Plasmacytoid Dendritic Cells: No Longer an Enigma and Now Key to Transplant Tolerance?

Plasmacytoid (p) dendritic cells (DC) are a specialized subset of DC whose primary role was initially defined by the production of type I interferons in response to viral infection. They are now known to also possess a repertoire of functions capable of determining T cell fate and activation. Under homeostatic conditions, non‐lymphoid tissue‐resident pDC play a critical role in the regulation of mucosal immunity, as well as the development of central and peripheral tolerance. Although these cells display a number of characteristics that differ from conventional DC, particularly altered costimulatory molecule expression and poor allostimulatory capacity when interacting with T cells, this phenotype favors the generation of alloantigen‐specific regulatory CD4⁺ or CD8⁺ T cells critical to the development of graft tolerance. In this minireview, we discuss pDC ontogeny, functional biology and the emerging data that demonstrate the importance of pDC in the induction of tolerance, as well as recent studies that define mechanisms underlying pDC‐mediated tolerance to both solid organ and haematopoietic stem cell transplants. We also highlight their use in clinical settings and the potential of pDC both as targets and cellular therapeutic agents to improve the outcome of organ transplantation.     

Humanized Mouse Models for Transplant Immunology

Our understanding of the molecular pathways that control immune responses, particularly immunomodulatory molecules that control the extent and duration of an immune response, have led to new approaches in the field of transplantation immunology to induce allograft survival. These molecular pathways are being defined precisely in murine models and translated into clinical practice; however, many of the newly available drugs are human‐specific reagents. Furthermore, many species‐specific differences exist between mouse and human immune systems. Recent advances in the development of humanized mice, namely, immunodeficient mice engrafted with functional human immune systems, have led to the availability of a small animal model for the study of human immune responses. Humanized mice represent an important preclinical model system for evaluation of new drugs and identification of the mechanisms underlying human allograft rejection without putting patients at risk. This review highlights recent advances in the development of humanized mice and their use as preclinical models for the study of human allograft responses.     

The Fourth International Workshop on Clinical Transplant Tolerance

The International Workshop on Clinical Transplant Tolerance is a biennial meeting that aims to provide an update on the progress of studies of immunosuppression minimization or withdrawal in solid organ transplantation. The Fourth International Workshop on Clinical Tolerance was held in Pittsburgh, Pennsylvania, September 5-6, 2019. This report is a summary of presentations on the status of clinical trials designed to minimize or withdraw immunosuppressive drugs in kidney, liver, and lung transplantation without subsequent evidence of rejection. All protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. The workshop also included presentations of mechanistic studies designed to improve understanding of the cellular and molecular basis of tolerance and to identify potential predictors/biomarkers of tolerance. Strategies to enhance the safety of hematopoietic cell transplantation and to improve patient selection/risk stratification for clinical trials were also discussed.     

皮肤移植免疫研究

Skin grafting has been one of the most important approaches for covering burn wounds, however long-term survival of allogeneie or xenogeneic skin graft is currently not successful. How to induce immune tolerance for life-time survival of allogeneic or xenogeneie skin graft is still remote objective to be solved. However, clinicians and scientists in China have worked very hard and made great contribution to this field during the past 50 years, no matter how diffieult it is. They are the re spected pioneers in the understanding of immunological change in "Chinese Method" skin grafting, its local immune tolerance, immunology of pre-treatment of skin graft, etc. Herein, the most outstanding and impressive progresses in immunological responses after skin grafting in the past 50 years in China have been re viewed and presented for memory, for future and for extanding a salute.     

树突状细胞在器官移植免疫耐受中的研究进展

树突状细胞（DC）是具有特异性功能的专职抗原提呈细胞,可特异性吞噬抗原、加工并提呈给效应性T细胞,在免疫耐受与免疫应答方面发挥重要作用。耐受性DC（tol-DC）是一群具有负向免疫调控功能的DC亚群,可通过中枢与外周机制诱导器官移植免疫耐受状态。本文拟对DC的表型与功能特征、DC诱导移植免疫耐受机制、tol-DC在器官移植领域的应用进行总结,旨在为临床转化医学研究提供基础理论支持。     

What's New and What's Hot? Basic Science at the American Transplant Congress 2012

Application of advanced molecular techniques and novel animal models has provided new insights into basic mechanisms underlying clinical transplantation. Investigations in diverse areas, including graft rejection and tolerance, autoimmunity and infectious diseases, have revealed increasing complexity of the mechanisms controlling immune function, notably at the interface of the innate and adaptive immune systems and within secondary lymphoid organs. New roles have been identified for NK and dendritic cells, B‐lymphocytes and for Th17 and regulatory T cells, notably in novel animal models of costimulatory blockade and tolerance. Confirmation of these observations will be needed in normal animals and in humans undergoing organ and cell transplantation. The impact of the microbiome, of vaccines, and of antimicrobial therapies on immune memory and reconstitution after lymphocyte depletion is beginning to be defined.     

胰腺移植免疫耐受研究进展

目的总结胰腺移植免疫耐受的研究进展。方法分析近年来有关胰腺移植免疫耐受研究进展的文献报道。结果外周性耐受及中枢性耐受是诱导免疫耐受的主要方法，其中通过供体特异性骨髓细胞输注诱导嵌合体形成是目前的研究热点。结论供体特异性骨髓细胞输注联合一种或多种外周性耐受方法有望诱导胰腺移植免疫耐受，但需进行深人研究。     

自发免疫耐受大鼠移植肝内调节性T细胞的生物学特性

目的研究大鼠肝移植后自发免疫耐受的形成与移植肝内CD4~ CD25~ 调节性T细胞(Tr细胞)的关系。方法按供、受者不同将实验分为3组。急性排斥组:DA大鼠为供者,LEW大鼠为受者;自发耐受组:LEW大鼠为供者,DA大鼠为受者;同基因组:供、受者均为DA大鼠。各组均建立大鼠原位肝移植模型。分别在肝移植术后4、7、14、30和90 d时采用密度梯度离心法分离移植肝内淋巴细胞,免疫磁珠分离(MACS)法分选出CD4~ CD25~ Tr细胞;用流式细胞术(FCM)检测细胞纯度,同时分析CD4~ CD25~ Tr细胞比例的变化;体外细胞增殖试验研究CD4~ CD25~ Tr细胞对CD4~ CD25~-T细胞的免疫抑制作用。结果肝移植早期,急性排斥组和自发耐受组移植肝内CD4~ CD25~ Tr细胞比例均明显增加,其中急性排斥组增加更为明显;移植后4 d左右,两组CD4~ CD25~ Tr细胞比例开始下降,急性排斥组的下降幅度较大;移植后30 d,自发耐受组受者的移植肝内CD4~ CD25~ Tr细胞比例达到第2次高峰,约在移植后90 d时下降至正常生理水平。移植后7 d左右,急性排斥组受者均因发生排斥反应而死亡,而自发耐受组受者均存活。此外,CD4~ CD25~ Tr细胞能有效抑制CD4~ CD25~-T细胞的增殖。结论CD4~ CD25~ Tr细胞是一种具有特异免疫调节功能的T细胞亚群,其主动的免疫抑制功能可能是诱导大鼠肝移植自发免疫耐受的机制之一。     

嵌合体在同种心脏移植免疫耐受中的作用

目的探讨嵌合体在同种心脏移植免疫耐受中的作用.方法采用大鼠腹部心脏移植模型,将30只Lewis大鼠随机分成正常对照组(Ⅰ组)、排斥反应组(Ⅱ组)、免疫耐受组(Ⅲ组),每组10只.观察移植心存活时间,供心病理学改变,供、受者间的混合淋巴细胞反应(MLR)和脾、胸腺嵌合体.结果Ⅲ组供心平均存活时间(85.28±7.48天)较Ⅱ组(7.33±1.03天)显著长(P＜0.01);Ⅱ组供心见大量炎性细胞浸润,Ⅲ组供心仅见少量炎性细胞浸润;Ⅲ组供、受者间MLR较Ⅰ组显著低(P＜0.01);Ⅲ组受者的脾、胸腺形成了稳定的供者细胞嵌合体.结论移植免疫耐受的受者形成了稳定的中枢和外周嵌合体,嵌合体的形成对移植耐受起重要的作用.     

免疫耐受标志物在器官移植中的研究进展

尽管器官移植在过去的50余年中取得了明显进步,但免疫抑制剂应用带来的相关不良反应是影响移植受体长期存活的因素之一,免疫耐受是解决这一问题的关键.近年来,临床上发现部分器官移植受体发生了临床免疫耐受.研究发现,外周血中调节性T淋巴细胞、B淋巴细胞数量和部分基因表达在肾移植免疫耐受者有明显差异;外周血中调节性T淋巴细胞、树突状细胞、γδTCR+T淋巴细胞数量和部分基因表达在肝移植免疫耐受者有明显差异,提示上述指标作为器官移植免疫耐受标志物的潜在价值.MicroRNA由于其在免疫系统中的重要作用,初步研究提示其可作为潜在的免疫耐受标志物.     

色氨酸2,3-双加氧酶在色氨酸分解代谢及免疫调节中的作用

色氨酸2,3-双加氧酶(TDO)是催化色氨酸由犬尿氨酸(Kyn)途径分解代谢的限速酶.TDO主要在肝内降解色氨酸,调整体内色氨酸水平,能够抑制T细胞增殖,参与抗菌及炎性反应.代谢产物Kyn为芳烃受体(AhR)的内源性配体,TDO-Kyn-AhR通路具有调节肿瘤生长作用.随着对TDO介导色氨酸代谢免疫机制研究的不断积累,其在肿瘤治疗及移植免受耐受领域的应用前景令人期待.本文就TDO介导的色氨酸分解代谢及免疫调节作用进行综述.     

猪肝肠联合移植免疫耐受的实验研究

目的 研究猪肝肠联合移植中肝移植物对同源小肠移植物免疫耐受的作用.方法 70头杂交长白猪分为4组,A、B、C组为辅助性同种异体肝肠联合移植(每组20头);D组为节段性间种异体小肠移植(10头).移植后A、D组未用免疫抑制剂治疗,B、C组分别采用常规剂量和小剂量的环孢素和甲基强的松龙治疗.结果 A组术后小肠移植物较D组排斥反应时间延迟,程度明显减轻(P＜0.05).常规剂量的B组与小剂量的C组在术后存活时间、排斥反应开始时间以及排斥反应程度方面差异无统计学意义(P＞0.05).结论 猪同种异体肝肠联合移植中肝移植物可以诱导同源小肠移植物免疫耐受.     

Transplant Tolerance in Non-Human Primates: Progress, Current Challenges and Unmet Needs

Given the significant morbidity associated with current post-transplant immunosuppressive regimens, induction of immune tolerance continues to be an important goal of clinical organ transplantation. While many strategies for inducing tolerance have been successfully applied in murine models, significant barriers are faced when translating these approaches to the clinic. This has necessitated pre-clinical studies in the more closely related model system, the non-human primates (NHP). In this review, we will discuss the four most prominent strategies for inducing transplantation tolerance and highlight their relative success and shortcomings in NHP. These strategies are: (1) T-cell costimulation blockade (2) mixed chimerism induction (3) T-cell depletion and (4) tolerance induction through regulatory T-cells. After discussing the progress that has been made with each of these strategies, we will identify this field's most pressing unmet needs and discuss how we may best overcome the resulting barriers to tolerance induction.     

异基因小鼠髓腔内骨髓移植诱导免疫耐受

目的探讨异基因小鼠髓腔内骨髓移植(IBM-BMT)诱导免疫耐受的效果。方法雄性BALB/c小鼠和雌性C57BL/6小鼠分别作为骨髓移植的供、受者。受者预处理后进行IBM-BMT,建立异基因小鼠骨髓移植模型。通过皮肤移植和混合淋巴细胞反应(MLR)对受者的耐受状态进行检测。结果接受过IBM-BMT的受者进行供者来源的皮肤移植,移植物的存活时间>300d,较对照组的(12.7±1.63)d明显延长(P<0.01),而受者接受来自无关供者(KM小鼠)的皮肤移植物存活时间未见延长。接受过IBM-BMT的受者脾细胞对供者脾细胞的MLR增殖率均明显降低,与对照组比较,P<0.01,而对无关供者的脾细胞仍表现强烈的增殖反应。结论应用IBM-BMT可以诱导受者获得供者抗原的特异性免疫耐受,使移植物存活时间延长。     

hIL-10修饰骨髓间充质干细胞对大鼠原位异种肝移植急性排斥反应的影响

目的 研究hIL-10基因修饰的骨髓间充质干细胞(MSCs)对大鼠原位异种肝移植排斥反应的影响及机制.方法 采用豚鼠对Wistar大鼠的非协调性异种原位肝脏移植模型,实验动物随机分为3组:空白对照组,MSCs组,hIL-10-MSCs组.观察受体存活时间、受体鼠肝功能变化.术后第24小时取移植肝脏,用RT-PCR、ELISA法观察E-Selectin、LFA-1、VCAM-1及NF-κB的表达情况.结果 与空白对照组相比,hIL-10-MSCs组大鼠生存时间延长、肝功能好转,黏附分子E-Selec-tin、LFA-1、VCAM-1和NF-κB表达明显降低(P＜0.05).结论 hIL-10-MSCs对移植肝脏保护作用可能与其抑制NF-κB、E-Selectin、LFA-1、VCAM-1的表达有关.     

男性肾移植受者性功能状态的调查

目的 :观察男性肾移植受者性功能状态变化。　方法 :随机选择 2 6～ 45岁、术后半年以上、血肌酐 2 0 0μmol/L以下的已婚男性肾移植受者 60例 ,对他们病前、肾衰后及肾移植术后性功能状态进行了回顾性调查并将结果进行统计学分析。　结果 :受者肾衰后性功能明显下降 ,而肾移植术后性功能普遍得到改善 ,但尚未恢复到病前水平。受者普遍担心性生活会对移植肾产生不良的影响。　结论 :肾移植可明显改善男性尿毒症病人性功能 ,对肾移植受者及其配偶进行性生理咨询和指导十分必要