Allosensitization in bridge to transplant Novacor left ventricular assist device patients: analysis of long-term outcomes with regard to acute rejection and chronic allograft vasculopathy

BACKGROUND: The true relevance of allosensitization in patients benefiting from left ventricular assist device (LVAD) as bridge to transplant (BTT) is still debated. Available registry data referred to numerous devices precluding LVAD-specific analysis. Therefore, we studied all patients with Novacor LVAD prior to transplantation. METHODS: From 1985 to 2006, 37 Novacor LVADs were implanted as BTT, with 30 patients surviving to transplantation (81%). Post-LVAD sensitization was determined for anti-HLA-class I and class II IgGs. Study endpoints were overall survival and/or graft loss, > or =3A cellular rejection and chronic allograft vasculopathy (CAV). The results from LVAD patients were compared to non-LVAD primary heart transplant recipients (n=318). RESULTS: After LVAD insertion, 5 out of 27 patients available for analysis developed anti-HLA antibodies (18.5%). The mean anti-HLA titer after Novacor LVAD implantation was 14% [SD 31]. Actuarial 5- and 10-year patient/graft survival for LVAD and non-LVAD transplant recipients were 73% and 55%, and 70% and 55%, respectively (p=NS). Overall prevalence of rejection > or =3A was 23.3 % (LVAD group) and 18.9% (non-LVAD group) (p=NS). At follow-up, the respective incidence of CAV was 8% (LVAD group) and 32.4% (non-LVAD group) (p<0.01). However, mean follow-up was significantly different for LVAD and non-LVAD patients, 46 vs 90 months (p<0.001). CONCLUSION: In this study, allosensitization occurred infrequently after Novacor LVAD implantation. Secondly, analysis of outcome variables shows that Novacor-LVAD BTT patients can anticipate similar survival to non-LVAD patients, thus minimizing the impact of allosensitization after LVAD implantation.     

'Chimeric' Grafts Assembled from Multiple Allodisparate Donors Enjoy Enhanced Transplant Survival

Certain components of a graft that provoke alloimmunity may not be vital for graft function or critical as targets of rejection. Corneal transplantation is an example of this, because graft epithelium plays a role in allosensitization, whereas corneal graft endothelium—which shares the same alloantigens—is the critical target in allorejection. In this study, we found that exploiting this biology by replacing donor epithelium of an allograft with an allodisparate third-party epithelium yields a marked enhancement in transplant survival. Such 'chimeric' allografts consisted of a C3H/He (H-2^k) corneal epithelium over a C57BL/6 (H-2^b) epithelial-denuded cornea (or v.v. ) and orthotopically placed on BALB/c (H-2^d) hosts. Conventional corneal allografts (C3H/He or C57BL/6) or isografts (BALB/c) were also transplanted on BALB/c hosts. Alloreactive T-cell frequencies (CD4⁺ interferon [IFN]-γ⁺) primed to the graft endothelium were strongly diminished in chimeric hosts relative to conventionally allografted hosts. This was corroborated by a decreased T-cell infiltration (p = 0.03) and a marked enhancement of allograft survival (p = 0.001). Our results represent the first successful demonstration of chimeric tissue, epithelial-denuded allograft plus third-party allodisparate epithelium, in the promotion of allograft survival. Moreover, chimeric grafting can be readily performed clinically, whereby corneal allograft rejection remains a significant problem particularly in inflamed graft beds.     

The expression of proteins and activities of metabolic enzymes in transplanted brain tissue

The middle three-fifths of the forebrains of 14-day-old embryos were obtained and transplanted into the cortical cavities of adult rats made 7 days prior to the transplantation. The expression of proteins, as revealed by 2-dimnsional gel electrophoresis studies, and the activities of energy metabolizing enzymes in the mature allografts were compared with those in the 14-day-old embryonic forebrains and corresponding areas in the contralateral cerebral hemispheres of the host. They were shown to approach adult pattern and adult values after 10–12 weeks of growth. The biochemical findings were discussed and correlated with some of the anatomical observations.     

带血供骨膜瓣包裹同种异体骨修复骨缺损的实验研究

目的探讨带血供骨膜瓣包裹去抗原异体骨修复骨缺损的效果。方法将兔的股骨经去抗原化后作为供体，制作带血供骨膜瓣色裹同种异体骨修复免大段骨缺损模型，实验设置对照组，即未用血管化骨膜瓣包裹移植物。分别在术后第4周、8周和16周分别行X线摄片，并对移植物及周围软组织、骨组织进行组织学观察（HE染色），对两组移植物骨形态发生蛋白（BMP）进行免疫组织化学染色。结果X线表现为实验组骨痂形成的速度快于对照组，骨痂形成的质和量优于对照组，组织学观察显示实验组骨质更新速度以及新生血管速度均快于对照组，BMP免疫组织化学染色显示在相同时期实验组的表达明显强于对照组。结论带血供骨膜瓣包裹异体骨修复骨缺损优于单纯异体骨移植，明显缩短骨缺损的修复时间。     

CD154 Deficiency Uncouples Allograft CD8+ T‐Cell Effector Function from Proliferation and Inhibits Murine Airway Obliteration

Obliterative bronchiolitis (OB) limits the long‐term success of lung transplantation, while T‐cell effector mechanisms in this process remain incompletely understood. Using the murine heterotopic tracheal transplant model of obliterative airway disease (OAD) to characterize airway allograft rejection, we previously reported an important role for CD8⁺ T cells in OAD. Herein, we studied the role of CD154/CD40 costimulation in the regulation of allospecific CD8⁺ T cells, as airway rejection has been reported to be CD154‐dependent. Airway allografts from CD154^−/− recipients had significantly lower day 28 OAD scores compared to wild‐type (WT) recipients, and adoptive transfer of CD8⁺ T cells from WT recipients, but not CD154^−/− recipients, were capable of airway rejection in fresh CD154^−/− allograft recipients. Intragraft CD8⁺ T cells from CD154^−/− mice showed similar expression of the surface markers CD69, CD62L^low CD44^high and PD‐1, but markedly impaired IFN‐γ and TNF‐α secretion and granzyme B expression versus WT controls. Unexpectedly, intragraft and systemic CD8⁺ T cells from CD154^−/− recipients demonstrated robust in vivo expansion similar to WT recipients, consistent with an uncoupling of proliferation from effector function. Together, these data suggest that a lack of CD154/CD40 costimulation results in ineffective allospecific priming of CD8⁺ T cells required for murine OAD.     

Four Stages and Lack of Stable Accommodation in Chronic Alloantibody-Mediated Renal Allograft Rejection in Cynomolgus Monkeys

The etiology of immunologically mediated chronic renal allograft failure is unclear. One cause is thought to be alloantibodies. Previously in Cynomolgus monkeys, we observed a relationship among donor-specific alloantibodies (DSA), C4d staining, allograft glomerulopathy, allograft arteriopathy and progressive renal failure. To define the natural history of chronic antibody-mediated rejection and its effect on renal allograft survival, we now extend this report to include 417 specimens from 143 Cynomolgus monkeys with renal allografts. A subset of animals with long-term renal allografts made DSA (48%), were C4d positive (29%), developed transplant glomerulopathy (TG) (22%) and chronic allograft arteriopathy (CAA) (19%). These four features were highly correlated and associated with statistically significant shortened allograft survival. Acute cellular rejection, either Banff type 1 or 2, did not correlate with alloantibodies, C4d deposition or TG. However, endarteritis (Banff type 2) correlated with later CAA. Sequential analysis identified four progressive stages of chronic antibody-mediated rejection: (1) DSA, (2) deposition of C4d, (3) TG and (4) rising creatinine/renal failure. These new findings provide strong evidence that chronic antibody-mediated rejection develops without enduring stable accommodation, progresses through four defined clinical pathological stages and shortens renal allograft survival.     

慢性肾衰竭大鼠肾移植后骨髓红细胞生成素受体的变化

目的通过观察慢性肾衰竭大鼠肾移植前后骨髓红系祖细胞的红细胞生成素受体(EPOR)的变化及与肾功能和贫血的关系,探讨红细胞生成素受体(EPOR)抑制在肾性贫血中的作用。方法以慢性肾衰竭(CRF)大鼠作为受者行同种异体肾移植术模拟人类肾移植。模型建立后RT-PCR法测定假手术组、CRF组和肾移植后不同时间大鼠骨髓红系祖细胞EPORmRNA表达的变化,WesternBlot分析EPOR蛋白质含量变化趋势,同时作EPORmRNA、EPOR蛋白质含量、Scr、Hb之间的相关性分析。结果CRF模型在5／6肾切除后90d时成功,接受肾移植后其血清肌酐和尿素氮迅速下降。CRF时EPORmRNA的表达和EPOR蛋白质含量较正常对照组明显降低,肾移植术后第7d开始二者明显升高,14d时恢复正常。相关性分析显示,EPORmRNA、EPOR蛋白含量、血红蛋白(Hb)均与血清肌酐呈显著性负相关,而EPORmRNA、EPOR蛋白含量与Hb呈显著性正相关。结论大鼠接受肾移植,尿毒症毒素完全清除后EPORmRNA及EPOR蛋白质含量显著增加至正常水平,提示EPOR抑制是引起肾性贫血的重要机理之一。