肾移植致敏受者处理措施的选择

在肾移植中，习惯上将群体反应性抗体（PRA）阳性的受者称为致敏受者。这些受者体内往往存在针对供体的特异性抗体（DSA），包括HLA—Ⅰ，Ⅱ类抗体和一些非HLA类的抗体，是移植术后排斥的高危人群。受者术前体内如果预存大量的DSA，术后会立即引起超急性排斥，直接导致移植肾丢失。即使预存少量的DSA（尤其是HLA—Ⅱ类抗体）也能导致术后短期内发生急性体液性排斥，影响移植肾的存活率。不过，致敏受者接受移植的风险虽然比较大，但是移植后患者的存活率和生活质量通过努力仍然在不断的提高，因此不能剥夺这些患者接受移植的权利。为了使高敏受者获得移植机会，移植界一直在不懈的努力，采取各种手段以改善这些受者的预后。致敏患者的处理一直被视为临床肾移植领域的一个重要课题。     

术前非供者特异性HLA抗体弱阳性的肾移植受者术后早期肾功能、移植排斥反应、移植肾存活情况

目的 观察术前非供者特异性人类白细胞抗原（HLA）抗体弱阳性的肾移植受者术后早期肾功能、移植排斥反应、移植肾存活情况。方法 接受公民逝世后器官捐献供肾移植的肾移植受者57例，依据肾移植术前HLA抗体检测结果分为HLA抗体弱阳性组26例、HLA抗体阴性组31例。观察受者术后早期肾功能，以术后1周移植物功能延迟恢复（DGF）率表示。对术后怀疑发生排斥反应的受者进行移植肾穿刺病理活检和病理诊断，测算移植排斥反应发生率。术后随访满5年，观察并比较两组受者移植肾5年存活率。结果 移植术后1周，HLA抗体弱阳性组受者DGF率为34.62%(9/26),HLA抗体阴性组受者DGF率为9.68%(3/31)，两组相比，P<0.05。HLA抗体弱阳性组受者移植排斥反应发生率为26.92%(7/26),HLA抗体阴性组受者移植排斥反应发生率为6.45%(2/31)，两组相比，P>0.05。HLA抗体弱阳性组受者移植肾5年存活率为73.08%(19/26),HLA抗体阴性组受者移植肾5年存活率为87.1%(27/31)，两组相比，P>0.05。结论 与HLA抗体阴性受者相比，术前非供者特异...     

高敏肾移植受者的脱敏治疗策略

高敏受者肾移植术后发生超急性和急性排斥反应风险明显增加.针对供者的特异性抗体及记忆性T细胞在高敏受者肾移植排斥反应中起关键作用,是制约移植成功和移植物的长期存活的主要障碍.寻找有效的脱敏方法是当前移植临床的重大挑战之一.本文总结分析接受脱敏疗法受者的临床资料,探讨当前临床脱敏方法的效果,包括急、慢性抗体介导排斥反应的发生率,新型脱敏制剂的使用及高敏受者治疗策略的方向.     

同种异体肾移植患者术后肺部感染的临床高危因素分析及护理

肺部感染在肾移植术后无论是早期还是远期都是常见并发症,其病因对移植肾和受者的影响都有很多不确定性,严重时可危及生命。通过对肾移植术后患者肺部感染高危因素进行分析发现,术后重视呼吸道管理、预防排斥反应发生的相关护理措施,可以提高人肾存活率,降低同种异体肾移植患者病死率。     

血浆分离技术在肾移植中的应用

血浆分离技术包括血浆置换、双重血浆滤过和免疫吸附。在肾移植领域,血浆分离技术主要用于清除受者体内的供者特异性抗体和其他致病因子或抗体。因此,临床上常用于治疗肾移植术后抗体介导的排斥反应和移植后复发性局灶节段性肾小球硬化等。同时,该技术在肾移植术前致敏受者的处理、ABO血型不相容的肾移植中也起到关键作用。本文就血浆分离技术在肾移植中的应用做一综述。     

肾移植高度致敏受者的临床处理

目的：探讨肾移植高度致敏受者的临床处理方案。方法：报告10例高度致敏受者,肾移植术前连续监测群体反应性抗体（PRA）水平和抗体特异性,行供－受者HLA配型,7例患者采用血浆置换（PE）治疗;术后采用他克莫司（FK506）、霉酚酸酯（MMF）和强的松三联免疫抑制治疗,6例患者采用5－7天的抗胸腺细胞球蛋白（ATG）诱导治疗。结果：2例患者（4次）术后发生超急性排斥反应（HAR）;2例未采用ATG诱导治疗的患者术后第1个月发生急性耐激素性排斥反应,6例患者术后第1个月末发生急性排斥。随访3－24个月,1例患者因肺部毛霉菌感染死亡,7例患者移植肾功能正常。结论：对受者HLA抗体特异性的鉴定和良好的HLA配型是高敏受者肾移植成功的基础,PE对降低高度致敏受者的PRA水平,预防超急性排斥反应以及对术后急性体液性排斥反应的治疗均有一定的作用。     

应重视肾移植术后急性抗体介导排斥反应的诊治

近10年来,肾移植术后早期急性排斥反应(AR)的发生率进一步下降.但是,器官获取和移植网络/器官移植受者科学登记系统(OPFN/SR-TR)的数据显示,难治性排斥反应的比例却呈显著上升趋势,AR对慢性移植物肾病的危险度增加了5倍.相对于细胞性排斥反应,肾移植术后急性抗体介导的排斥反应(AMR),一般是由于受体体内预先存在抗供体人类白细胞抗原(HLA)和(或)非HLA抗体而导致AR的发生,治疗上常常对激素刎不敏感,且临床过程较为凶险,预后较差,逆转非常困难并经常造成移植肾失功,从而影响移植肾的长期存活,因此应高度重视肾移植术后AMR的诊治.     

浅谈高致敏肾移植受者术前处理策略

由于移植水平的不断提高和新型高效免疫抑制剂的问世，肾脏移植的适应证也在不断扩大，高危肾移植受者接受移植也越来越多。所谓高危顾名思义应该是同时存在有可能危及肾移植受者生命安全或影响移植肾近期或远期存活的诸多因素。如合并糖尿病、动脉硬化、冠心病、心功能不全、传染性肝病，或二次移植、多次输血、长期血液透析及妊娠等原因，使受者致敏，有广泛的多价抗HLA抗体，移植时易发生超急性排斥反应（超排）及各种难以逆转的急性排斥反应（AR），导致移植失败，严重者甚至可能危及受者生命。笔者主要针对后者即高致敏肾移植受者的术前处理作一粗浅阐述。     

肾移植急性体液性排斥反应的诊断及治疗

同种异体肾移植术后早期发生急性排斥反应时 ,如果受者体内出现新的针对供者特异性的ＨＬＡ抗体 ,通常称为急性体液性排斥反应 (ａｃｕｔｅｈｕｍｏｒａｌｒｅｊｅｃｔｉｏｎ ,ＡＨＲ) ,其发病率为 4 6%～ 6 8%。ＡＨＲ临床表现为移植术后早期急性难治性排斥反应或加速性排斥反应 ,并具有独特的病理学特点和血清学特点 ,从发病机制上讲 ,被认为是一种独立类型的排斥反应。ＡＨＲ预后较差 ,常导致移植物丧失功能。近年来 ,由于抗ＨＬＡ抗体检测技术的进展 ,以及血浆置换 /免疫吸附联合ＦＫ50 6、霉酚酸酯、γ 球蛋白或15 脱氧腈胍素等新型免…     

抗体介导的移植肾排斥

肾移植术后抗体介导的排斥（antibody-mediated rejection，AMR）又称为体液性排斥，主要由受者体内的抗供体特异性抗体（DSA）介导的一类排斥反应。AMR临床症状重，救治困难，对大剂量激素冲击治疗无效，预后很差，是影响移植肾存活的重要原因。AMR是国际移植界近期研究的一大热点。本文就肾移植中AMR的发生机制、诊断及治疗方面的现状进行综述。     

Apheresis in Thoracic Organ Transplantation

The beneficial addition of cyclosporine and tacrolimus to the immunosuppressive armamentarium have unfortunately only partially solved the problems of acute and chronic rejection in thoracic organ transplantation. Apheresis techniques offer creative avenues for modifications of allograft rejection. Plasmapheresis can be used for mechanical reduction of alloantibody burdens in highly sensitized patients and permit transplantation in an otherwise almost hopeless situation and can also be used on a short-term basis for the treatment of acute humoral rejection. Extracorporeal photochemotherapy holds promise as a possibly synergistic adjunct to conventional therapy and may even reduce the severity of graft vasculopathy. The increasing availability of highly specific column immunoadsorption techniques may further increase the applicability of apheresis in transplantation.     

Prevention of red cell alloimmunization by CD25 regulatory T cells in mouse models

Transfusion therapy is currently an effective therapeutic intervention in a number of diseases, including sickle cell disease. However, its use is complicated by a high incidence of red blood cell (RBC) alloimmunization in the transfusion recipients. The identification of T regulatory cells (Tregs) among the CD4⁺ CD25⁺ T cell subset as key regulators of peripheral tolerance in mice as well as humans has opened an exciting era in the prevention and treatment of autoimmune disease and for improving organ transplantation. However, their potential in inducing transfusion tolerance remains to be explored. We used red cells from mice transgenic for human glycophorin A blood group antigen as donor cells and transfused wild‐type mice to induce alloantibodies, as an experimental system to study RBC alloimmunization. We found that depletion with anti‐CD25 enhanced the alloantibody production, indicating that CD25 Tregs play an important role in regulation of alloantibody responses. More importantly, adoptive transfer of purified population of CD4⁺CD25⁺ but not CD4⁺CD25^? cells from naïve mice prevented the induction of IgG and IgM alloantibody production in transfusion recipients, with a concomitant reduction in activated splenic B cells and macrophages. Similarly, adoptive transfer of purified populations of CD4⁺CD25⁺ cells from naïve mice into naïve syngeneic recipients inhibited the anti‐Ig response to rat RBCs in the recipients but transfer of control CD4⁺CD25^? cells did not. Altogether, our results demonstrate that Tregs participate in the control of transfusion‐associated RBC alloantibody responses, opening up the possibility that Treg immunotherapy may be exploited for suppressing transfusion immunization events. Am. J. Hematol., 2007. © 2007 Wiley‐Liss, Inc.     

Antibody-mediated inhibition of the human alloimmune response to platelet transfusion in Hu-PBL-SCID mice

Severe combined immune deficient (SCID) mice were engrafted with human (Hu) peripheral blood lymphocytes (PBL) from a previously alloimmunized donor and transfused with HLA-mismatched platelets. We have previously shown this to be a useful model for platelet transfusion. These engrafted mice (Hu-PBL-SCID mice) produced high levels of alloantibody in response to standard platelet preparations. However, when the first platelet challenge was presensitized with anti-HLA antibody and then transfused there was a marked reduction in the amount of alloantibody produced to five subsequent untreated platelet transfusions. Platelets pretreated with platelet-specific anti-HPA-1a (PL(A1)) sera did not induce a decrease in the anti-HLA alloantibody response. This demonstrated that platelet-induced HLA alloimmunization can be blocked by anti-HLA antibody-sensitized cells.     

Apparent reactivation of a red cell alloantibody in a healthy individual after G-CSF administration

Granulocyte-colony stimulating factor (G-CSF) has been successfully administered to healthy subjects to mobilize peripheral blood stem cells (PBSC) for allogeneic transplantation. Adverse events are moderate. We report the first case of apparent reactivation of an alloantibody to a blood cell antigen (Jk^a) after G-CSF administration to a healthy subject and its transmission to the PBSC transplant recipient; no concomitant reactivation of other alloantibodies was detected. This case raises questions on the effect of G-CSF on the immune system and its safety in healthy individuals.     

The value of alloantibody detection in predicting response to HLA-matched platelet transfusions

Alloantibody tests demonstrate immunological causes of insufficient increments in random platelet transfusions. The value of a positive or negative test result in predicting the outcome of human leucocyte antigen (HLA)-matched transfusions in patients refractory to leucodepleted random platelet transfusions has not been assessed. We retrospectively evaluated the outcome of the first HLA-matched platelet transfusion in 72 patients with haematological diseases in two ways: first, the strategy according to which the patient was selected for HLA-matched platelet transfusions was analysed. The strategies were: (i) results of alloantibody tests were not available, (ii) a positive alloantibody test, (iii) a negative alloantibody test. Secondly, the outcome of the first HLA-matched transfusion was investigated relative to the results of alloantibody tests, irrespective of the decision strategy. No significant association was found between the decision strategy and the outcome of the first HLA-matched platelet transfusion. Positive alloantibody tests, however, predicted a better outcome of the first HLA-matched platelet transfusion (P = 0.04 and P = 0.03 after 1 and 16 h respectively). In patients refractory to random platelet transfusions, positive alloantibody tests predicted a better outcome of HLA-matched platelet transfusions. Patients with negative alloantibody tests, however, may benefit from HLA-matched platelet transfusions.     

Stimulation of human neutrophils with sera containing HLA Class I alloantibody causes preferential degranulation of azurophilic granules and secretory vesicles

Background and Objectives The activation of neutrophils by human leukocyte antigen (HLA) Class I alloantibody is thought to be involved in transfusion‐related acute lung injury. Neutrophils contain various biological substances in four groups of granules, including secretory vesicles, azurophilic granules, specific granules and gelatinase granules. To characterize the activation of neutrophils by HLA Class I alloantibody, we investigated whether HLA Class I alloantibody could cause the degranulation of these groups of granules either coordinately or selectively. Materials and Methods Sera containing HLA‐A24 alloantibody were incubated with neutrophils in a washed whole blood system. CD11b expression (secretory vesicles) on neutrophils was analysed by flow cytometry, and the secretion of markers of each granule was determined by ELISA. Results The treatment of cross‐matching‐positive neutrophils with sera containing HLA‐A24 alloantibody caused the significant expression of CD11b, and the significant secretion of neutrophil elastase and myeloperoxidase, azurophilic granule markers and heparin‐binding protein (HBP), which is localized in secretory vesicles and azurophilic granules when compared with cross‐matching‐negative neutrophils. In contrast, no significant differences were observed in the secretion of lactoferrin, a marker of specific granules, and matrix methalloproteinase‐9, a marker of gelatinase granules between cross‐matching‐positive and cross‐matching‐negative cells upon stimulation with sera. CD11b expression and secretion of HBP by serum was partially inhibited by p38 mitogen‐activated protein (MAP)‐kinase inhibitors. Conclusion Neutrophils activated with sera containing HLA Class I alloantibody caused the preferential degranulation of azurophilic granules and secretory vesicles. This process was at least in part mediated by p38 MAP kinase‐involved signal transduction.     

In vivo platelet-endothelial cell interactions in response to major histocompatibility complex alloantibody

Platelets recruit leukocytes and mediate interactions between leukocytes and endothelial cells. Most studies examining this important platelet immune function have focused on the development of atherosclerosis, but similar mechanisms may contribute to acute and chronic vascular lesions in transplants. Platelets have been described as markers of transplant rejection, but little investigation has critically examined a role for platelets in transplant vasculopathy and, in particular, alloantibody-mediated transplant rejection. We now demonstrate using a skin transplant model that alloantibody indirectly induces platelet activation and rolling in vivo. Repeated IgG2a alloantibody injections result in sustained platelet-endothelial interactions and vascular pathology, including von Willebrand factor release, small platelet thrombi, and complement deposition. Maintenance of continued platelet-endothelial interactions are dependent on complement activation. Furthermore, we demonstrate that platelets recruit leukocytes to sites of alloantibody deposition and sustain leukocyte-endothelial cell interactions in vivo. Taken together, our model demonstrates an important role for platelets in alloantibody induced transplant rejection.     

Apparent ''Auto''-Anti-DE of the IgA and IgG Classes in a 16-Year-Old Girl with a Mature Cystic Ovarian Teratoma

Prior to the removal of a mature cystic teratoma in a girl, aged 16, we had difficulties in Rh typing due to immunoglobulin coating of the red blood cells (RBCs). Further examination revealed the presence of anti-D and anti-E antibodies; the clinical course and the serological characteristics indicated that the Rh antibodies originated from the tumor itself, that is, there was alloantibody formation against the host's RBCs. The specific alloantibody production, as well as the fact that these antibodies belong to the IgA and IgG1 classes provide further evidence for the pluripotency of mature cystic ovarian teratomas.     

Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans

Chronic GVHD (cGVHD) poses a significant risk for HSCT patients. Preclinical development of new therapeutic modalities has been hindered by models with pathologic findings that may not simulate the development of human cGVHD. Previously, we have demonstrated that cGVHD induced by allogeneic HSCT after a conditioning regimen of cyclophosphamide and total-body radiation results in pulmonary dysfunction and airway obliteration, which leads to bronchiolitis obliterans (BO), which is pathognomonic for cGVHD of the lung. We now report cGVHD manifestations in a wide spectrum of target organs, including those with mucosal surfaces. Fibrosis was demonstrated in the lung and liver and was associated with CD4(+) T cells and B220(+) B-cell infiltration and alloantibody deposition. Donor bone marrow obtained from mice incapable of secreting IgG alloantibody resulted in less BO and cGVHD. Robust germinal center reactions were present at the time of cGVHD disease initiation. Blockade of germinal center formation with a lymphotoxin-receptor-immunoglobulin fusion protein suppressed cGVHD and BO. We conclude that cGVHD is caused in part by alloantibody secretion, which is associated with fibrosis and cGVHD manifestations including BO, and that treatment with a lymphotoxin-β receptor-immunoglobulin fusion protein could be beneficial for cGVHD prevention and therapy.     

Factor VIII coagulant antigen in hemophilic plasma: a comparison of five alloantibodies

Five independent alloantibodies directed to factor VIII coagulant antigen (VIII:CAg) were assessed against normal, von Willebrand's disease, and severe hemophilia A plasmas. Immunoradiometric assays (IRMAs) were developed for each antibody, one of which had arisen "spontaneously" and four in transfused hemophiliacs. The correlations between assays were very high for normal, vWd, and both CRM+ and CRM- hemophiliacs. This suggests that IRMAs maybe developed from almost any reasonably high titered alloantibody and used with confidence in diagnosing CRM- hemophilia A in utero by fetoscopy.