Keever-Taylor C A, Passweg J, Kawanishi Y, Casper J, Flomenberg N, Baxter-Lowe L A
Bone Marrow Transplantation Program of the Medical College of Wisconsin, Milwaukee 53226, USA.
Bone Marrow Transplant. 1997 May;19(10):1001-9. doi: 10.1038/sj.bmt.1700779.
Recipients of marrow from alternative donors (unrelated or HLA-mismatched related donors) have a higher incidence of post-transplant complications compared to recipients of marrow from HLA-identical siblings. HLA disparity undetected by routine typing techniques has been suggested as one cause for the increased complications observed. Limiting dilution analysis (LDA) of donor-derived, host-reactive T cell precursor frequency prior to transplant has been proposed as a surrogate indicator of underlying HLA disparity which might be used to predict transplant outcome and aid in donor selection. We compared results of LDA of host-reactive IL-2 producing helper T lymphocytes (HTLp) and/or cytolytic T lymphocytes (CTLp) in 77 alternative marrow donor/recipient pairs with transplant outcome using univariate and multivariate analysis. All donor grafts were depleted ex vivo of mature T cells. Median patient age was 15 years (1-53). Donor selection was based on serologic typing for HLA class I and high resolution oligotyping for HLA-DRB1-DRB5, and HLA-DQB1. HLA-A and HLA-B locus antigens were retrospectively defined by one dimensional isoelectric focusing (IEF). Cox proportional hazards regression models were used to assess the impact of frequency and estimated cell dose of CTLp and HTLp on outcome. The CTLp assay was most sensitive to HLA-A and HLA-B locus disparity detected by serology or IEF. The HTLp assay detected class I disparity but was most strongly reactive in the presence of HLA-DRB1 disparity. Univariate analysis indicated a significant association of CTLp frequency and dose with severe (grades 3-4) acute graft-versus-host disease (GVHD), and of CTLp dose with chronic GVHD. Both assays were associated with survival and neither assay was associated with relapse. After adjustment for other significant covariables including known HLA disparity, the association of CTLp with acute GVHD was lost, however, CTLp frequency and CTLp dose remained associated with survival and HTLp frequency was associated with chronic GVHD. These data support the hypothesis that post-BMT complications may be influenced not only by T cell dose but by the alloreactive potential of the cells infused. LDA of alloreactive potential was useful in detecting disparity and in predicting survival or chronic GVHD in recipients of alternative donor TCD marrow grafts.
与接受来自 HLA 完全相同的同胞的骨髓移植者相比，接受来自其他供者（无关供者或 HLA 不匹配的亲属供者）的骨髓移植者移植后并发症的发生率更高。常规分型技术未检测到的 HLA 差异被认为是观察到的并发症增加的一个原因。移植前对供者来源的、宿主反应性 T 细胞前体频率进行有限稀释分析（LDA），已被提议作为潜在 HLA 差异的替代指标，可用于预测移植结果并辅助供者选择。我们使用单因素和多因素分析，比较了 77 对其他骨髓供者/受者中宿主反应性产生白细胞介素-2 的辅助性 T 淋巴细胞（HTLp）和/或细胞毒性 T 淋巴细胞（CTLp）的 LDA 结果与移植结果。所有供者移植物在体外均去除了成熟 T 细胞。患者中位年龄为 15 岁（1 - 53 岁）。供者选择基于 HLA - I 类血清学分型以及 HLA - DRB1 - DRB5 和 HLA - DQB1 的高分辨率寡核苷酸分型。HLA - A 和 HLA - B 位点抗原通过一维等电聚焦（IEF）进行回顾性定义。使用 Cox 比例风险回归模型评估 CTLp 和 HTLp 的频率及估计细胞剂量对结果的影响。CTLp 检测对血清学或 IEF 检测到的 HLA - A 和 HLA - B 位点差异最为敏感。HTLp 检测可检测到 I 类差异，但在存在 HLA - DRB1 差异时反应最为强烈。单因素分析表明，CTLp 频率和剂量与重度（3 - 4 级）急性移植物抗宿主病（GVHD）显著相关，CTLp 剂量与慢性 GVHD 相关。两种检测均与生存率相关，且两种检测均与复发无关。在对包括已知 HLA 差异在内的其他显著协变量进行调整后，CTLp 与急性 GVHD 的相关性消失，然而，CTLp 频率和 CTLp 剂量仍与生存率相关，HTLp 频率与慢性 GVHD 相关。这些数据支持这样的假设，即骨髓移植后并发症可能不仅受 T 细胞剂量影响，还受输注细胞的同种异体反应潜能影响。同种异体反应潜能的 LDA 有助于检测差异，并预测其他供者 T 细胞去除骨髓移植物受者的生存率或慢性 GVHD。
