文章：

移植物抗白血病作用的分子和机制

Molecules and mechanisms of the graft-versus-leukaemia effect

原文发布日期：2004-05-01

DOI: 10.1038/nrc1365

类型: Review Article

开放获取: 否

要点：

1. Allogeneic stem-cell transplantation, in which donor immune cells transplanted with bone-marrow stem cells recognize and eliminate leukaemia, is now recognized as an immunological modality for cancer therapy.
2. New approaches to transplantation take advantage of the allogeneic graft-versus-leukaemia (GVL) effect and facilitate the eradication of malignancies with low and minimally toxic doses of chemotherapy.
3. In human leukocyte antigen (HLA)-matched transplant recipients, T-cell responses to minor histocompatibility antigens are responsible for antileukaemic activity, but also cause graft-versus-host disease (GVHD). The discovery of the polymorphic genes that encode minor histocompability antigens is now proceeding rapidly and has identified a subset of these antigens that can be targeted for selective destruction of leukaemic cells without GVHD.
4. Non-polymorphic self-proteins are often overexpressed in leukaemic cells as a consequence of molecular dysregulation. Many of these proteins are expressed at low levels on a limited subset of normal cells, and T cells of sufficient avidity to distinguish malignant cells from normal cells can be identified and might also contribute to GVL activity.
5. The development of effective methods for isolating and propagating antigen-specific T cells indicates that adoptive T-cell therapy using T cells that are selected for recognition of leukaemic cells will be a useful adjunct to stem-cell transplantation for treating or preventing leukaemic relapse.
6. Approaches to regulate the fate and migration of adoptively transferred T cells are being developed and promise to improve the safety and efficacy of T-cell therapy for leukaemia.

要点翻译：

1. 异基因干细胞移植——即将供体免疫细胞与骨髓干细胞一同移植，使供体免疫细胞能够识别并清除白血病细胞——现已被视为癌症治疗的一种免疫学方法。
2. 新型移植策略利用异基因移植物抗白血病（GVL）效应，通过低剂量、低毒性的化疗方案实现恶性肿瘤的清除。
3. 在人类白细胞抗原（HLA）相合的移植受者中，T细胞对次要组织相容性抗原的应答既介导了抗白血病活性，也引发了移植物抗宿主病（GVHD）。目前对编码次要组织相容性抗原的多态性基因的发现进展迅速，已鉴定出可靶向清除白血病细胞且不引发GVHD的抗原亚群。
4. 由于分子调控异常，非多态性自身蛋白常在白血病细胞中过度表达。这类蛋白多数在少量正常细胞中低水平表达，现已能筛选出可区分恶性细胞与正常细胞的高亲和力T细胞，这类T细胞也可能增强GVL效应。
5. 有效分离和扩增抗原特异性T细胞的方法的发展表明，采用经筛选可识别白血病细胞的T细胞进行过继性T细胞治疗，将成为干细胞移植治疗或预防白血病复发的有效辅助手段。
6. 目前正在开发调控过继性T细胞归巢与迁移的新策略，这将有望提升白血病T细胞治疗的安全性与有效性。

英文摘要：

The ability of allogeneic bone-marrow cells and peripheral-blood stem cells to cure leukaemia remains the most striking example of the ability of the human immune system to recognize and destroy tumours. However, harnessing this 'graft-versus-leukaemia' effect to improve outcome for patients with advanced disease and segregating it from graft-versus-host disease have proven to be key challenges. The recent identification of molecules that are specifically expressed by leukaemic cells and that can be recognized by T cells has indicated that immunological reactivity can be targeted. This anticancer specificity of T cells should soon be routinely incorporated into allogeneic stem-cell transplant regimens to promote tumour eradication.

摘要翻译： 

异体骨髓细胞和外周血干细胞治愈白血病的能力，仍是人类免疫系统识别并摧毁肿瘤最引人注目的例证。然而，如何在不引发移植物抗宿主病的前提下，利用这种“移植物抗白血病”效应来改善晚期患者的预后，一直是关键难题。近期发现白血病细胞特异性表达、且可被T细胞识别的分子，表明免疫反应可以被精准导向。这种T细胞的抗癌特异性即将被常规纳入异体干细胞移植方案，以促进肿瘤清除。

原文链接：

Molecules and mechanisms of the graft-versus-leukaemia effect