Unique features and clinical importance of acute alloreactive immune responses
Unique features and clinical importance of acute alloreactive immune responses
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DOI：
10.1172/jci.insight.97219
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发表时间：
2018-05-17
期刊：
影响因子：
8
通讯作者：
Moss, Paul
中科院分区：
文献类型：
--
作者：
Inman, Charlotte F.;Eldershaw, Suzy A.;Moss, Paul
异基因造血干细胞移植（allo-SCT）可以治愈一些造血系统恶性肿瘤患者，但这依赖于供体T细胞同种异体反应性免疫反应的发展。尽管早期同种异体反应性免疫应答的临床效应通常直到后来才出现，但allo-SCT后前2周的T细胞活性在确定结果方面至关重要。然而，由于严重淋巴细胞减少症的影响，在该时间点难以研究同种异体环境对T细胞的影响。我们通过比较同种异体移植后第2周的T细胞与自体移植患者的T细胞来解决这个问题。同种异体T细胞存在于少量，但表现出强烈的增殖与自发细胞因子的产生。第2周的寡克隆扩增代表了已建立的T细胞库的很大一部分，并被招募到受移植物抗宿主病影响的组织中。转录分析揭示了一系列免疫操作的潜在靶标，包括OX40L、TWEAK和CD70。这些发现揭示了同种异体抗原的识别驱动幼稚T细胞朝向独特的表型。此外，他们证明早期克隆T细胞应答被募集到随后的组织损伤部位，并为潜在的治疗性免疫调节提供了一系列靶点。
Allogeneic stem cell transplantation (allo-SCT) can cure some patients with hematopoietic malignancy, but this relies on the development of a donor T cell alloreactive immune response. T cell activity in the first 2 weeks after allo-SCT is crucial in determining outcome, despite the clinical effects of the early alloreactive immune response often not appearing until later. However, the effect of the allogeneic environment on T cells is difficult to study at this time point due to the effects of profound lymphopenia. We approached this problem by comparing T cells at week 2 after allograft to T cells from autograft patients. Allograft T cells were present in small numbers but displayed intense proliferation with spontaneous cytokine production. Oligoclonal expansions at week 2 came to represent a substantial fraction of the established T cell pool and were recruited into tissues affected by graft-versus-host disease. Transcriptional analysis uncovered a range of potential targets for immune manipulation, including OX40L, TWEAK, and CD70. These findings reveal that recognition of alloantigen drives naive T cells toward a unique phenotype. Moreover, they demonstrate that early clonal T cell responses are recruited to sites of subsequent tissue damage and provide a range of targets for potential therapeutic immunomodulation.