Laboratory of Pediatric Immunology and Onco-Hematology Transplant, Infant-Maternal Department, Fondazione IRCCS Policlinico San Matteo, Piazzale Golgi 19, Pavia, Italy.
Biol Blood Marrow Transplant. 2012 Jul;18(7):1108-18. doi: 10.1016/j.bbmt.2011.12.586. Epub 2012 Jan 3.
The transplantation of two cord blood (CB) units obtained from unrelated donors (double CBT) is an effective strategy for adult patients with hematologic malignancies. Sustained hematopoiesis after double CBT is usually derived from a single donor, and only a few transplantation recipients displaying a stable mixed donor-donor chimerism have been reported. We investigated the mechanisms underlying single-donor predominance in double CBT by studying in vitro the role of the graft-versus-graft cell-mediated immune effect in two-way mixed-lymphocyte culture, along with the contribution of differential hematopoietic progenitor (HP) potency in HP mixed cultures. Results for the two-way mixed-lymphocyte culture showed that despite the weak and variable alloantigen-specific cytotoxic potential displayed by CB mononuclear cells, an immune-mediated dominance for one of the two CB units was detected in the majority of experiments. Alloantigen-induced cytotoxic activity was directed toward both CB-HP and phytohemagglutinin (PHA)-activated T lymphoblastoid cells. The CB unit with the higher fold expansion of CD34(+) cells in single-expansion culture was prevalent in the HP mixed-expansion culture, as shown by DNA chimerism evaluation. Based on these data, we hypothesize that the dominant CB unit is able to develop prevalent cytotoxic activity toward activated lymphocytes of the other CB unit, thereby preventing them from exerting alloantigen-specific cytotoxic potential against both activated lymphocytes and HPs of the dominant unit. In accordance with this hypothesis, we propose the evaluation of alloantigen-induced cytotoxic activity generated in two-way mixed-lymphocyte culture and directed toward PHA-activated T lymphoblastoid cells as a tool to identify the potentially predominant CB unit before double CBT.
双份无关供者脐血（double CBT）移植是血液系统恶性肿瘤成人患者的有效治疗策略。双份 CBT 后持续的造血通常来源于单个供者，仅有少数报道的移植受者显示稳定的混合供者-供者嵌合体。我们通过研究体外移植物抗宿主细胞介导的免疫效应在双向混合淋巴细胞培养中的作用，以及在混合造血祖细胞（HP）培养中不同造血祖细胞（HP）效力的贡献，研究了双份 CBT 中单个供者优势的机制。双向混合淋巴细胞培养的结果表明，尽管 CB 单核细胞显示出弱且可变的同种异体抗原特异性细胞毒性潜能，但在大多数实验中仍检测到两个 CB 单位中的一个存在免疫介导的优势。同种异体抗原诱导的细胞毒性活性针对 CB-HP 和植物血凝素（PHA）激活的 T 淋巴母细胞。在单个扩增培养中具有更高 CD34(+)细胞倍数扩增的 CB 单位在 HP 混合扩增培养中占优势，如 DNA 嵌合率评估所示。基于这些数据，我们假设优势 CB 单位能够对另一个 CB 单位的活化淋巴细胞产生占优势的细胞毒性活性，从而阻止它们对活化淋巴细胞和优势单位的 HP 发挥同种异体抗原特异性细胞毒性潜能。根据这一假设，我们建议在进行双份 CBT 之前，评估双向混合淋巴细胞培养中产生的针对 PHA 激活的 T 淋巴母细胞的同种异体抗原诱导的细胞毒性活性，并将其作为识别潜在优势 CB 单位的工具。
