Complement in transplant rejection: diagnostic and mechanistic considerations

After decades of neglect, complement has been rediscovered as a potent mediator and diagnostic indicator of inflammation and rejection in organ transplants. In part, this reflects a better understanding of the biology of complement, but it also reflects changes in clinical practice. The relevance of complement to clinical transplantation has increased as access to transplantation continues to be extended. Extended criteria for organ donors include older donors and non-heart beating donors. Simultaneously, the criteria for recipients have been extended to include more presensitized and blood group incompatible recipients. All of these variables can increase complement activation. As a result, several components of complement have received attention as potential diagnostic tools, and, with more sophisticated reagents, evidence of complement activation has been found in larger numbers of biopsy samples. Understanding the biology of complement is important to appreciate fully the diagnostic and mechanistic implications of complement activation in organ transplants. Mechanistically, a series of effector molecules in the complement cascade mediate proinflammatory functions that can account for chemotaxis and activation of cells of the innate immune system, such as granulocytes and monocytes. Simultaneously, many of these same complement mediators activate and disrupt the endothelial cell interface between the recipient and the transplant. In addition, there is growing appreciation that complement can stimulate B and T lymphocytes of the adaptive immune system. More recent evidence indicates that complement participates in the non-inflammatory clearance of apoptotic cells. Therefore, the complement cascade can be activated by multiple mechanisms and various components of complement can modulate the response to transplants in different directions.     

Morphologic aspects of antibody-mediated rejection in renal allografts

Recent studies have illustrated the important role of alloantibodies in mediating renal allograft rejection. Compared to T-cell mediated-rejection, antibody-mediated rejection is usually more refractory to conventional anti-rejection treatment and more likely to contribute to allograft failure. Antibody-mediated rejection can occur in three principal forms: hyperacute, acute, and chronic active. This brief review aims to characterize the main pathological features attributed to antibody-mediated rejection including light microscopy manifestations, ultrastructural alterations, and immunopathologic markers.     

The sensitivity and specificity of Hippuran renography as a diagnostic investigation of renal transplant rejection

Renography is a valuable investigation of a graft, as it can alert suspicions of rejection before it is clinically discernible. Renographic signs of rejection are delayed excretory phase and decreased Hippuran uptake in phase 1 and 2. A prospective trial was performed including 319 necrokidney transplanted patients. In 139 patients, acute rejection was diagnosed on clinical parameters. The material was divided into two groups: 1. Transplant patients suffering from acute tubulointerstitial nephropathy and having unmeasurably low creatinine clearance and an initial renogram showing an accumulation curve. 2. Patients with functioning grafts exposing a renogram with an excretion phase. The prevalence of rejection was 0.19 and 0.33, respectively, in the two groups. The sensitivity and specificity of renography as a parameter for diagnosing rejection was for group 1: Sensitivity 0.77 and specificity 0.95. Group 2: Sensitivity 0.68 and specificity 0.84. Efficiency of renography as a predictive test for the whole material was 74 percent. In group 1: 92 percent and in group 2: 79 percent. Acute rejection was diagnosed with renography in group 1 in 30/39 episodes before it was clinically evident. In group 2, with functioning grafts, rejection was diagnosed in 67 percent of the cases one to two days before it was clinically manifest. On the day of clinically manifest rejection, 92 percent of the renograms showed positive signs of rejection. False positive renographic signs of rejection were mainly caused by urinary tract obstruction, infection, and medication.     

补体片段C4d与肾移植抗体介导排异反应的病理诊断

同种异体肾移植排异无非是以T细胞介导的细胞性排异和以抗体介导的体液性排异两种形式.在组织学上虽然对肾移植急性细胞性排异已有较好的认识,但对抗体介导的体液排异由于病变不典型,缺乏足够的认识和共识[1].近10年来,补体片段C4d在移植肾毛细血管上沉积与抗体介导排异的相关性研究备受瞩目[2-4],2007年发表的Banff分类也将C4d免疫阳性染色作为诊断急、慢性抗体介导排异的标准之一[5].我们就移植肾抗体介导排异、补体片段C4d及C4d在排异诊断中的意义做一综述如下.     

Psychiatric considerations in renal transplant surgery

Kidney transplantation offers the patient with end stage renal disease an opportunity for a prolonged and nearly normal life. However, the procedure itself may create fear, anxiety, and depression in the recipient. Other problems include sexual dysfunction, distorted self-image, and suicide risk. Using a composite case history, the authors describe the complex reactions that may occur in the individual and his family. The psychiatrist can function as an integral part of the transplant team both in helping to prevent problems and in helping to meet the needs of the patient when difficulties do occur.     

Acute antibody-mediated rejection of skin grafts without involvement of granulocytes or complement.

In immunosuppressed mice that carry rat skin xeno-grafts, acute antibody-mediated graft rejection (AAR) can be induced by intravenous administration of mouse anti-rat globulin. Dependent on the amount of antibody injected and on the complement status of the recipient, an Arthus-like or a Shwartzman-like pattern of vasculitis occurs. The role of polymorphonuclear granulocytes (PMNs) in either type of vasculitis was tested by inducing AAR in recipients depleted of PMNs by total body irradiation. Despite the absence of PMNs in the graft vessels, AAR occurred both in the Arthus-like and in the Shwartzman-like type. Moreover, AAR could be elicited in PMN-depleted recipients that were complement-depleted by cobra venom factor treatment or were congenitally C5-deficient. We conclude that neither the PMN nor complement is an essential mediator the PMN nor complement is an essential mediator in this form of antibody-mediated vasculitis.     

Noninvasive diagnosis of cellular and antibody-mediated rejection by perforin and granzyme B in renal allografts

A major milestone in transplantation would be the use of biomarkers to monitor rejection. We examined the association between perforin and granzyme-B gene expression detected in the peripheral blood of renal allograft recipients with cellular and antibody-mediated rejection. Furthermore, we judged the appropriateness of assigning negative rejection statuses to persons without a biopsy whose grafts were functioning well clinically. Of the 46 patients who completed the study, recipients with cellular rejection had higher perforin and granzyme-B levels compared with nonrejectors (p = 0.006). Interestingly, recipients with antibody-mediated rejection also had higher perforin and granzyme-B levels compared with nonrejectors (p = 0.04). Patients with high levels of granzyme B had a probability of rejecting that was 26.7 times greater than those patients with low levels of granzyme B. Perforin and granzyme B had sensitivities of 50% and specificities of 95% in predicting rejection (cutoff value = 140). Assigning negative rejection statuses to recipients without a biopsy whose grafts were functioning well did not have a major effect on the direction or significance of covariate values. This study suggests that perforin and granzyme-B gene expressions in peripheral blood are accurate in detecting both cellular and antibody-mediated rejection.     

肾移植后急性排斥反应及免疫抑制剂的应

背景：肾移植后急性排斥反应在临床较为常见,免疫抑制剂的出现促进和推动了肾移植质量的提高,免疫抑制剂的合理应用对肾移植患者至关重要,成为影响患者生存率的重要因素。 目的：对肾移植后急性排斥反应和免疫抑制剂研究文献进行多层次分析。 方法：以电子检索方式对Web of Science数据库2002至2011年收录肾移植后急性排斥反应和免疫抑制剂研究的文献进行分析,采用检索词为“肾移植;急性排斥反应;免疫抑制剂”。对肾移植后排斥反应进行分类,了解肾移植后免疫抑制剂的种类,分析各种免疫抑制剂的特点。 结果与结论：Web of Science数据库2002至2011年收录肾移植后急性排斥反应和免疫抑制剂研究的文献共6 105篇,文献数量总体呈现出逐步上升的发展状态,《移植学会会报》杂志是发表肾移植后急性排斥反应和免疫抑制剂研究文献较多的期刊。美国在此类研究中发表文献最多,其次为德国。收录文献按被引频次由高到低排序前10位中,有4篇来源于《新英格兰医学》杂志。中国在过去10年间被收录文章总量排在第9名,共发表238篇相关文献,中国的国家自然科学基金资助文献有17篇。     

Susceptibility of corneal allografts and xenografts to antibody-mediated rejection

The effects of passive transfer of antisera containing cytotoxic antibodies to allo- and xenoantigens on survival of corneal allografts and xenografts were evaluated in experimental models. Corneas from allogeneic B10 or xenogeneic rat Lewis donors were grafted orthotopically into BALB/c mice. Recipient mice were treated with donor-specific antisera administered at the period of grafting or at 2 weeks after transplantation. Rejection was determined by the severity of corneal opacity using a standard scoring system. Treatment of graft recipients with donor-specific antisera accelerated the onset of graft rejection and significantly shortened survival times of both corneal allografts and xenografts. Corneal xenografts, which had been accepted after treatment with anti-CD4 monoclonal antibody, were acutely rejected by the passive transfer of antiserum against xenoantigens. The results suggest that corneal grafts are vulnerable to antibody-dependent immunity and that cytotoxic antibodies against graft donor antigens can mediate rejection of both corneal allografts and xenografts.     

Early acute antibody-mediated rejection of a negative flow crossmatch 3rd kidney transplant with exclusive disparity at HLA-DP

Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA.     

Late antibody-mediated rejection by de novo donor HLA-DP-specific antibody after renal transplantation: A case report

The role of donor HLA-DP-specific antibodies after renal transplantation is controversial, and only preformed HLA-DP-specific antibodies have been shown to mediate rejection. Here we present a case of late humoral rejection mediated by de novo donor HLA-DP-specific antibodies in a non-sensitized recipient. This unique case demonstrates the pathogenic role of de novo anti-DP antibodies and suggests that HLA-DP matching might be relevant for renal transplantation.     

RANTES与移植排斥

RANTES为趋化因子C-C家族成员之一，主要产生于活化的T细胞。它通过活化T细胞，控制免疫细胞定向迁移，不仅向移植物内募集免疫炎性细胞，加速排斥反应，还诱导T细胞、单核巨噬细胞与血管内皮细胞粘附，参与慢性排斥反应中移植物结构的损伤和纤维化。RANTES参与皮肤、心脏、肾脏、小肠等多种器官移植的排斥反应。针对RANTES的抗排斥治疗在多项研究中有效。