大鼠同种异体心脏移植免疫耐受的特异性实验研究

目的：研究大鼠同种异体心脏移植免疫耐受的特异性。方法：建立大鼠异位心脏移植模型,应用抗淋巴血清（ALS）及／或胸腺内注射脾细胞抗原预处理受体,21天后进行心脏移植,经过心脏移植并产生免疫,耐受的受体鼠在心脏移植60天后再次接受供体鼠的皮肤移植。结果：同时应用ALS及胸腺注射脾细胞抗原组的移植心平均存活时间较其它组显著延长（平均＞72天）,移植的皮肤在移植心耐受组中平均存活7．4天即被排斥,这与未处理组的皮肤移植无判别,但移植皮肤的排斥并不影响移植的心脏。结论：同种异体心脏移植产生的特异性免疫耐受是胸腺内注射供体脾细胞和腹腔注射ALS共同作用的结果。胸腺预注射供体脾细胞并腹腔注射ALS诱导产生的免疫耐受有器官特异性及组织特异性,。     

细胞间黏附因子-1在器官移植排斥反应中作用的研究进展

器官移植开展至今，移植器官的保存、手术及术后处理已日益成熟，受者存活率有所增高，但移植排斥反应仍然是威胁受者长期存活的重要因素，这一点在肺移植方面尤为明显。如何早期、有效地诊断及治疗排斥反应是目前研究的热点。     

骨髓移植的预处理中全身照射技术的应用

骨髓移植的预处理是指骨髓移植前14天内（－14天）到骨髓移植时（0天）给予病人大剂量化疗及全身放射治疗，为骨髓移植创造条件。全身放射治疗（T0talBodyIrradiationTBI）的作用有三点：1．消灭化疗后机体内残存的瘤细胞。2．抑制机体的免疫反应，防止发生移植物抗宿主病，保证移植的成功率。3．杀灭全部存活的骨髓，使骨髓腔出现空腔。我院放疗科自1992年率先在本省开展首例自体骨髓移植与全身放射治疗，并与空军南京454医院血液科协作成功地进行12例骨髓移植前的全身照射（TBI）。一、TBI前的准备：进行TBI一般选用加速器或钻”治…     

细胞间黏附分子1在肾脏移植排异反应中的作用

随着新型免疫抑制剂的出现及现代医学技术迅速发展。肾脏移植已经越来越多地运用于临床并成为治疗终末期肾病的首选方法。在肾脏移植中。由于供受者主要组织相容性抗原不一致而引起的排异反应是影响移植肾功能的主要因素。如何降低移植物的免疫原性。诱导免疫耐受，探索新的免疫抑制剂是当前的研究热点。近年来随着对细胞间黏附分子-1（ICAM-1）在同种移植排异的深入研究，抗ICAM-1分子的单克隆抗体的产生．动物实验也证实这些单克隆抗体能延长移植物存活时同。并诱导受者对移植物的免疫耐受。     

异种移植中的耐受诱导

异种器官移植中的耐受诱导，倍受国内外学者的关注，动物实验显示，移植前给血可以提高肾移植的成活率；胰脾联合移植能延长移植胰的成活时间，骨髓移植诱导的造血嵌合体可以阻断移植后所引起的急慢性排斥反应，T淋巴细胞疫苗可延长移植心脏的存活时间；抗CD4单体克隆抗体使小鼠接受胰岛异种移植而不需要其他免疫抑制剂。     

CP-690550抑制同种异基因小鼠心脏移植后急性排斥反应

目的观察心脏移植术后小鼠使用CP-690550对移植心脏信号转导和转录活化因子3（STAT3）及TH1型细胞因子IL-12的含量的影响,从而探讨CP-690550抗急性排斥反应的作用机制。方法建立同种异基因小鼠颈部异住心脏移植模型,随机分为对照组（n=6）和干预组（n=6）。干预组小鼠手术当天及术后给予CP-690550口服（10H培／kg／d）至观察终止,记录移植心脏存活时间,取移植心脏标本,以western blotting法检测标本STAT3表达,以ELISA法检测标本IL-12;对照组除不口服CP-690550外,其它情况同干预组。结果CP-690550干预组移植心脏存活时间（4．66±0．52）d,明显长于对照组（3．00士0．63）d（P〈O．01）,HE染色对照组心肌淋巴细胞浸润情况较干预组严重;STAT3及IL-12在移植心脏均有明显表达,且两组含量比较有统计学意义（P〈0．01）。结论CP-690550通过调控JAK激酶3（Janus Kinase3）-STAT3信号通路,抑制树突状细胞（DC）成熟及IL-12的释放,诱导T细胞无能,引起免疫耐受而实现抗急性排斥反应。     

骨髓干细胞诱导大鼠心脏移植免疫耐受的实验研究

目的探讨注射供者的骨髓十细胞对大鼠异位移植心的影响。方法以wistar大鼠为供者．SD大鼠为受者,制作Wistar大鼠的骨髓干细胞．建立大鼠同种异体异位心脏移植模型。心脏移植术前2h经受者阴茎静脉注射骨髓干细胞0．3m1．心脏移植术后分别观察受者注射同一供者和无关供者的骨髓干细胞后移植心脏的存活时间;心脏停跳后取移植心做病理检查及免疫组织化学检测。结果心脏移植术前受者接受同一供者和无关供者的骨髓干细胞后,前者移植心脏存活时间延长,分别为（37．0±16．5）d和（9．5±2．4）d．两组比较,差异有统计学意义（P〈0．01）;且前者心肌出血、坏死程度更轻,心肌组织内IgM和IgG沉积更少。结论注射同一供者的骨髓干细胞能特异性减轻大鼠移植心脏的排斥反应．明显延长其存活时间。     

骨髓移植联合肾移植、亲属肾移植、尸体肾移植疗效的探讨

目的评价骨髓移植联合肾移植、亲属活体肾移植、尸体肾移植的疗效。方法对比三类肾移植各48例术后三个月内排斥反应的发生率。结果尸体肾移植联合骨髓移植较之单一尸体肾移植的急性排斥反应发生率显著降低,与亲属供肾肾移植相比急性排斥反应发生率已无明显差别。结论肾移植联合骨髓移植能通过增加混合嵌舍体形成,从而诱导受体免疫耐受,可以减少排斥反应的发生,延长移植肾存活时间。     

简讯

单克隆抗体有希望治疗骨髓移植排斥反应美国Xoma公司发展了一种单克隆抗体疗法,能有效地治疗骨髓移植的移植物抗宿主病。该疗法由抗全T淋巴细胞单克隆抗体与蓖麻蛋白A链结合所组成,可攻击引起疾病的成熟T细胞。此疗法已用于1名患急性排斥反应的10岁儿童。结果提     

骨髓细胞门静脉输注诱导移植肾免疫耐受的临床研究初探

目的 探索供者骨髓细胞受者门静脉输注诱导移植肾免疫耐受的临床应用方法。方法 8例亲属供肾肾移植受者（实验组），移植术前经门静脉注射供者的骨髓细胞，进行移植后的临床效果观察，移植肾肾内免疫状态分析，尿细胞流式细胞分析和细胞因子测定，结果与6例亲属供肾肾移植病人（对照组）进行比较。结果 实验组在临床上和移植肾免疫状态上均表现出免疫低反应性，IL－10（Interleukin-10)表达较高，TNF－a(Tumor necrosis factor-α）表达较低。结论 我们认为，将供者骨髓细胞进行受者的门静脉输注是一种可行的诱导免疫耐受的方法，可以诱导产生临床肾移植的免疫低反应。     

异基因骨髓移植和非清髓性干细胞移植嵌合形成过程的比较

目的 研究异基因骨髓移植（allo-BMT）和非清髓性干细胞移植（NST）两种移植方式在供体细胞嵌合状态的形成及转归上的差异,探讨早期供体细胞植入的关键因素。方法 对20例接受allo-BMT和18例NST的患者进行回顾性比较,研究两组患者疾病类型、干细胞来源、预处理方案和移植物抗宿主病预防方案。用复合扩增荧光标记STR-PCR结合毛细管电泳方法对移植后＋7、＋14、＋21d,＋1、＋3、＋6、＋9、＋12个月的嵌合体进行动态检测。结果 （1）NST组在受体年龄、单个核细胞（MNC）、CD34^＋及T细胞数量上均明显高于BMT组,造血重建方面,中性粒细胞绝对值恢复时间与BMT组无差别,但血小板恢复明显早于BMT组。（2）NST组患者供体细胞完全嵌合状态（FDC）的建立比BMT组早（1个月vs 3个月）,移植后早期（＋1个月）FDC比例亦明显高于BMT组（38．9％vs 20%）,而混合嵌合状态（MC）的发生率明显低于BMT组（61．2％ vs 80％）,移植1个月后各时间段两组在嵌合体形成上均无显著性差别。（3）氟达拉滨为基础的NST预处理方案与标准预处理方案相比并未延迟供体细胞的植入。（4）NST组慢性移植物抗宿主病的发生率明显高于BMT组（80％vs 50%,P〈0．01）,与NST组输入高剂量的CD34^＋细胞相关。结论 在供体细胞早期植入和嵌合体形成的过程中,移植物中造血干细胞和T细胞数量至关重要,并可能起决定性作用。     

Allogeneic bone marrow transplantation in the treatment of hematologic diseases

The current use of allogeneic bone marrow transplantation in various hematologic diseases is reviewed. Bone marrow transplantation (BMT) involves infusion of bone marrow from a suitable donor into a properly conditioned recipient. Most BMT is allogeneic, in which the donor is genetically dissimilar but shares some common tissue antigens with the recipient. Almost all patients undergoing allogeneic BMT must be "prepared" with high-dose cyclophosphamide to prevent graft rejection. Most patients with hematologic malignancy also receive total body irradiation to eradicate malignant cells located in areas inaccessible to the systemic circulation. Bone marrow transplantation is the treatment of choice for severe aplastic anemia. In acute myelogenous leukemia, the best results are observed in young patients undergoing BMT in first remission. In acute lymphoblastic leukemia, BMT is usually reserved for patients in second or subsequent remission. Early results are promising in patients with chronic myelogenous leukemia who receive BMT before the accelerated phase or blast crisis of this disease. Allogeneic BMT offers an opportunity for cure in some patients with relapses of Hodgkin's disease or those with certain subtypes of non-Hodgkin's lymphoma. Other diseases for which BMT has been used include severe combined immune deficiency disease, Fanconi's anemia, and multiple myeloma. Complications of BMT include graft failure or rejection, acute and chronic graft-versus-host disease, and infectious complications; late complications, such as restrictive and obstructive pulmonary disease, cataracts, sterility, and secondary malignancies, may also occur. Bone marrow transplantation has become an important treatment for many hematologic diseases, but it will probably remain a treatment reserved for only a few highly specialized centers. If morbidity and mortality caused by transplant-related complications can be reduced, BMT may be offered to older patients and those without HLA-identical sibling donors.     

改良大鼠腹腔内心脏移植模型80例复制体会

目的 总结复制改良大鼠腹腔异位心脏移植模型的体会.方法 健康远交系Wistar大鼠为供体,SD大鼠为受体,各80只,将供心移植于受体的腹腔内,供心的升主动脉及右肺动脉分别与受体的腹主动脉和下腔静脉做端侧吻合;术后第3、5、7天各取5例移植心脏行组织学检查.结果 成功建立75例大鼠异位心脏移植模型,供心缺血时间(28±5.5)min,手术成功率93.75%(75/80).大鼠移植后均呈急性排斥反应改变.结论 通过调整动脉吻合口与静脉吻合口管径比率进一步完善改良移植模型,可稳定诱导急性排斥反应发生.     

Xenotransplantation: application of disease resistance

1. Organ transplantation is now clinically routine for patients with end-stage organ failure. One major limitation in transplantation is chronic rejection involving the loss of the graft despite the use of immunosuppressive agents. Haematopoietic stem cell (HSC) chimerism, achieved through bone marrow transplantation (BMT), induces donor-specific tolerance to transplanted organs and prevents chronic rejection. 2. A second major limitation to organ transplantation is the donor shortage. Xenotransplantation, the transplantation of organs between different species, would have the ability to increase the availability of donor organs. 3. Current immunosuppressive therapies do not prevent the rejection of xenografts. Therefore, the only reliable method for achieving donor-specific tolerance to xenografts may require HSC chimerism. 4. In order to justify the use of BMT to induce transplantation tolerance in patients with non-life-threatening diseases, the morbidity and mortality associated with current conditioning regimens must be addressed. 5. The use of partial conditioning regimens to promote engraftment of xenogeneic HSC and the development of donor-specific tolerance may eventually make xenotransplantation in humans a clinical reality. 6. Additional advantages of xenotransplantation are the ability to genetically engineer the donor xenograft and resistance of some xenografts to infection by human viruses because of the species specificity of most viruses. 7. The clinical application of disease resistance for HIV and hepatitis B virus is the focus of the present review.     

Current and future approaches to treat graft failure after allogeneic hematopoietic stem cell transplantation

Introduction: One significant obstacle to the success of allogeneic hematopoietic stem cell transplantation (HSCT) is represented by graft failure, defined as either lack of initial engraftment of donor cells (primary graft failure) or loss of donor cells after initial engraftment (secondary graft failure). Graft failure mediated by host immune cells attacking donor stem cells is named graft rejection. Factors associated with graft failure include HLA disparity in the donor/recipient pair, underlying disease, viral infections, type of conditioning regimen and stem cell source employed.

Areas covered: In this article, the experts summarize current approaches to treat graft failure/rejection after HSCT, and they discuss new strategies of graft manipulation and immune therapy of particular interest for preventing/treating this complication.

Expert opinion: A limited array of options is available to treat graft failure. The experts believe that re-transplantation from another donor or the same donor (if there is no evidence of immunologically mediated graft failure) is the treatment of choice for patients with primary graft failure or acute graft rejection. The experts think that strategies based on innovative approaches of graft manipulation, new agents or cellular therapies could render in the future graft failure a much less relevant problem for HSCT recipients.     

Involvement of dendritic cells in allograft rejection new implications of dendritic cell-endothelial cell interactions

For almost half a century immunologists have tried to tear down the MHC barrier, which separates two unrelated individuals during transplantation. Latest experimental data suggest that a breakthrough in vitro is imminent. Dendritic cells (DCs), which activate na?ve allo-reactive T-cells (TCs), play a central role in the establishment of allo-antigen-specific immunity. Allograft solid organ rejection is initiated at the foreign endothelial cell (EC) layer, which forms an immunogenic barrier for migrating DCs. Thus, DC/EC interactions might play a crucial role in antigen-specific allograft rejection. Organ rejection is mediated by host allo-reactive TCs, which are activated by donor DCs (direct activation) or host DCs (indirect activation). Direct allo-antigen presentation by regulatory dendritic cells (DCreg) can play an instructive role towards tolerance induction. Several groups established that, DCregs, if transplanted beforehand, enter host thymus, spleen, or bone marrow where they might eventually establish allo-antigen-specific tolerance. A fundamental aspect of DC function is migration throughout the entire organism. After solid organ transplantation, host DCs bind to ECs, invade allograft tissues, and finally transmigrate into lymphoid vessels and secondary lymphoid organs, where they present allo-antigens to na?ve host TCs. Recent data suggest that in vitro manipulated DCregs may mediate allo-transplantation tolerance induction. However, the fundamental mechanisms on how such DCregs cause host TCs in the periphery towards tolerance remain unclear. One very promising experimental concept is the simultaneous manipulation of DC direct and indirect TC activation/suppression, towards donor antigen-specific allo-transplantation tolerance. The allo-antigen-specific long-term tolerance induction mediated by DCreg pre-transplantation (with simultaneous short-term immunosuppression) has become reproducible in the laboratory animal setting. Despite the shortcomings of laboratory animal studies, strong promises are deriving from these studies for clinical kidney, heart, and liver transplantation.     

雌二醇对小鼠颈部移植心脏免疫耐受影响的初步研究

目的 探讨雌二醇对小鼠颈部移植心脏免疫耐受的影响.方法 建立小鼠颈部心脏异位移植模型,供、受体均为近交系健康雄性BALB/c和C57BL/6小鼠,分别在受体小鼠心脏移植术后1 d,3 d,7 d腹腔注射不同剂量外源性雌二醇实现干预.实验分为4组:A组:对照组,供、受体均无特殊处理;B组:2 mg/kg;C组:4 mg/...     

Allogeneic bone marrow transplantation: procedures and complications

Bone marrow transplantation (BMT) is discussed in terms of immunology, procedures, and complications and their treatment. Any patient with a disorder of the hematopoietic or immune system or a disease in which a transferable hematopoietic cell can supply a missing enzyme is a candidate for BMT. A priority in allogeneic BMT is the identification of a compatible donor through matching of human lymphocyte antigens (HLAs). The greater the disparity in HLAs, the greater the chance of rejection. The ideal donor is a monozygotic twin or an HLA-matched sibling, but only 30% of patients have such a donor. Before receiving the bone marrow infusion, patients must be conditioned to create space in the marrow for donor cells, suppress the immune system, and eradicate any tumor in patients with malignancies. Conditioning is achieved by the combination of total body irradiation and cyclophosphamide treatment; busulfan, etoposide, and cytarabine have also been used. For patients given unmanipulated marrow, the number of nucleated cells infused is about 3 X 10(8) per kilogram. Signs of engraftment are usually seen 14-21 days later. Toxic effects related to conditioning appear during this period and include infection, gastroenteritis, mucositis, and congestive heart failure. The most serious complication is graft-versus-host disease (GVHD), which can affect multiple organ systems. Prednisone, methylprednisolone, methotrexate, antithymocyte globulin, and cyclosporine have been used in an effort to prevent or treat GVHD. Bone marrow transplantation offers the chance of long-term survival to many patients with terminal disease, but associated morbidity and mortality rates remain high. Research is needed to address the problems of infection, leukemic relapse, and GVHD and the difficulty in obtaining and matching donors.     

不同类型造血干细胞移植术后重型β-地中海贫血患儿长期生存质量情况

目的　了解同胞人类白细胞抗原（HLA）全合、非亲缘HLA全和及单倍体造血干细胞移植术后重型β-地中海贫血患儿长期生存质量情况。方法　选取2012—2019年于广西医科大学第一附属医院干细胞移植病区收治的不同移植类型的133例重型β-地中海贫血患儿为研究对象,其中男87例,女46例,平均年龄为5.39岁。使用单因素分析和多重线性回归分析重型β-地中海贫血患儿造血干细胞移植术后长期生存质量的相关因素。计量资料采用独立样本t检验或单因素方差分析,计数资料采用χ²检验。结果　133例重型β-地中海贫血患儿及其家长参与本次问卷调查。急性移植物抗宿主病（GVHD）发生率为14.3%（19/133）,慢性GVHD发生率为3.8%（5/133）。接受非亲缘HLA全合移植的患儿生活质量评分均较高,急性GVHD、慢性GVHD和合并症发生率均低于接受单倍体造血干细胞源移植的患儿（均P<0.05）。外周血干细胞移植（PBSCT）或脐血干细胞移植（UCBT）、PBSCT+骨髓移植（BMT）、BMT、BMT+UCBT均对生活质量无明显影响（均P>0.05）。单因素分析表明年龄（B=-3.234,P<0.001）、慢性GVHD（B=-19.452,P=0.001）、并发症（B=-23.327,P<0.001）和移植时长（B=13.369,P<0.001）与移植后重型β-地中海贫血患儿生活质量相关,其他因素如性别、移植物类型、供者类型、HLA是否相合、供受者血型是否相合、GVHD预防方案、急性GVHD与患儿生活质量均无显著相关性（均P>0.05）。多元线性回归分析表示患儿年龄越大、并发症种类越多,患儿移植后生活质量越差,而随着移植后时间延长,患儿生活质量越好（均P<0.05）。结论　有合适供者重型地中海贫血患儿尽早进行异基因造血干细胞移植,注重控制移植并发症,保证患儿移植后生活质量。