The natural killer cell activating receptor,NKG2D,is critical to antibody-dependent chronic rejection in heart transplantation

Chronic rejection is among the most pressing clinical challenges in solid organ transplantation. Interestingly, in a mouse model of heterotopic heart transplantation, antibody-dependent, natural killer (NK) cell-mediated chronic cardiac allograft vasculopathy occurs in some donor–recipient strain combinations, but not others. In this study, we sought to identify the mechanism underlying this unexplained phenomenon. Cardiac allografts from major histocompatibility complex (MHC) mismatched donors were transplanted into immune-deficient C57Bl/6.rag^−/− recipients, followed by administration of a monoclonal antibody against the donor MHC class I antigen. We found marked allograft vasculopathy in hearts from C3H donors, but near-complete protection of BALB/c allografts from injury. We found no difference in recipient NK cell phenotype or intrinsic responsiveness to activating signals between recipients of C3H versus BALB/c allografts. However, cardiac endothelial cells from C3H allografts showed an approximately twofold higher expression of Rae-1, an activating ligand of the NK cell receptor natural killer group 2D (NKG2D). Importantly, the administration of a neutralizing antibody against NKG2D abrogated the development of allograft vasculopathy in recipients of C3H allografts, even in the presence of donor-specific antibodies. Therefore, the activating NK cell receptor NKG2D is necessary in this model of chronic cardiac allograft vasculopathy, and strain-dependent expression of NK activating ligands correlates with the development of this disease.     

Targeting NF-κB c-Rel in regulatory T cells to treat corneal transplantation rejection

The relevance of Tregs in the induction of tolerance against corneal allografts has been well established. Although it is well known that the conversion of Tregs into effector-like cells contributes to the loss of corneal immune privilege, the underlying mechanism is still not fully understood. Using heterologous penetrating keratoplasty model, we found that Tregs from corneal allograft rejected mice (inflam-Tregs) exhibit impaired function and characteristics of effector T cells. Further study showed that the expression of NF-κB c-Rel, a key mediator of effector T cell function, was significantly increased in inflam-Tregs. Mechanistic study revealed that elevated NF-κB c-Rel level in inflam-Tregs impaired Treg function through the promotion of inflammatory cytokine production and glycolysis. More importantly, we demonstrated that targeting NF-κB c-Rel was able to improve the immune suppressive function of inflam-Tregs in vitro and enhance the potential of them to suppress corneal transplantation rejection. Therefore, our current study identified NF-κB c-Rel as a key mediator of the conversion of Tregs into effector-like cells when under inflammatory environment.     

Administration of ATG according to the absolute T lymphocyte count during therapy for steroid-resistant rejection

In renal transplantation, treatment of steroid-resistant rejection (SRR) with antithymocyte globulin (ATG) has been widely reported but over-immunosuppression remains a common problem. In the first ten patients (group 1) treated for SRR with rabbit ATG, three developed serious viral infections and two deaths occurred due to CMV pneumonitis. ATG was only omitted if thrombocytopenia or neutropenia occurred. In the next 17 patients (group 2) with SRR, ATG was administered according to the absolute T lymphocyte count. T lymphocytes were measured by flow cytometric analysis of CD3-labelled lymphocytes. ATG dosage was adjusted on a daily basis to keep the absolute T lymphocyte count under 50 cells/l. Administration of ATG according to the absolute T lymphocyte count resulted in a significant reduction in the mean dose of ATG given to the group 2 patients (P<0.001). A significant decrease in the incidence of serious viral infections (P=0.04) was achieved without reducing the ability of ATG to reverse the SRR (P=0.29) or increasing the number of grafts lost at 1 year in the group 2 patients (P=0.23).     

Binding and specificity of major immunoglobulin classes of preformed human anti-pig heart antibodies

Preformed human anti-pig antibodies isolated from perfused pig hearts were used to analyze the binding of various immunoglobulin classes to cultured pig kidney cells. All anti-pig immunoglobulins (i.e., IgG, IgA, and IgM) were localized on the cell surface by the use of an indirect immunofluorescence technique. Anti-pig immunoglobulins also competed for the pig cell surface epitopes with Griffonia simplicifolia lectin (GS-I-B₄), which is specific for -galactosyl residues. This study provides further evidence that preformed human antibodies recognizing -glactosyl-containing epitopes (anti-gal antibodies) could be an important factor in hyperacute rejection of pig organs.     

移植肾慢性排斥纤维化中巨噬细胞和NO作用机制的探讨

目的：探讨移植肾慢性排斥中纤维化过程扣形成机制。方法：采用免疫化技术及图像分析技术,观察移植肾慢性斥形成过程中巨噬细胞的形态学特征及NO含量的变化。结果：移植肾慢必排斥早、中期,损害的肾小球、肾小管处巨噬细胞增多、聚集,NO表达率增加,Ⅲ、Ⅳ型胶原的表达增强;后期,已硬化的肾小班干部、肾小管处的巨噬细胞无NO表达,Ⅲ、Ⅳ型胶原的表达减弱,CD68阳性细胞计数,NO以及Ⅲ、Ⅳ型胶原的含量在移植性肾小球病型的肾小球以及肾间质硬化型的肾小管中最高。结论：移植肾慢性排斥形成过程中巨噬细胞增多且NO表达增加,可能与肾纤维化形成有关。     

豚鼠至大鼠异种小肠移植超急性排斥的初步观察

目的 建立袖套法豚鼠至大鼠异种小肠移植模型,初步观察异种小肠移植超急性排斥反应的过程。方法 行异种异位全小肠移植,移植小肠脾性系膜上动脉（腹主动脉）与受体肾以下腹主动脉作端侧吻合,切除受体左肾,移植小肠肠系膜上静脉（门静脉）与受体左肾静脉行袖套吻合;在手术显策镜下观察超急性排斥的大体变化。结果 共实施异种小肠移植４０例,成功３４例,供受体手术时间平均１５０ｍｉｎ,血管吻合成功率达９０％。再灌流后１     

Pediatric intestinal transplantation

Advancements in donor management, organ preservation and operative techniques, as well as immunosuppressive therapies, have provided children with intestinal failure and its complications a chance not only for enteral autonomy but also long-term survival through intestinal transplantation (ITx). First described in the 1960’s, experience has grown in managing these complex patients both pre- and post-transplant. The goals of this review are to provide a brief history of intestinal transplantation and intestinal rehabilitation in pediatric patients, followed by focused discussions of the indications for ITx, induction and maintenance immunosuppression therapies, common post-operative complications, and outcomes/quality of life post-transplant.     

Paediatric intestinal transplantation: where are we now?

Intestinal transplantation (ITx) is the only curative treatment option for children with irreversible intestinal failure (IF) and complications of parenteral nutrition (PN). ITx is an immunologically difficult transplant due to the immune load of the donor gut; therefore, main causes of death and graft loss are immunological complications like sepsis or acute and chronic rejection. This article aims to help paediatricians in training understand when children should be referred for ITx, the different types of ITx, the complications these children might present with, and to learn about the journey a candidate for ITx must take with the support of the IF and ITx multidisciplinary teams (MDT).     

Does subclinical rejection contribute to chronic rejection in renal transplant patients?

Renal allograft biopsies have traditionally been performed in the setting of acute graft dysfunction. However, several groups have performed graft biopsies at times of stable graft function, and more recently, after treatment of rejection episodes. Surprisingly, unequivocal histologic criteria for acute rejection have been demonstrated in a high proportion of these protocol biopsies. The Winnipeg Transplant Group has documented the high prevalence of clinically silent inflammatory infiltrates in early protocol biopsies, and demonstrated their inflammatory and cytotoxic potential by immunohistochemical and molecular biological techniques. Furthermore, in a randomized trial, our group has demonstrated that subclinical rejection, if untreated, is associated with the development of early chronic pathology and late graft dysfunction. In this overview, we will summarize the early data on subclinical allograft inflammation, present the experience of the Winnipeg Transplant Group, and discuss the possible implications of subclinical rejection on the development of chronic rejection.     

The effect of macrophage depletion on delayed xenograft rejection: studies in the guinea pig-to-C6-deficient rat heart transplantation model

The purpose of this study was to investigate the effect of macrophage depletion, using liposome‐encapsulated dichloromethylene diphosphonate (Lip‐Cl₂MDP), on delayed xenograft rejection (DXR) in the guinea pig‐to‐C6‐deficient rat heart transplantation model. In this model, hyperacute rejection does not occur, but, in untreated recipient s, xenografts are still destroyed by DXR within 1–2 days. Graft survival was 68 ± 8.4 h in splenectomized control rats, 77 ± 16.3 h with Lip‐Cl₂MDP alone, 99 ± 10.4 h with deoxysperguarlin (DSG; P < 0.01 vs. controls), and 127 ± 19.4 h with Lip‐Cl₂MDP plus DSG (P < 0.01 vs. DSG alone). Treatment with DSG alone or in combination with Lip‐Cl₂MDP resulted in significant reductions in serum IgM levels at rejection. Immunohistological studies showed that Lip‐Cl₂MDP alone or in combination with DSG reduced infiltration of grafts by both ED1 + and ED2 + macrophages. These experiments support the concept that macrophages play an important role in DXR and suggest that strategies targeting macrophages may be useful in controlling DXR.