HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation
HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation
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DOI：
10.1038/leu.2016.210
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发表时间：
2017-02-01
期刊：
影响因子：
11.4
通讯作者：
Thomas, S.
中科院分区：
文献类型：
--
作者：
Herr, W.;Eichinger, Y.;Thomas, S.
难治或复发的急性髓系白血病(AML)是异基因造血干细胞移植(HSCT)后常见的并发症。我们的研究表明，CD45RA选择的干细胞捐献者的CD4T细胞与10/10的HLA相合的AML原始细胞体外刺激可导致几乎所有识别HLA-DPB1错配等位基因的细胞溶解T淋巴细胞(CTL)的扩增，临床上高达80%的供者-患者对会发生这种情况。原代AML细胞强烈表达HLA-DPB1，而成纤维细胞和角质形成细胞作为移植物抗宿主病的替代靶细胞仅在干扰素-α上表达。前置处理。由于患者的AML原始细胞在临床上很少使用，我们开发了一种方案，该方案基于供者来源的CD45RA选择的CD4T细胞与编码患者HLADPB1错配等位基因的RNA电穿孔的自体树突状细胞刺激。短期刺激的T细胞系可特异性地裂解表达HLA-DPB1错配的AML细胞，但不能裂解成纤维细胞和角质形成细胞。值得注意的是，这些CD4CTL在过继转移到移植白血病的NSG小鼠时有效地消除了AML原始细胞。综上所述，我们在干细胞捐献者的CD45RA选择的CD4T细胞中显示出了很强的免疫原性，并提出了一种新的策略来可靠地产生HLA-DPB1特异性的CD4CTL，这可能是治疗HSCT后复发或难治性AML的有效细胞疗法。
Refractory or relapsed acute myeloid leukemia (AML) represents a frequent complication after allogeneic hematopoietic stem-cell transplantation (HSCT). We show herein that primary in vitro stimulation of CD45RA-selected CD4 T cells of stem-cell donors with 10/10 HLA-matched AML blasts results in expansion of cytolytic T-lymphocytes (CTL) that almost all recognize HLA-DPB1 mismatch alleles, which clinically occur in up to 80% of donor-patient pairs. Primary AML blasts were found to strongly express HLA-DPB1, whereas fibroblasts and keratinocytes used as surrogate target cells for graft-versus-host disease did express HLA-DPB1 only upon IFN-. pre-treatment. Since patients' AML blasts are rarely available in clinical routine, we developed a protocol based on stimulation of donor-derived CD45RA-selected CD4 T cells with autologous dendritic cells electroporated with RNA encoding patients' HLADPB1 mismatch alleles. Short-term stimulated T cell-lines specifically lysed HLA-DPB1 mismatch-expressing AML blasts, but not fibroblasts and keratinocytes without IFN-gamma pre-treatment. Notably, these CD4 CTL efficiently eliminated AML blasts upon adoptive transfer into leukemia-engrafted NSG mice. In conclusion, we show strong immunogenicity of HLA-DPB1 mismatch alleles in CD45RA-selected CD4 T cells of stem-cell donors and introduce a novel strategy to reliably generate HLA-DPB1-specific CD4 CTL that might be powerful cellular therapeutics in relapsed or refractory AML after HSCT.