Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells
Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells
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DOI：
10.1182/blood-2009-12-260539
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发表时间：
2010-06-10
期刊：
影响因子：
20.3
通讯作者：
Riddell, Stanley R.
中科院分区：
文献类型：
--
作者：
Bleakley, Marie;Otterud, Brith E.;Riddell, Stanley R.
靶向受体造血细胞选择性呈递的次要组织相容性（H）抗原（包括白血病）的T细胞免疫疗法可以预防和治疗造血细胞移植后白血病复发，而不会引起移植物抗宿主病。为了提供可应用于大多数移植受者的免疫治疗，有必要鉴定白血病相关的次要H抗原，其由在人群中平衡的基因多态性引起，并由常见的人类白细胞抗原等位基因呈递。目前用于衍生次要H抗原特异性T细胞的方法依赖于体内引发，并且通常是不成功的，所述方法为编码抗原的多态性基因的分子鉴定和表征提供必需的试剂。我们发现，次要H抗原特异性细胞毒性T淋巴细胞前体主要存在于初始CD 8（+）T细胞亚群中，并提供了一种有效的策略，用于体外引发天然T细胞，以产生具有常见人类白细胞抗原等位基因的多种次要H抗原的T细胞。我们使用这种方法获得了一组稳定的细胞毒性T淋巴细胞克隆，用于发现编码次要H抗原的基因，并鉴定在急性髓性白血病干细胞上表达且在移植物抗宿主病靶组织中表达最少的新型抗原。（血。2010;115（23）：4923-4933）
T-cell immunotherapy that targets minor histocompatibility (H) antigens presented selectively by recipient hematopoietic cells, including leukemia, could prevent and treat leukemic relapse after hematopoietic cell transplantation without causing graft-versus-host disease. To provide immunotherapy that can be applied to a majority of transplantation recipients, it is necessary to identify leukemia-associated minor H antigens that result from gene polymorphisms that are balanced in the population and presented by common human leukocyte antigen alleles. Current approaches for deriving minor H antigen-specific T cells, which provide essential reagents for the molecular identification and characterization of the polymorphic genes that encode the antigens, rely on in vivo priming and are often unsuccessful. We show that minor H antigen-specific cytotoxic T lymphocyte precursors are found predominantly in the naive CD8(+) T-cell subset and provide an efficient strategy for in vitro priming of native T cells to generate T cells to a broad diversity of minor H antigens presented with common human leukocyte antigen alleles. We used this approach to derive a panel of stable cytotoxic T lymphocyte clones for discovery of genes that encode minor H antigens and identify a novel antigen expressed on acute myeloid leukemia stem cells and minimally in graft-versus-host disease target tissues. (Blood. 2010;115(23):4923-4933)