间充质干细胞与免疫抑制剂联合应用研究进展

移植受者长期免疫抑制明显增加感染性疾病及恶性肿瘤的发生概率,且免疫抑制剂无法阻止或延缓慢性移植物排斥反应的发生。间充质干细胞（MSC）兼有免疫抑制能力及诱导免疫耐受的特性。MSC联用免疫抑制剂旨在通过低剂量免疫抑制剂来维持有效的免疫抑制作用,确保MSC输注后不发生排斥反应,同时减少了免疫抑制剂的副作用;利用MSC具有诱导免疫耐受的特性,在特异性耐受形成后安全撤除免疫抑制剂,实现移植物及受者的长期存活。临床最理想的结果是两者协同发挥作用。本文就上述内容进行了文献综述。     

临床可操作性耐受预测指标的研究现状

器官移植是治疗终末期器官衰竭的有效手段。免疫耐受一直是器官移植领域的研究热点。近年来发现在一些停用免疫抑制剂的受者中发生自发耐受现象,被称之为临床可操作性耐受。临床可操作性耐受是指在不使用免疫抑制剂的情况下,至少1年以上无发生移植物排斥反应,获得移植器官长期存活的现象。本文就临床可操作性耐受的临床证据、预测指标两大方面的研究进展作一综述,以期为后续研究提供参考。     

调节性B淋巴细胞在免疫耐受中作用的研究进展

虽然免疫抑制剂能够改善肾移植受者的早期预后,但移植物的远期存活率并未得到明显提高,移植物10年存活率仅有50％.免疫抑制剂的不良反应是导致移植物功能丧失及受者死亡的重要因素.因此,诱导受者对供者特异性的免疫耐受是解决这些问题的根本途径.近几年来虽然诱导免疫耐受的临床工作已取得了较大的进展,部分移植中心已成功诱导受者对移植物的免疫耐受[1-2],但对于免疫耐受诱导方案并无共识,且诱导成功率并不高.这主要是由于免疫耐受形成机制复杂,不仅涉及中枢免疫耐受的形成,且外周免疫耐受对于耐受状态长期维持可能更为重要.大量研究提示,调节性T淋巴细胞(Treg细胞)可以通过与其他免疫细胞间接触、分泌调节性细胞因子等途径参与外周免疫耐受的形成[3],但针对获得性免疫的另一类重要细胞——B淋巴细胞在免疫耐受中作用的研究则较少.最新研究提示,B淋巴细胞不仅具有介导体液免疫排斥反应的正向免疫促进作用,还可能存在具有与Treg细胞类似的负性免疫调节作用的调节性B淋巴细胞(Breg细胞).这些发现为完善免疫耐受形成机制,进而制定有效的临床免疫耐受诱导方案奠定了基础.本文就Breg细胞在免疫耐受中作用的研究进展作如下综述.     

肝移植免疫抑制治疗临床应用进展

自从开展器官移植以来,外科手术技术和免疫抑制治疗发生了巨大变化。在过去十年中,排斥反应和移植物失功发生率已明显下降。目前,应用免疫抑制剂的长期并发症已取代排斥反应成为移植治疗的主要挑战。与肾移植和心脏移植相比,肝移植术后急性排斥反应发生率并不高,并且对移植物存活的影响较小,但不合理使用免疫抑制剂也会导致移植失败。如何诱导产生稳定而持久的免疫耐受,适当的免疫调节治疗将是肝移植良好开展的主要保证。本文拟对免疫抑制剂的种类、应用情况和目前的治疗进展进行综述,并探讨肝移植免疫抑制治疗的前景。     

树突状细胞的研究进展

排斥反应,特别是慢性排斥反应,是困扰器官移植的一大难题.诱导受者机体对移植物产生耐受反应是彻底克服器官排斥的理想措施.研究表明,未成熟树突状细胞(immature dendritic cells,iDC)在诱导机体免疫耐受中至关重要,其通过分泌内源性物质可诱导器官产生免疫耐受,而成熟的树突状细胞(dendritic cells,DC)则是体内最重要的抗原呈提细胞,诱导免疫排斥.现就DC的内分泌免疫机制综述如下.     

儿童移植免疫耐受的研究与思考

<正>器官移植技术已经成为挽救终末期器官衰竭患者生命的治疗策略之一。儿童肝移植术后5年的移植物和受者生存率≥90%[1,2]。人体对移植器官产生排斥反应, 使移植工作面临巨大挑战。理论上来说, 诱导移植术后免疫耐受能从根本上解决这个问题。免疫耐受是指器官移植受者停止免疫抑制药物治疗后, 移植物仍能维持正常功能, 机体对感染、肿瘤等产生正常的免疫应答[1]。中枢免疫耐受是指机体在免疫系统未发育成熟的胚胎期     

临床可操作性耐受机制的研究进展

器官移植是治疗终末期器官功能衰竭的有效手段,但因终身服用免疫抑制剂而增加了肿瘤、感染等风险,并有可能导致受者死亡和移植物失功。因此,免疫耐受一直是移植研究工作者的最终目标。近年来发现在一些停用免疫抑制剂的受者中发生自发耐受现象,称之为可操作性耐受。可操作性耐受是指在不使用免疫抑制剂的情况下,至少1年以上无发生移植物排斥反应,获得移植器官长期存活的现象。这一现象引起了移植免疫学家的广泛关注。本文介绍了临床可操作性耐受的临床监控及机制(包括调节性T细胞、B细胞和天然免疫细胞)方面的研究进展,以期为后续研究提供参考。     

肝移植术后免疫抑制剂的减停与免疫耐受

肝移植受者术后需要长期服用免疫抑制剂,但免疫抑制过度可能产生多种不良反应及副作用。目前世界范围内已有成功将免疫抑制剂减量到最小甚至停用的病例,然而停药很可能使移植肝出现纤维化等组织学异常,进而导致移植物功能丧失。诱导免疫耐受、检测外周血中能够反映免疫耐受的生物标志物,或运用某些临床参数建立的预测模型提前评估移植受者成功停药的概率,均有助于筛选出可以安全减停免疫抑制剂的潜在候选者,减少不良事件的发生。     

抗体诱导治疗在肝移植中的应用进展

应用生物蛋白制剂——抗体作为器官移植早期实施免疫抑制覆盖治疗的方法,可显著减少器官移植术后早期急性排斥反应的发生,且未显著增加移植后感染发生率,同时可延迟或减少CNI的应用,有利于保护肾功能、促进移植物功能恢复及受者长期存活。本文通过总结常见抗体免疫诱导剂的特点及作用机制,分析不同抗体诱导治疗应用于肝移植的临床获益与风险,为肝移植抗体诱导剂的合理使用提供参考。     

树突状细胞诱导肝移植术后免疫耐受作用机制的研究进展

本综述系统回顾了树突状细胞(DC)诱导肝移植术后免疫耐受的多种机制。为临床预防和治疗移植术后慢性排斥反应、改善受者长期存活率启发新思路。     

What do we know about the clinical impact of complete withdrawal of immunosuppression in liver transplantation?

The liver is a privileged organ with a lower incidence of rejection than other organs. However, immunosuppressive regimens are still required to control the alloreactive T-lymphocyte response after transplantation. These treatments may lead to severe complications, such as infectious diseases, cancers, cardiovascular diseases, and chronic renal insufficiency. In clinical transplantation, there is increasing evidence that some liver transplant recipients who cease taking immunosuppressive drugs maintain allograft function, suggesting that tolerance is already present. This strategy is feasible in 25% to 33% of liver transplant recipients. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression (IS) withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with it. In preliminary studies, IS withdrawal was safely achieved in selected liver transplant patients, and improved not only kidney function, but also other IS-associated side-effects such as hypercholesterolemia, hyperuricemia, hypertension, and diabetes control. However, longer follow-up periods are needed to confirm the benefits of IS withdrawal in liver transplant patients.     

Advances and effectiveness of the immunotherapy after liver transplantation

Transplant recipients usually have increased chances of graft rejection and graft vs host disease, requiring chronic immunosuppressive therapy. Nonetheless, long-term immunosuppression risks malignancies such as skin cancer, lymphoma, and Kaposi sarcoma. However, there are very few studies that included solid organ transplant recipients while studying the efficacy of immunotherapy. “Immunotherapy after liver transplantation: Where are we now?” is a study, where the authors described the mechanism of action and outcomes of immune checkpoint inhibitors specific to liver transplant recipients. The authors reported the graft rejection rates and the factors contributing to the rejection in the liver transplant recipients.     

'Prope' tolerance in a noncompliant living related small bowel transplant recipient after severe rejection

Advances in immunosuppression and surgical technique have greatly improved patient outcomes after intestinal transplantation. However, the procedure remains one of the most challenging among solid organ transplantation as a result of the high rate of acute rejection, sepsis, and posttransplantation lymphoproliferative disorder. Recently, clinical trials to explore tolerance protocols in humans have been initiated, including small bowel transplant recipients, with results not always reproducible. The concept of operational tolerance is more meaningful in the clinical setting when physiological stability of graft function is achieved in the absence of maintenance immunosuppression. We report the intriguing case of a living related small bowel transplant recipient who developed clinical "prope" tolerance to the graft after treatment of severe acute rejection despite continuous noncompliance with immunosuppressive therapy.     

Identification of a gene expression profile associated with operational tolerance among a selected group of stable kidney transplant patients

Despite their utility, immunosuppressive treatments have numerous side effects, including infectious complications, malignancies and metabolic disorders, all of which contribute to long‐term graft loss. In addition to the development of new pharmaceutical products with reduced toxicity and more comfortable modes of administration, tailoring immunosuppression according to the immune status of each patient would represent a significant breakthrough. Gene expression profiling has been shown to be a clinically relevant monitoring tool. In this paper, we have assessed the overall long‐term kidney transplant outcome and attempted to identify operationally tolerant‐like patients among recipients with stable clinical status at least 5 years post‐transplantation. We thus measured a combination of noninvasive blood biomarkers of operational tolerance in a cohort of 144 stable patients and showed that only 3.5% exhibited a gene expression profile of operational tolerance, suggesting that such a profile can be detected under immunosuppressive therapy but that its frequency is low in kidney transplant recipients when compared with liver transplant recipients. We suggest that a rational approach to patient selection, based on a combination of clinical and biological characteristics, may help to provide a safer method for identification of patients potentially suitable for immunosuppressive drug weaning procedures.     

Operational tolerance in intestinal transplantation

By presenting the first case report of true operational tolerance in an intestinal transplant patient, we aim to demonstrate that tolerance is possible in a field that has been hampered by suboptimal outcomes. Although operational tolerance has been achieved in liver and kidney transplantation, and some intestinal transplant patients have been able to decrease immunosuppression, this is the first instance of true operational tolerance after complete cessation of immunosuppression. A patient received a deceased-donor small intestinal and colon allograft with standard immunosuppressive treatment, achieving excellent graft function after overcoming a graft-versus-host-disease episode 5 months posttransplant. Four years later, against medical advice, the patient discontinued all immunosuppression. During follow-up visits 2 and 3 years after cessation of immunosuppression, the patient exhibited normal graft function with full enteral autonomy and without histological or endoscopic signs of rejection. Mechanistic analysis demonstrated immune competence against third party antigen, with in vitro evidence of donor-specific hyporesponsiveness in the absence of donor macrochimerism. This proof of principle case can stimulate future mechanistic studies on diagnostic and therapeutic strategies, for example, cellular therapy trials, that can lead to minimization or elimination of immunosuppression and, it is hoped, help revitalize the field of intestinal transplantation.     

An Appraisal of Tolerance in Liver Transplantation

Human liver allografts have a lower susceptibility to rejection than other organs. In addition, in some liver transplant recipients immunosuppressive drugs can be completely withdrawn, and these patients are considered as 'operationally' tolerant. Careful scrutiny of accumulated clinical experience indicates that elective immunosuppressive drug weaning is feasible in almost 20% of selected liver transplant recipients. This is associated with an incidence of 12% to 76% of acute cellular rejection, but these episodes are commonly mild and often resolve by return to baseline immunosuppression (IS), many times without the need to administer steroid boluses. Study of tolerance in liver transplantation (LT) has been hampered by confusion regarding the definitions of rejection and tolerance, and by the absence of prospective studies correlating results of immune monitoring assays and clinical outcome. Thus, we lack a clinically validated treatment-stopping rule capable of predicting the success of IS withdrawal and this procedure has to be performed on a 'trial and error' basis. The search for an accurate means to identify allograft tolerance among immunosuppressed recipients should become a priority in LT research. This information would provide a biological basis for guiding IS withdrawal protocols and for the implementation of tolerance-promoting strategies in LT.     

Isolated Hepatic Chronic Ductopenic Rejection Requiring Liver Retransplant in the Absence of Kidney Graft Rejection After Combined Liver-Kidney Transplant: A Case Report

The liver is considered the most immunotolerant organ among all solid-organ transplants. Liver transplant recipients have a lower incidence of rejection and better outcomes after episodes of rejection, with spontaneous operational tolerance developing in up to 20%. In multiorgan transplants, a protective effect of the liver allograft on simultaneously transplanted organs from the same donor has been demonstrated. We describe an unusual case of isolated liver allograft rejection in a patient with polycystic liver and kidney disease who received a combined liver-kidney transplant from the same donor. After initial discharge from the hospital, our patient had 2 episodes of biopsy-proven late acute cellular rejections, despite higher levels of immunosuppression required for her kidney allograft, which were addressed with pulsed steroid therapy. She had no evidence of ischemic cholangiopathy on imaging. Later, a subsequent liver biopsy demonstrated features consistent with chronic ductopenic rejection. She was eventually listed for liver retransplant and has recently received a second liver transplant while continuing to have no concerns with her kidney allograft function. Examination of the explanted liver confirmed graft loss from chronic ductopenic rejection. The exact reasons why our patient developed acute graft rejection progressing to chronic end-stage rejection of the liver allograft despite not developing graft rejection in the kidney allograft from the same donor remains elusive. Our experience demonstrates that graft tolerance in multiorgan transplant recipients can be organ specific and despite the belief of “immunologic privilege,” isolated liver allograft rejection can occur in multiorgan transplant, resulting in graft loss.