Zoledronic acid boosts γδ T-cell activity in children receiving αβ+ T and CD19+ cell-depleted grafts from an HLA-haplo-identical donor
Zoledronic acid boosts γδ T-cell activity in children receiving αβ+ T and CD19+ cell-depleted grafts from an HLA-haplo-identical donor
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DOI：
10.1080/2162402x.2016.1216291
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发表时间：
2017-01-01
期刊：
影响因子：
7.2
通讯作者：
Airoldi, I.
中科院分区：
文献类型：
--
作者：
Bertaina, A.;Zorzoli, A.;Airoldi, I.
我们证明，在去除α β（+）T细胞和CD 19（+）B细胞后，给予HLA半相合HSCT的患者的γ δ T细胞在用唑来膦酸（ZOL）离体治疗后被赋予杀死白血病细胞的能力。因此，我们测试了在接受这种类型移植物的患者中输注ZOL可能增强γ δ T细胞对白血病细胞的细胞毒活性的假设。43例患者每28天输注一次ZOL，大多数患者至少接受两次治疗。通过高分辨率质谱、流式细胞术和脱粒测定法，在这43名患者中的33名中研究了ZOL治疗前后的γ δ T细胞，直到HSCT后至少7个月。诱导V δ 2细胞分化，增加V δ 1和V δ 2细胞对原代白血病母细胞的细胞毒性，与ZOL治疗有关。细胞毒性活性进一步增加，在V δ 2细胞，但不是在V δ 1淋巴细胞在这些患者给予一个以上的治疗。从患者中纯化的γ δ T细胞的蛋白质组学分析显示，参与活化过程和免疫应答的蛋白质上调，参与增殖的蛋白质下调。此外，每种ZOL处理都鉴定了蛋白质组特征。接受三次或三次以上ZOL输注的患者的生存概率高于接受一次或两次治疗的患者（分别为86% vs. 54%，p = 0.008）。我们的数据表明，ZOL输注在α β T细胞和B细胞耗尽HLA半相合HSCT的儿科受者中促进γ δ T细胞分化和细胞毒性，并可能影响患者的结局。
We demonstrated that gamma delta T cells of patients given HLA-haploidentical HSCT after removal of alpha beta(+) T cells and CD19(+) B cells are endowed with the capacity of killing leukemia cells after ex vivo treatment with zoledronic acid (ZOL). Thus, we tested the hypothesis that infusion of ZOL in patients receiving this type of graft may enhance gamma delta T-cell cytotoxic activity against leukemia cells. ZOL was infused every 28 d in 43 patients; most were treated at least twice. gamma delta T cells before and after ZOL treatments were studied in 33 of these 43 patients, till at least 7 mo after HSCT by high-resolution mass spectrometry, flow-cytometry, and degranulation assay. An induction of V delta 2-cell differentiation, paralleled by increased cytotoxicity of both V delta 1 and V delta 2 cells against primary leukemia blasts was associated with ZOL treatment. Cytotoxic activity was further increased in V delta 2 cells, but not in V delta 1 lymphocytes in those patients given more than one treatment. Proteomic analysis of gamma delta T cells purified from patients showed upregulation of proteins involved in activation processes and immune response, paralleled by downregulation of proteins involved in proliferation. Moreover, a proteomic signature was identified for each ZOL treatment. Patients given three or more ZOL infusions had a better probability of survival in comparison to those given one or two treatments (86% vs. 54%, respectively, p = 0.008). Our data indicate that ZOL infusion in pediatric recipients of alpha beta T- and B-cell-depleted HLA-haploidentical HSCT promotes gamma delta T-cell differentiation and cytotoxicity and may influence the outcome of patients.