Early Enrichment and Restitution of the Peripheral Blood Treg Pool Is Associated With Rejection-Free Stable Immunosuppression After Liver Transplantation.
Early Enrichment and Restitution of the Peripheral Blood Treg Pool Is Associated With Rejection-Free Stable Immunosuppression After Liver Transplantation.
复制标题
外周血 Treg 库的早期富集和恢复与肝移植后无排斥的稳定免疫抑制相关
DOI：
10.1097/tp.0000000000001190
复制
发表时间：
2016
期刊：
影响因子：
6.2
通讯作者：
Hutchinson JA
中科院分区：
文献类型：
--
作者：
Haarer J;Riquelme P;Hoffmann P;Schnitzbauer A;Schlitt HJ;Sawitzki B;Geissler EK;Hutchinson JA
许多人试图通过测量外周血中的免疫学参数来预测实体器官移植的结果。1-3这些研究的一个一致而令人惊讶的特点是，当孤立地考虑时，具有机械重要性的生物标志物的预测价值有限，例如调节T细胞频率。4、5一种可能的解释是，与生物相关的这些生物标志物的表达变化与个体之间的自然差异相比相形见绌。特别是，与个体间的生物变异相比，供者抗原反应性淋巴细胞亚群频率的变化可能非常小。因此，研究生物标记物表达随时间的变化可能比进行“静态”病例对照比较更有价值；换句话说，研究患者对异基因移植挑战的个体反应。为了验证这一概念，前瞻性地从两个不同的临床试验中收集了原位肝移植受者的系列样本，即RISET-Regensburg研究和Build研究。用流式细胞仪检测外周血中CD4+CD25+CD127低FoxP3+Treg频率。RISET-Regensburg研究中的患者接受了传统的三重免疫抑制治疗，包括钙调神经磷酸酶抑制剂、MMF和强的松龙。有趣的是，那些在移植后第一年没有发生排斥反应的研究患者表现出早期在他们的总CD4+T细胞隔室内Treg的浓缩，在8周内衰退到移植前的水平(图1A)。在这组患者中，与移植前相比，移植后1周的Treg频率显著升高，这是“基线”值，但在移植后的时间点没有。相比之下，在移植后第一年发生一次或多次排斥事件的患者中，Treg频率并未观察到相对增加(图1B)。值得注意的是，非排斥患者的Treg绝对计数并不高于排斥患者(图1C)。在已建立的研究(临床试验)中也进行了类似的观察。GOV：NCT01023542)患者，他们接受了传统的三联免疫抑制或自下而上的方案(补充信息，sdc，http://links.LWW。COM/TP/B261)：非排斥受者的Treg频率在移植后2周达到峰值，并在移植后4周消退；相比之下，在移植后第一年发生排斥反应的患者中没有观察到一过性Treg增加(图1D)。这种反应的动力学提示主要是T细胞反应；因此，我们试探性地提出，外周血Treg池的丰富和随后的恢复是非排斥患者免疫调节反应的证据。6我们推测，早期的富集期代表Treg的多克隆激活和扩增，而衰退期可能反映了供体抗原反应性克隆的选择。或者，Treg频率的变化可能是因为与排斥者相比，非排斥者更有效地抑制了非Treg。“高粒度”免疫监测研究捕获了移植后早期不断演变的免疫反应的动力学信息，可能有助于预测长期移植结果。在移植后1周，非排斥患者的Treg频率显著高于排斥患者(图1E)；然而，单独治疗每个时间点忽略了从连续采样中获得的动力学信息。评估白细胞亚群频率随时间的变化可能需要新的统计方法，包括…
Many attempts have been made to predict solid organ transplant outcomes by measuring immunological parameters in peripheral blood. 1-3 A consistent and surprising feature of these studies has been the limited predictive value of mechanistically important biomarkers when considered in isolation, such as regulatory T cell frequencies. 4, 5 One possible explanation is that biologically relevant changes in expression of these biomarkers are dwarfed by natural variation between individuals. In particular, changes in the frequency of donor antigen-reactive lymphocyte subsets may be very small compared with interindividual biological variations. Hence, it may be more informative to investigate changes in biomarker expression over time rather than making “static” case–control comparisons; in other words, to study the individual response of patients to the challenge of allogeneic transplantation. To test this concept, serial samples were prospectively collected from orthotopic liver transplant recipients from 2 separate clinical trials, namely, the RISET-Regensburg Study and the BUiLT Study. Estimates of peripheral blood CD4+ CD25+ CD127low FoxP3+ Treg frequencies were made using flow cytometry. Patients in the RISET-Regensburg Study received conventional triple immunosuppressive treatment comprising calcineurin inhibitor, MMF, and prednisolone. Interestingly, those study patients who did not experience a rejection episode during the first year after transplantation exhibited an early enrichment of Treg within their total CD4+ T cell compartment, which decayed to pretransplant levels within 8 weeks (Figure 1A). In this group, Treg frequency at 1 week after transplantation was significantly elevated compared with pretransplant,“baseline” values but not later time points. By contrast, no relative increase in Treg frequency was observed in patients registering one or more rejection episodes during the first year posttransplant (Figure 1B). Notably, absolute Treg counts were not higher in nonrejecting patients than rejecting patients (Figure 1C). Similar observations were made in the BUiLT study (clinicaltrials. gov: NCT01023542) patients, who received either conventional triple immunosuppression or a “bottom-up” regimen (Supplementary Information, SDC, http://links. lww. com/TP/B261): Nonrejecting recipients showed a peak in Treg frequency at 2 weeks’ posttransplant that subsided by week 4; by comparison, no transient Treg enrichment was observed in patients who experienced a rejection episode during the first year posttransplant (Figure 1D). The kinetic of this response is suggestive of a primary T cell response; therefore, we tentatively propose that the enrichment and subsequent restitution of the peripheral Treg pool is evidence of an immunoregulatory reaction in nonrejecting patients. 6 We speculate that the early enrichment represents a polyclonal activation and expansion of Treg, whereas the decay phase might reflect the selection of a subset of donor antigen-reactive clones. Alternatively, changes in Treg frequency might be explained by more efficient suppression of non-Treg in nonrejectors compared with rejectors.“High granularity” immune monitoring studies that capture kinetic information about evolving immune responses in the early posttransplant period may be useful in predicting long-term transplant outcome. Treg frequency in nonrejectors at 1-week posttransplant was significantly higher than in rejectors (Figure 1E); however, treating each time point separately ignores the kinetic information won from serial sampling. Evaluating changes in leukocyte subset frequency over time may require new statistical approaches, including …