Prediction of graft-versus-host disease in humans by donor gene-expression profiling.
Prediction of graft-versus-host disease in humans by donor gene-expression profiling.
复制标题
通过供体基因表达分析对人类的移植物抗宿主疾病的预测。
DOI：
10.1371/journal.pmed.0040023
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发表时间：
2007-01
期刊：
影响因子：
15.8
通讯作者：
Perreault C
中科院分区：
文献类型：
--
作者：
Baron C;Somogyi R;Greller LD;Rineau V;Wilkinson P;Cho CR;Cameron MJ;Kelvin DJ;Chagnon P;Roy DC;Busque L;Sékaly RP;Perreault C
移植物抗宿主病（GVHD）是同种异体造血细胞移植（AHCT）后供体T细胞识别宿主抗原的结果。值得注意的是，供体和受体之间的组织不相容是引起GVHD的必要条件，但不足以引起GVHD。因此，我们测试了这样一个假设，即一些供者可能比其他人“更强的同种异体反应者”，因此更有可能引发GVHD。为此，我们用微阵列测量了来自50个AHCT供者的CD4+和CD8+ T细胞的基因表达谱。我们报道ahct前基因表达谱分离供体的受体是否患有GVHD。通过定量PCR、已建立的统计测试和多个独立训练测试数据集的分析，我们发现慢性GVHD的“危险供体”特征（受体发生GVHD）受到多基因控制，并由调节转化生长因子-β信号传导和细胞增殖的基因活性决定。这些发现强烈表明，供体基因表达谱对受体GVHD的发生有主要影响。利用基因表达谱区分强弱同种异体应答者的能力可以为个性化移植医学铺平道路。供体基因表达谱似乎对受体中移植物抗宿主病的发生有主要影响。人体血液中含有红细胞、白细胞和血小板，它们分别为全身输送氧气、抵抗感染和帮助血液凝固。正常情况下，骨髓中的造血干细胞（及其后代，外周血干细胞）不断提供新的血细胞。来自骨髓的肿瘤（如白血病和淋巴瘤，两种类型的造血肿瘤）通常通过健康供体的骨髓或外周血干细胞移植来治疗，以提供新的造血干细胞，作为化疗或放疗的后续治疗，旨在尽可能多地根除肿瘤。这个过程被称为同种异体造血细胞移植（AHCT）——同种异体一词表示供体和受体在基因上不相同。当实体器官（例如肾脏）被移植时，受者的免疫系统可以识别供体器官上的异体抗原（个体之间不同的蛋白质）并将其排斥。为了降低排斥反应的风险，供体和受体必须具有相同的主要组织相容性复合体（MHC）蛋白。MHC匹配在AHCT中也很重要，但还有其他原因。供体T淋巴细胞（一种白细胞）可以攻击宿主的皮肤和其他组织。这种移植物抗宿主病（GVHD）影响许多接受AHCT的患者，尽管在移植后不久（急性GVHD）或几个月后（慢性GVHD）进行MHC匹配。顺便说一句，移植也可能对肿瘤本身起作用——这被称为移植物抗白血病效应。GVHD通常可以用抑制免疫系统的药物（免疫抑制药物）来治疗，但最好完全避免GVHD。事实上，GVHD仍然是AHCT后非复发死亡率的主要原因。不幸的是，在mhc匹配的AHCT后，决定谁会发生GVHD的因素尚不清楚。虽然GVHD只有在供体和宿主的组织相容性抗原不匹配时才会发生，但它并不是必然发生的。到目前为止，科学家们主要研究了ACHT受体之间的差异是否可以解释这一观察结果。但是，在这项研究中，研究人员检查了供体，看看他们免疫反应的差异是否会使一些供体比其他供体更强，从而更有可能引起GVHD。研究人员使用一种称为微阵列表达谱的分子生物学技术来检测外周血干细胞供者T淋巴细胞中的基因表达模式。从这些模式中，他们发现了许多基因，这些基因的表达水平区分了mhc相同的移植受体在AHCT后发生GVHD的供者（GVHD+供者）和未发生GVHD的供者（GVHD -供者）。研究人员利用第二种称为定量逆转录聚合酶链反应的技术，证实了其中17种基因的表达水平在GVHD+和GVHD -供体之间有区别。这些基因中有许多与TGF-β信号（TGF-β是一种帮助控制免疫系统的蛋白质）、细胞生长或增殖有关。研究人员还确定了四对相互作用的基因对，以确定给定供体诱导GVHD的可能性。最后，研究人员通过计算重新测试了他们的数据，结果表明，测量这些基因中的每一个基因和四个相互作用的基因对的表达水平，可以正确地识别出可能导致高达80%的样本中GVHD的供体样本。这些发现提供了供体基因表达谱影响AHCT后受体GVHD发展的第一个证据。研究人员认为，“危险的供体”（强同种异体应答者）是决定AHCT后是否发生GVHD的关键因素，并提出供体T淋巴细胞的基因表达谱可能识别那些可能导致GVHD的供体。在这种方法可以用于减少AHCT后GVHD的发病率之前，这些发现需要在更多的供者中得到证实。此外，开发一种足够准确的临床测试——既不遗漏危险的供体，又不抛弃太多安全的供体——可能需要识别更大的相互作用基因群。但是，如果它能经受住进一步的研究，危险供体的概念可能代表着移植医学的一个重要进步，它可以帮助临床医生选择低风险的供体进行AHCT，并根据供体决定的GVHD风险来定制患者的免疫抑制药物方案。请通过本摘要的在线版本http://dx.doi.org/doi:10.1371/journal.pmed.0040023访问这些网站。•国家骨髓捐赠计划为患者和医生提供关于造血干细胞移植的所有方面的信息，包括GVHD•MedlinePlus百科全书有关于骨髓移植，GVHD和移植排斥的页面•美国国家癌症研究所有关于骨髓和外周血干细胞移植的情况说明书
Graft-versus-host disease (GVHD) results from recognition of host antigens by donor T cells following allogeneic hematopoietic cell transplantation (AHCT). Notably, histoincompatibility between donor and recipient is necessary but not sufficient to elicit GVHD. Therefore, we tested the hypothesis that some donors may be “stronger alloresponders” than others, and consequently more likely to elicit GVHD. To this end, we measured the gene-expression profiles of CD4+ and CD8+ T cells from 50 AHCT donors with microarrays. We report that pre-AHCT gene-expression profiling segregates donors whose recipient suffered from GVHD or not. Using quantitative PCR, established statistical tests, and analysis of multiple independent training-test datasets, we found that for chronic GVHD the “dangerous donor” trait (occurrence of GVHD in the recipient) is under polygenic control and is shaped by the activity of genes that regulate transforming growth factor-β signaling and cell proliferation. These findings strongly suggest that the donor gene-expression profile has a dominant influence on the occurrence of GVHD in the recipient. The ability to discriminate strong and weak alloresponders using gene-expression profiling could pave the way to personalized transplantation medicine. The donor gene expression profile appears to have a dominant influence on the occurrence of graft-versus-host disease in the recipient. Human blood contains red blood cells, white blood cells, and platelets, which carry oxygen throughout the body, fight infections, and help blood clot, respectively. Normally, blood-forming (hematopoietic) stem cells in the bone marrow (and their offspring, peripheral blood stem cells) continually provide new blood cells. Tumors that arise from the bone marrow (such as leukemia and lymphoma, two types of hematopoietic tumor) are often treated by a bone marrow or peripheral blood stem cell transplant from a healthy donor to provide new blood-forming stem cells, as a follow-up to chemotherapy or radiotherapy designed to eradicate as much of the tumor as possible. This procedure is called allogeneic hematopoietic cell transplantation (AHCT)—the word allogeneic indicates that the donor and recipient are not genetically identical. When solid organs (for example, kidneys) are transplanted, the recipient's immune system can recognize alloantigens (proteins that vary between individuals) on the donor organ as foreign and reject it. To reduce the risk of rejection, the donor and recipient must have identical major histocompatibility complex (MHC) proteins. MHC matching is also important in AHCT but for further reasons. Here, donor T lymphocytes (a type of white blood cell) can attack the skin and other tissues of the host. This graft versus host disease (GVHD) affects many people undergoing AHCT despite MHC matching either soon after transplantation (acute GVHD) or months later (chronic GVHD). As an aside, the transplant may also act against the tumor itself—this is known as a graft versus leukemia effect. GVHD can usually be treated with drugs that damp down the immune system (immunosuppressive drugs), but it would be preferable to avoid GVHD altogether. Indeed, GVHD continues to be the leading cause of nonrelapse mortality following AHCT. Unfortunately, what determines who will develop GVHD after MHC-matched AHCT is unclear. Although GVHD only develops if there are some mismatches in histocompatibility antigens between the donor and host, it does not inevitably develop. Until now, scientists have mainly investigated whether differences between ACHT recipients might explain this observation. But, in this study, the researchers have examined the donors instead to see whether differences in their immune responses might make some donors stronger “alloresponders” than others and consequently more likely to cause GVHD. The researchers used a molecular biology technique called microarray expression profiling to examine gene expression patterns in the T lymphocytes of peripheral blood stem cell donors. From these patterns, they identified numerous genes whose expression levels discriminated between donors whose MHC-identical transplant recipient developed GVHD after AHCT (GVHD+ donors) and those whose recipient did not develop GVHD (GVHD− donors). The researchers confirmed that the expression levels of 17 of these genes discriminated between GVHD+ and GVHD− donors using a second technique called quantitative reverse transcriptase polymerase chain reaction. Many of these genes are involved in TGF-β signaling (TGF-β is a protein that helps to control the immune system), cell growth, or proliferation. The researchers also identified four gene pairs that interacted with each other to determine the likelihood that a given donor would induce GVHD. Finally, the researchers computationally retested their data and showed that the measurement of expression levels of each of these genes and of the four interacting gene pairs could correctly identify a donor sample likely to cause GVHD in up to 80% of samples. These findings provide the first evidence that the donor's gene expression profile influences the development of GVHD in the recipient after AHCT. The researchers suggest that a “dangerous donor” (strong alloresponder) is a key factor in determining whether GVHD occurs after AHCT and propose that gene expression profiling of donor T lymphocytes might identify those donors likely to cause GVHD. Before this approach can be used to reduce the incidence of GVHD after AHCT, these findings need to be confirmed in many more donors. Also, the development of a test that is accurate enough for clinical use—one that does not miss dangerous donors but does not discard too many safe donors—may require the identification of larger groups of interacting genes. But, if it survives further investigation, the concept of a dangerous donor could represent an important advance in transplantation medicine, one that could help clinicians select low-risk donors for AHCT and tailor patients' immunosuppressive drug regimens according to their donor-determined risk of GVHD. Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040023. • The National Marrow Donor Program provides information for patients and physicians on all aspects of hematopoietic stem cell transplantation, including GVHD • The MedlinePlus encyclopedia has pages on bone marrow transplants, GVHD and transplant rejection • The US National Cancer Institute has a factsheet on bone marrow and peripheral blood stem cell transplantation
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影响因子：
6.2
作者：
GLUCKSBERG, H;STORB, R;THOMAS, ED
通讯作者：
THOMAS, ED
影响因子：
9.8
作者：
Baranzini SE;Mousavi P;Rio J;Caillier SJ;Stillman A;Villoslada P;Wyatt MM;Comabella M;Greller LD;Somogyi R;Montalban X;Oksenberg JR
通讯作者：
Oksenberg JR
影响因子：
3.2
作者：
FONTAINE, P;LANGLAIS, J;PERREAULT, C
通讯作者：
PERREAULT, C
影响因子：
8
作者：
Erez, A;Perelman, M;Izraeli, S
通讯作者：
Izraeli, S
影响因子：
7
作者：
Colland, F;Jacq, X;Gauthier, JM
通讯作者：
Gauthier, JM