器官移植免疫抑制剂应用现状及其发展趋势

器官移植的发展取得了令人瞩目的成绩,除了外科技术的日臻成熟外,更为有效、安全的新型免疫抑制剂的不断推出及临床应用起了重要作用。由于移植免疫耐受机制未能弄清,器官克隆,干细胞移植(从细胞→组织→器官→临床应用)到移植临床实际应用尚需经历漫长的道路,因此,21世纪最初的10～15年,器官移植领域依然是免疫抑制为主的时代,但免疫抑制的发展引入了新概念,新趋势。新一代免疫抑制剂使早期移植器官失功的危险性降到最低限度,但同种肾移植长期存活的改善并不乐观。慢性移植肾失功已经成为影响肾脏移植长期存活的最主要因素。此外,移植受者的感染,心血管疾病,免疫抑制剂尤其是calcineurin抑制剂长期应用造成的肝,肾毒性,移植肾血移植肾血管病变及肝功能严重受损,移植后恶性肿瘤的发生等诸多问题,给免疫抑制剂的调控提出了新的课题及要求。未来免疫抑制剂研究与应用的趋势:(1)免疫抑制须建立在对免疫应答的充分理解基础上;(2)尽管许多新型免疫抑制剂在细胞内靶分子作用点的不断完善能产生淋巴细胞特异性免疫抑制作用,而无特异的毒副作用,但免疫抑制的最终目的依然是应当诱导产生/建立供者特异性耐受状态;(3)新型免疫抑制剂应同时保留宿主对病毒、真菌、肿瘤等抗原的免疫反应功能。皮质激素撤除,CNIs的减?     

肾移植后恶性肿瘤16例：临床报告并文献复习

背景：肾移植后发生恶性肿瘤的原因是多方面的,其高发率与大剂量免疫抑制剂的长期应用密切相关。 目的：回顾性分析肾移植后免疫抑制剂应用情况、恶性肿瘤发生率、移植后肿瘤发生时间,发病特征及其相关因素,探讨肿瘤与免疫抑制剂的相关性。 方法：对512例肾移植中并发恶性肿瘤的16例患者的临床资料进行回顾性分析。15例患者肾移植后采用霉酚酸酯 +环孢素A+甲泼尼龙三联预防排异反应,1例患者采用霉酚酸酯+硫唑嘌呤+甲泼尼龙。移植后肿瘤的治疗方法：手术12例,单纯化疗1例,因病情晚期出现多处转移或患者放弃治疗3例。 结果与结论：肾移植后患者肿瘤发生率为3.13%,其中泌尿系肿瘤6例,占37.5%;消化道肿瘤4例(结肠癌2例,直肠癌、胃癌各1例),占25.0%;肝癌3例,占18.75%;皮肤癌、肺癌、卵巢癌各1例,各占6.25%。提示肾移植后患者最常见的恶性肿瘤为泌尿系肿瘤,其次为消化道肿瘤。对移植后患者,减少免疫抑制剂用量是防止移植后肿瘤发生、提高移植后患者长期存活率的主要因素之一。     

移植免疫相关的转化医学研究进展

器官(组织)移植是20世纪临床医学一项重大成就,已成为治疗多种终末期疾病的有效手段.本文简述移植免疫相关的转化医学研究进展. 1新型免疫抑制剂 免疫抑制剂仍是防治移植排斥反应的主要策略.     

α-1抗胰蛋白酶在器官移植中的保护性作用

器官移植是目前终末期器官衰竭患者的主要替代治疗手段.免疫抑制剂的应用虽然降低了器官移植后急性排斥反应的发生率,但是并没有从根本上改善移植受者的长期生存.究其原因,主要是由于非特异性免疫抑制剂的毒副作用所致.因而减少免疫抑制剂毒副作用的最理想方案是诱导机体免疫耐受的形成,但是目前在临床上还无法常规实现.近期有研究证实,外源性α-1抗胰蛋白酶能明显减轻肝脏、胰腺、肺等器官移植的缺血再灌注损伤引起的凋亡和炎症,为器官移植的保护性研究提供了新的方向.     

短期免疫抑制同种异体肢体移植大鼠周围神经的损伤与再生

背景:肢体移植后肢体生存时间的延长和移植后肢体功能的恢复是关系到肢体同种异体移植能否在临床广泛开展的决定性因素。目的:观察短期免疫抑制治疗对肢体移植后神经再生和功能恢复的影响。方法:将30只SD大鼠随机分为3组。短期组:肢体移植后应用免疫抑制剂14d;长期组:肢体移植后长期应用免疫抑制剂直到取材。对照组单纯肢体移植组术后腹腔内注射生理盐水。术后采用足迹分析、免疫组织化学对组织形态观察评价神经再生和功能恢复的情况。结果与结论:短期组与长期组的功能恢复无明显差别(P0.05),均明显优于对照组(P0.05)。组织形态观察显示短期组神经功能恢复优于对照组(P0.05),短期组与长期组神经纤维再生差异无显著性意义。长期组有3只大鼠因为免疫抑制剂影响导致死亡,对照组与短期组均没有动物模型死亡现象。结果提示,短期应用免疫抑制治疗可迅速减轻周围神经损伤后发生的免疫排斥反应,从而快速改善周围神经损伤后再生的微环境,提高神经的再生速度和质量,取得了与长期应用免疫抑制剂同样的效果而没有致命的不良反应,对于临床应用免疫抑制剂有潜在的意义。     

CD4~+CD25~+调节性T细胞在同种异体移植免疫耐受中的研究进展

同种异体器官移植已经成为终末器官衰竭患者修复病损的组织和器官,并重建其功能必要的治疗方法。受者往往都需要长期接受免疫抑制剂来维持移植物在其体内的存活。由于免疫抑制剂的非特异性及毒副作用,长期应用该类药物会导致受者免疫力低下而出现易感染、癌症等副作用。因此,解决该问题的关键是诱导受者对供者移植抗原产生特异性地"移植免疫耐受"。大量研究结果显示,CD4+CD25+调节性T细胞能特异性地抑制免疫排斥反应,在调控免疫应答与维持外周免疫耐受中发挥着重要作用。本文对近年来CD4+CD25+调节性T细胞的作用机制及其在同种异体移植免疫耐受方面的研究进行了综述。     

移植后高尿酸血症

随着新型免疫抑制剂不断涌现，器官移植爱者存活率大幅提高。高尿酸血症在受者中普遍存在，但常被忽视。爱者高尿酸血症主要与药物相关，尤其环孢素和利尿剂。高尿酸血症影响爱者和移植器官的存活率。预防和治疗移植后高尿酸血症是受者管理的重要环节。     

免疫抑制剂在非清髓性造血干细胞移植预处理中的应用

非清髓性造血干细胞移植(non-myeloablative stem celltransplantation,NST)已经广泛应用于血液系统恶性疾病、某些实体器官肿瘤以及非恶性疾病的治疗,在某些疾病方面有取代标准移植的趋势.NST的预处理方案中应采用较强的免疫抑制剂,以促进供者细胞的植入,通过移植物抗肿瘤效应(GVT)来清除受者造血细胞及肿瘤细胞[1].随着对NST研究的深入,越来越多的免疫抑制剂被用于NST预处理方案中,现就NST预处理中常用的免疫抑制剂的作用机制、研究进展及临床应用、不良反应作一综述.     

免疫抑制剂在肾移植中的应用

目的:探讨免疫抑制剂在肾移植急性排斥反应中的作用和安全性。方法:应用计算机检索2000-01/2009-10维普数据库和清华同方数据库。以"肾移植、免疫抑制剂、霉酚酸酯、他克莫司、环孢素、雷帕霉素、抗CD25单克隆抗体、抗CD3单克隆抗体"为检索词。文章所述内容应与免疫抑制剂预防、治疗肾移植术后急性排斥反应的研究相关。结果:肾移植应用免疫抑制剂可以降低急性排斥发生率,使得移植肾短期存活明显改善,免疫抑制剂的肾毒性仍然是制约移植肾长期存活的重要因素。近年来出现新型免疫移植剂如雷帕霉素、FFY720等使得移植肾的长期存活成为可能。新型免疫抑制方案应着重减少毒副反应而不是单纯降低排斥反应发生率。结论:随着近年来对移植免疫认识的深入,在免疫抑制剂上取得了很大的进步,给临床医生提供了越来越多的选择,但是令人满意的免疫抑制剂和免疫抑制方案还需不断探索。     

肾移植后肺部感染治疗中免疫抑制剂的应用

背景：肾移植后肺部感染病情进展快,重症肺炎死亡率高,对其进行早期诊断及治疗具有重要意义,但部分患者因免疫抑制剂的调整,出现移植肾功能受损。 目的：探讨肾移植后肺部感染治疗过程中免疫抑制剂的应用方案。 方法：回顾分析85例肺部感染的肾移植患者的临床资料。肺部感染发生于肾移植后1-6个月43例(其中2-4个月39例),6-12个月7例,12-24个月7例,24-36个月6例,大于36个月22例。根据患者病情,予以调整免疫抑制剂,联合应用小剂量激素抗炎保护移植肾功能,针对病原学抗感染,呼吸衰竭者给予呼吸机辅助呼吸,同时予以降温及营养支持等对症治疗。肺部感染早期减少或停用免疫抑制44例,进展期减少或调整免疫制剂19例,重症肺炎期停用免疫抑制剂5例,肺炎早期及进展期逐步调整免疫抑制15例,肺炎早期减量至重症肺炎停用免疫抑制剂2例。减少或停用免疫抑制剂3-51 d,平均10.7 d。 结果与结论：85例患者中治愈81例,死亡4例。4例死亡病例中,2例死于急性呼吸衰竭,2例死于多器官功能衰竭。治愈的81例中出现急性排异反应3例,移植肾功能受损6例。结果提示,肾移植后肺部感染短时间减少或停用免疫抑制剂,有利于提高治愈率,减少死亡率,及时恢复免疫制剂的应用,能有效保护移植肾功能,尤其是移植肾功能不全患者,肺部炎症进展控制住,及时恢复免疫抑制,在保护移植肾功能的意义更大。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

Islet Transplantation in Patients with Diabetes Mellitus

Islet transplantation offers patients with type 1 diabetes mellitus freedom from long-term insulin therapy and a degree of metabolic control that is far superior to injected insulin. The hope is that near-perfect glucose control sustained over time will prevent progression of secondary diabetic complications. The selection of optimal immunosuppressive agents for islet transplantation has been a formidable challenge, given the need to overcome both autoimmune and alloimmune barriers, as well as the potential toxicity of immunosuppressive agents on transplanted islets. Early strategies relied on protocols that had proven success in solid organ transplantation and consisted of azathioprine, cyclosporine and corticosteroids. Under these protocols, fewer than 10% of patients were able to achieve insulin independence. The development of the 'Edmonton Protocol' dramatically transformed clinical outcomes in islet transplantation in recent years through the introduction of a more potent, less diabetogenic, and corticosteroid-free immunosuppressive regimen consisting of sirolimus, low-dose tacrolimus, and induction anti-interleukin-2 receptor antibody. While insulin independence rates under this protocol have been highly successful, patients must be maintained on lifelong immunosuppression. While the risk of malignancy, post-transplant lymphoma and sepsis have been low and diminishing in transplanted patients to date, fears of these complications and a host of drug-related adverse effects have precluded broader application. Patients undergoing islet transplantation today must exchange insulin for chronic immunosuppressive therapy, and therefore the procedure can only be justified in patients with very unstable forms of diabetes, or in those with another solid organ allograft who already endure the risks of immunosuppression. Advances in more specific and less toxic immunosuppressive agents together with progress in better understanding the biology of diabetes will lead to more suitable strategies to control both alloimmune and recurrent autoimmune reactions. These protocols, ultimately aimed at establishing tolerance, are an essential pre-requisite to move towards providing islet transplantation earlier in the course of the disease, including transplantation in children. This review addresses the evolution of immunosuppressive strategies in islet transplantation, and highlights some novel agents in pre-clinical development or in early clinical trials that may offer considerable promise in facilitating the induction of tolerance.     

PERIPHERAL TOLERANCE TO ALLOANTIGEN: STRATEGIES FOR THE FUTURE

The mature, adult immune system is specifically designed to eliminate any foreign material that may enter the body, but not to respond to the body's own tissues and molecules. Indeed, during development, the potential of the immune system to respond to self antigens is removed, by eliminating or effectively silencing any autoreactive cells. These features are well adapted under normal circumstances, as they result in the efficient elimination of potentially harmful agents thereby protecting the body from infection and malignancy. However, in the context of transplantation, this ‘normal’ response is diametrically opposed to the desired clinical outcome, which is clearly the long term function and survival of the transplanted tissue. To prevent graft rejection the immune system of the transplant recipient has to be manipulated to ensure that it is incapacitated. Immunosuppressive drugs can be used for this purpose and are undoubtedly effective; indeed they have had a dramatic impact on success rates in clinical organ transplantation. However, as the mechanism of action of these chemical immunosuppressants is immunologically non-specific, any immune response the recipient may need to make after transplantation, as well as the rejection response, is suppressed. In addition, to maintain graft survival the drugs have to be taken indefinitely after transplantation and therefore their use is not only associated with immunological complications such as increased risks of infection and malignancy, but also numerous non-immunological side-effects. One way to overcome these problems would be to develop strategies for specific immunosuppression, such that only leukocytes capable of responding to the foreign histocompatibility or alloantigens expressed by the transplanted tissue would be affected. The ability to manipulate or reprogramme the adult immune system in such a way as to induce specific immunological unresponsiveness or tolerance to the alloantigens of the organ donor would offer many advantages over conventional immunosuppressive therapy. Only leukocytes reactive with donor alloantigens would be affected, thus allowing transplant recipients to respond effectively to other immunological stimuli, such as virus infections.     

Clinical transplantation tolerance

Transplantation is the treatment of choice for many if not most causes of end-stage organ failure. Over 20,000 organ transplant procedures were performed in the USA in 2009 to treat patients with failed or failing kidneys, livers, hearts, lungs, and intestines, and there remain 85,000 individuals waiting on the transplant list. Currently, in the USA, there are over 170,000 individuals living with a transplanted organ. Virtually, all of these individuals receive maintenance immunosuppression in an attempt to maximize the function and survival of the transplanted organ. However, it is clear that the long-term use of immunosuppressive agents is associated with an extensive list of undesirable side effects that have the potential to limit the survival of the patient and transplanted organ as well as to compromise quality of life. Although the ability to induce reproducibly a state of robust, stable tolerance would address this problem, tolerance remains an infrequent event in clinical transplantation that is largely a consequence of chance. Factors limiting the broader investigation of clinical transplantation tolerance include the lack of therapeutic regimens known to favor tolerance in humans, the lack of validated assays or biomarkers predictive of tolerance, and concerns about the safety and ethics of complete withdrawal of immunosuppression given the very good results achievable with current immunosuppression. Despite these barriers, a number of investigators have continued to conduct well-designed and carefully supervised studies with the long-term goal of making clinical transplantation tolerance more feasible. The aim of this review is to summarize the status of these studies.     

Developments in Inhaled Immunosuppressive Therapy for the Prevention of Pulmonary Graft Rejection

Cyclosporin is the main immunosuppressive treatment for lung and heart-lung transplantation. When combined with azathioprine and oral corticosteroids, repeated episodes of acute rejection are limited to a minority of transplant patients. Despite early successful transplantation, many patients developed a disabling and fatal condition called obliterative bronchiolitis. This is currently thought to be a result of chronic rejection. The principal risk factor for the development of obliterative bronchiolitis is undercontrolled acute rejection in the first 3 months after transplantation. Frequent early acute rejection increases the later risk of death and disability. A new approach to immunosuppressive therapy is needed to prevent this complication. Simply increasing the dosage of cyclosporin or oral corticosteroids results in the major complications of opportunistic infection and renal failure. Targeted immunosuppressive treatment delivered to the transplanted organ may offer certain advantages, since a high topical inhaled dosage should be relatively free from systemic complications. The lung as a transplanted organ is easily accessible to targeted therapy by means of inhalation. Inhaled nebulised corticosteroids have been shown to be effective in preventing obliterative bronchiolitis in patients at risk after heart-lung transplantation. Similarly, inhaled cyclosporin has also been reported to be more effective than oral administration, with substantially lower blood concentrations. Such new approaches to targeting immunosuppressive treatment could have specific advantages in long term therapy of lung and heart-lung transplant recipients. They might also be of use in other types of solid organ transplantation.     

Transplantation tolerance by donor MHC gene transfer

Replacing the function of diseased organs by transplantation has proved to be highly successful in the past four decades. The immune system poses the most significant barrier to the long term survival of the transplanted organs. Without lifelong treatment with powerful immunosuppressive agents to keep the immune response at bay, organ grafts will invariably be rejected. However, current immunosuppressive agents are non-specific and leave transplant recipients more susceptible to opportunistic infections and tumour development. Achieving donor specific tolerance would eliminate the need for lifelong treatment with these agents and thereby, avoid the associated side effects. There have been many exciting new developments in immunopharmacology and in the understanding of the mechanisms of rejection and tolerance. These developments on their own, or in combination with the use of gene therapy techniques may allow the induction of transplantation tolerance in human recipients of allografts in the future. Pretransplant exposure to donor MHC antigens has been highly successful strategy for tolerance induction in experimental models. Pretransplant blood transfusion, and more recently administration of donor bone marrow, has been used in an attempt to prolong graft survival in human. However, using fully allogeneic donor bone marrow carries the risk of graft versus host disease. Gene therapy may allow this approach to be used without this risk. Here, we review efforts to induce transplantation tolerance by gene transfer of donor MHC genes to recipient derived cells and show that this may be a potential strategy to achieve the holy grail of organ transplantation: donor specific tolerance.     

Invasive mycosis in solid organ transplantation]

Invasive mycosis in solid organ transplantation is mainly caused by Candida and Aspergillus, and its risk is higher in small bowel, liver, pancreas, and lung transplantation. Although limited analyses propose not a few risk factors for invasive mycosis in respective transplanted organs, the efficacy of prophylactic use of antifungal agents or preemptive treatments based on the information is not fully supported by prospective randomized controlled clinical data. The final guideline should be helpful for tailor-made evidence-based management based on the stratification of patients by pretransplant, surgical, immunosuppressive and organ specific characteristics. The process of repeated proposals and verification in a large number of patients is necessary.     

Role of Mesenchymal Stem Cells in Immunological Rejection of Organ Transplantation

The discovery that Mesenchymal Stem Cells (MSCs) can strongly inhibit T cell proliferation in vitro and in vivo and exert similar inhibitory effects on B cells, dendritic cells, and natural killer cells has highlighted the potential for clinical translation of these cells as a new class of stem cell therapy for autoimmune disease, organ transplantation and treatment of graft-versus-host disease (GVHD). Even though the mechanism underlying these immunosuppressive effects of MSCs has not been clearly defined, their immunosuppressive properties are already being exploited in the clinical setting. Most of these early clinical studies are investigating the effect of MSCs in suppressing GVHD after allogenenic hematopoietic stem cell transplantation (HSCT). Additional studies, mostly in animal models, are being conducted in solid organ transplantation, such as: heart, renal, liver and skin. While the early results of these studies are conflicting, the potential for clinical benefit remains high and further studies are warranted in order to discover the best methods and settings for consistent clinical results. MSCs have opened a series of opportunities for researchers in the areas of transplantation and autoimmune disease. While it is important not to overestimate the potential therapeutic effects of MSCs, and well-designed preclinical trials should be done before clinical use.     

Gene therapy for the induction of chimerism and transplant tolerance

Technical advances in transplant surgery and the development of powerful and effective immunosuppressive drugs have contributed to the success of organ transplantation as a medical treatment for patients with end-stage diseases. Associated with this procedure, however, is a dependence on life-long immunosuppressive drugs, which are required to prevent graft rejection. These agents render the patient susceptible to infections, tumors and various side affects. The ability to achieve tolerance to organ grafts would free transplant patients from lifelong dependency on pharmacological agents with harmful side effects. Several laboratories have shown that tolerance can be achieved by the induction of mixed cell chimerism and/or by molecular chimerism achieved by gene transfer techniques prior to graft placement. Molecular chimerism, induced by transplantation of autologous bone marrow expressing either allo- or xenoantigens has the potential to induce tolerance without the development of graft vs. host disease. The application of gene transfer techniques to induce chimerism has been shown to reshape the immune repertoire by mechanisms that include clonal deletion, the induction of central tolerance or generation of regulatory T cells that would eliminate the need for immunosuppressive drugs. Optimization of this methodology for clinical use could therefore revolutionize the field of transplantation. This review summarizes the recent studies which have compared the efficacy of different vectors, conditioning regimens, and transduction conditions leading to new and improved techniques for the application of gene therapy to induce chimerism and transplant tolerance to both allografts and xenografts.     

Filtering lymphocytes may decrease the need for immunosuppression in solid organ transplantation

Organ transplantation has become very important for patients with irreversible organ diseases. The transplanted organ is foreign to the host and, therefore, it induces a complex immune response of the patient. Therefore, Immunosuppressive agents are usually required to suppress both specific and nonspecific immunity and prevent allograft rejection in recipients who undergo organ transplantation. Of the late years, newer immunosuppressive agents with non-overlapping toxicities have been used in combinations in order to provide better patient and graft survival. However, these medications are associated with significant adverse effects that impact quality of life and sometimes long-term survival of the patient. Adverse effects can differ between the immunosuppressants, but many result from the overall state of immunosuppression. Strategies to manage immunosuppressant adverse effects often involve minimizing exposure to the drugs while balancing the risk for rejection. However, to prevent rejection of the transplanted organ, there may be unproven approaches other than immunosuppressive drugs. Filtering lymphocytes by a specific filter with respect to their size can be an alternative way. Our hypothesis was concerning of if such a filter could manage this and take the place of these drugs.