Sarwal Minnie M
Division of Transplant Surgery, University of California San Francisco, San Francisco, CA, USA.
Clin Biochem. 2016 Mar;49(4-5):404-10. doi: 10.1016/j.clinbiochem.2016.01.007. Epub 2016 Jan 13.
HLA incompatible organ transplant tolerance is the holy grail of transplantation. Stable engraftment of an HLA mismatched allograft and life-long tolerance induction, though feasible in highly selected cohorts with depletional protocols, is not ready for generalized application to the entire transplant recipient pool. It has thus been important to harness biomarkers that can uncover mechanisms and tools for monitoring HLA mismatched recipients that develop a state of operational tolerance, during accidental immunosuppression withdrawal secondary to problems of over-immunosuppression (infection or malignancy) or toxicity (mostly cosmetic or cardiovascular). A restricted and unpredictable group of patients can demonstrate a clinical state of operational tolerance, manifested by state of stable graft function of a graft with HLA mismatches between recipient and donor, intact immune responses to third party antigens and no measurable immunosuppression. These patients have served as the basis for the discovery of clinically correlative biomarkers, in distal biofluids (mainly blood), that can define the existing state of operational clinical tolerance. Operationally tolerant patients are rare, as withdrawal of immunosuppression most often results in rejection and graft loss. Nevertheless, operationally tolerant kidney, liver and heart allograft recipients have been reported. The presence of similar biomarker signature profiles in HLA mismatched transplant recipients on immunosuppression, suggests the feasibility of utilizing these biomarkers for educated immunosuppression minimization with a view to retaining immunological quiescence, while reducing the maintenance immunosuppression burden to a "safe" alloimmune threshold. Though clinical operational tolerance is rare, as immunosuppression cessation most often results in increased alloimmunity and rejection, the biomarker profile studies that have harnessed whole genome profiling suggest that the frequency of this state may be ~8% in kidney allograft recipients, and even more frequent in pediatric recipients and in liver transplantation: 25% in adult liver allograft recipients and ~60% in pediatric liver allograft recipients. In this review we discuss putative molecular mechanisms, cellular players and correlative biomarkers that have been developed through clinically associative studies of tolerant and non-tolerant patients. Through mechanisms of carefully constructed and monitored randomized, prospective clinical trials, the transplant community stands at the cusp of improved quality of recipient life through educated immunosuppression minimization.
HLA不相容器官移植耐受是移植领域的圣杯。HLA错配同种异体移植物的稳定植入和终身耐受诱导，虽然在采用清除方案的高度选择队列中是可行的，但尚未准备好广泛应用于整个移植受者群体。因此，利用生物标志物来揭示机制和工具以监测HLA错配受者在因过度免疫抑制（感染或恶性肿瘤）或毒性（主要是美容或心血管方面）问题导致意外免疫抑制撤减期间发展为操作耐受状态非常重要。一组受限且不可预测的患者可表现出操作耐受的临床状态，表现为受者与供者之间HLA错配的移植物具有稳定的移植物功能状态、对第三方抗原的完整免疫反应且无可测量的免疫抑制。这些患者已成为发现临床相关生物标志物的基础，这些生物标志物存在于远端生物流体（主要是血液）中，可定义操作临床耐受的现有状态。操作耐受的患者很罕见，因为免疫抑制撤减最常导致排斥反应和移植物丢失。然而，已有关于操作耐受的肾、肝和心脏同种异体移植受者的报道。在接受免疫抑制的HLA错配移植受者中存在相似的生物标志物特征谱，这表明利用这些生物标志物进行有针对性的免疫抑制最小化是可行的，目的是保持免疫静止，同时将维持免疫抑制负担降低到“安全”的同种异体免疫阈值。尽管临床操作耐受很少见，因为免疫抑制停止最常导致同种异体免疫增加和排斥反应，但利用全基因组分析的生物标志物特征研究表明，这种状态在肾同种异体移植受者中的发生率可能约为8%，在儿科受者和肝移植中更为常见：在成人肝同种异体移植受者中为25%，在儿科肝同种异体移植受者中约为60%。在本综述中，我们讨论了通过对耐受和不耐受患者的临床关联研究开发的推定分子机制、细胞参与者和相关生物标志物。通过精心构建和监测的随机、前瞻性临床试验机制，移植界正处于通过有针对性的免疫抑制最小化来提高受者生活质量的关键时刻。
