
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。
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