Rat cytomegalovirus and Listeria monocytogenes infection enhance chronic rejection after allogenic rat lung transplantation

The role of infection in the pathomechanism of obliterative bronchiolitis (OB) after human lung transplantation is controversial. In a rat lung transplantation model, we analyzed the effect of viral [rat cytomegalovirus (RCMV)] and bacterial infection [Listeria monocytogenes (LM)] on the development of chronic allograft rejection. Fisher rats underwent single left lung transplantation with allografts from Lewis rats. Postoperatively, animals were infected with either RCMV or LM, or served as noninfected controls. Animals were killed on day 120 and both lungs were evaluated histopathologically for chronic airway and chronic vascular rejection. Infection with RCMV produced a significant increase in the incidence of chronic airway rejection (66.7% vs. 20%), compared with noninfected long-term surviving animals. In rats with bacterial infection (LM) a similar increase of chronic airway changes as in viral infection (50% vs. 20%) was observed. Chronic rejection of allografts infected with either RCMV or LM was associated with significantly enhanced expression of intercellular adhesion molecule-1 (ICAM-1) on the endothelium. More infiltrating leukocytes (CD18, CD11a, CD44) and ED1-positive macrophages were found in allografts of infected animals. In this experimental model of chronic airway rejection in long-term surviving rats, not only viral but also bacterial infection resulted in enhanced development of chronic airway and vascular rejection. These results support our hypothesis that infectious complications have a substantial influence on the development of OB in human lung allografts.     

肾移植术后早期肾功能恢复对人肾长期存活的影响

目的 探讨肾移植术后早期肾功能恢复情况对人肾长期存活的影响。方法 总结1990-1998年652例肾移植患者资料。根据肾功能恢复情况分为3组：肾功能恢复迅速（IGF）组（A组）473例，肾功能恢复缓慢未行透析治疗（SGF）组（B组）82例，肾功能延迟恢复（DGF）组（C组）97例。对3组患者5、10年人。肾存活率及1年急性排斥反应和带肾死亡情况进行比较分析。结果 A组5、10年人／肾存活率分别为74．0％／70．2％、66．9％／60．3％，B组为64．6％／61．0％、62．2％／42．2％，C组为60．8％／43．3％、55．7％／23．0％。5年人存活率A、B组高于C组，5年。肾存活率A组高于C组，5年人／肾存活率A、B组差异无统计学意义。10年人／肾存活率A组〉B组〉C组，差异均有统计学意义。3组1年急性排斥反应发生率为20．1％、30．5％、43．2％，组间差异有统计学意义。3组1年带肾死亡率为4．7％、4．9％、12．4％，A、B组〈C组，A、B组间差异无统计学意义。急性排斥反应和带肾死亡病例排除后进行比较，3组长期存活率差异无统计学意义。结论 肾移植术后早期肾功能恢复情况对移植患者长期人肾存活有明显影响，DGF患者的影响最明显，SGF预后介于IGF和DGF间。SGF和DGF对长期存活的影响可能源于移植早期较高的急性排斥反应或并发症发生率。     

Peritubular capillaritis in early renal allograft is associated with the development of chronic rejection and chronic allograft nephropathy

Abstract:  Peritubular capillaritis (PTCitis) has been recognized as one form of acute/active allograft rejection, and its relation to humoral immunity has been suggested. However, its mechanisms remain to be fully clarified, and there are no criteria for evaluating the extent of PTCitis in a biopsied allograft. In this study, we first evaluated the extent of PTCitis in early allografts in patients presenting with acute cellular rejection (ACR) and antibody-mediated rejection (AbAR). We also included patients who showed no evidence of ACR and/or AbAR. Next, we investigated whether or not PTCitis persisted and if peritubular capillary basement membrane (PTCBM) thickening was present in their follow-up biopsy specimens. We adopted the scoring system of PTCitis, which was presented at the Seventh Banff Conference on Allograft Pathology in 2003. In total, 53 patients were included in this study. At first biopsy, 17 showed ACR, eight showed AbAR, 16 showed mild PTCitis only, and 14 were without significant pathologic changes. The PTC score was the highest in the AbAR group, and in some patients the score gradually increased during the follow-up period. Similar changes were also observed in the group with mild PTCitis only. In late allografts, half of the patients with AbAR developed chronic rejection (CR), and the PTCBM score was the highest in that group. Surprisingly, CR was present in more than 30% of patients without ACR and/or AbAR but mild PTCitis only. In the control group, only a few showed CR and/or chronic allograft nephropathy (CAN). In conclusion, it became clear that we should carefully monitor for mild PTCitis in early allografts. In addition, our data also proved the usefulness of the PTC score and PTCBM score.     

Complement C4d deposition in transplanted kidneys: preliminary report on long-term graft survival

Abstract:  The effects of antibody-mediated rejection on long-term graft survival have not been fully investigated. The aim of this study is to clarify the influence on long-term survival of deposition of the complement split product C4d in allografts using polyclonal anti-C4d antibody. Inclusion criteria were recipients who underwent graft biopsy during acute deterioration of graft function within the first 2 yr after transplantation. Patients whose graft did not survive more than 1 yr and who received graft from an human leucocyte antigen (HLA)-identical sibling or an ABO-incompatible donor were excluded. Among the 92 recipients investigated, 22 (23.9%) had peritubular capillary C4d deposition, 15 (16.3%) had glomerular capillary C4d deposition and seven (7.6%) had both peritubular and glomerular capillary C4d deposition. Twenty of these 22 patients revealed acute cellular rejection, including borderline changes. There was no significant relationship between pathological severity of acute rejection and presence or absence of peritubular capillary C4d deposition. Graft survival was inferior in patients with peritubular capillary C4d deposition to that in patients without C4d deposition (p = 0.0419). Graft survival in patients with glomerular C4d deposition did not differ from that in patients without C4d deposition. In conclusion, C4d deposition in peritubular capillaries has a substantial impact on long-term graft survival.     

Vascular Endothelial Growth Factor Expression and Cyclosporine Toxicity in Renal Allograft Rejection

The aim of this study was to evaluate the influence of vascular endothelial growth factor (VEGF) on renal function and on development of interstitial fibrosis (IF) in renal allografts. Tubular and interstitial expressions of VEGF and TNF-α, and density of macrophages in the interstitium were examined in 92 patients with nonrejected kidneys, acute rejection (AR), chronic allograft nephropathy (CAN), borderline changes (BC) and acute cyclosporin A (CsA) toxicity. Follow-up biopsy specimens from patients with AR and BC were evaluated for development of IF. A significant difference in tubular and interstitial VEGF expressions was found between patients with AR, BC, CAN and CsA toxicity (p < 0.001). Macrophage infiltration was positively correlated with VEGF and TNF-α expressions (p < 0.001). VEGF expression increased with increasing expression of TNF-α (p < 0.001). Renal function in first 6 months after initial biopsy was better in patients with marked tubular VEGF expression (p < 0.01); however, in follow-up, development of IF and graft loss was found earlier in these patients (p < 0.01 and p < 0.05, respectively). Increased renal VEGF expression has protective properties immediately following renal allograft but allows for increased risk of early IF, and therefore poor graft outcome in the long term.     

自体骨髓细胞诱导肝移植大鼠长期存活的机制探讨

目的 研究自体骨髓细胞诱导肝移植大鼠长期存活的可能机制.方法 雌性受体大鼠随机分成空白对照组(A组)、D-hanks液组(B组)、全骨髓细胞组(C组)、间充质干细胞组(D组).观察大鼠的中位生存时间(median survival time,MST)、肝功能、病理变化、Sry基因原位杂交和甲胎蛋白、白蛋白免疫组化双标检测观察自体骨髓细胞的分化情况.结果 C组、D组MST均>180 d(P<0.01);血肝功能指标C组、D组降低明显,有显著差异(P<0.01);C组、D组之间比较无显著差异(P>0.05);移植术后60 d C、D组均无明显的急性排斥反应;C组、D组Sry基因原位杂交和甲胎蛋白、白蛋白免疫组化双标检测呈阳性.结论 自体骨髓细胞能减少排斥反应、诱导大鼠肝移植术后长期存活,其中间充质干细胞在移植肝内诱导分化为肝细胞发挥肝细胞功能,是其中可能的机制.     

Outcome of Subclinical Antibody-Mediated Rejection in Kidney Transplant Recipients with Preformed Donor-Specific Antibodies

This study describes clinical relevance of subclinical antibody-mediated rejection (SAMR) in a cohort of 54 DSA-positive kidney transplant recipients receiving a deceased donor. In 3 months screening biopsies, 31.1% of patients met the criteria of SAMR. A total of 48.9% had an incomplete form of SAMR (g+/ptc+/C4d-negative) whereas 20% had no humoral lesions. Patients with SAMR at 3 months had at 1 year: a higher C4d score, ptc score, and arteriosclerosis score, higher rate of IFTA (100% vs. 33.3%, p < 0.01) and a higher rate of transplant glomerulopathy (43% vs. 0%, p = 0.02) compared to patients without 3-month SAMR. Patients with SAMR at 3 months exhibited at 1 year a higher class II MFImax-DSA and a lower mGFR compared to patients without SAMR (39.2 ± 13.9 vs. 61.9 ± 19.2 mL/min/1.73 m² respectively, p < 0.01). The group of patients with C4d-negative SAMR at 3 months developed more ptc and IFTA lesions, and lower GFR at 1 year in comparison to biopsies without humoral lesions. SAMR is a frequent entity in KTR with preexisting DSAs and promotes subsequent GFR impairment and development of chronic AMR. C4d-negative SAMR patients displayed an intermediate course between the no-SAMR group and the C4d+ SAMR group. Screening biopsies may be useful to recognize patients more likely to develop SAMR.     

肾移植术后急性体液性排斥反应的治疗

目的 总结肾移植术后急性体液性排斥反应中针对HLA抗体的检测和处理经验.方法 肾移植受者15例,术前行HLA分型、交叉配型和群体反应性抗体(PRA)的检测,术后采用他克莫司(或环孢素A)、霉酚酸酯和糖皮质激素预防排斥反应.15例于肾移植后1～14 d发生抗体介导的急性排斥反应(AMR),采用抗胸腺细胞球蛋白(100 mg/d,使用5 d)治疗,或将环孢素A转换为他克莫司,当PRA明显升高,且血清中出现供者特异性HLA抗体时,即行血浆置换(PP),共行1～5次,每次PP后静脉输注免疫球蛋白(IVIG)100～150 mg/kg,最后1次PP后给予WIG 200～500mg/kg.结果 术后出现抗供者特异性HLA Ⅰ类抗体者9例,抗HLAⅡ类抗体者4例,同时出现抗Ⅰ、Ⅱ类抗体者2例.14例的AMR逆转,1例术后发生移植肾功能恢复延迟,彩色多普勒超声波显示移植肾血流灌注差,于术后第10天切除移植肾.并行二行肾移植.2例AMR后并发急性肾小管坏死,透析后移植肾功能恢复正常.抗排斥反应治疗期间患者均未发生严重感染.随访12～52个月,1例因慢性移植肾肾病恢复血液透析治疗,1例死于心血管疾病,其余患者移植肾功能稳定.结论 将ATG、PP和IVIG联合应用能有效逆转AMR.     

临床小肠移植排斥反应的防治

采用环孢素Ａ、雷公藤多甙、甲基氢化泼尼松、前列腺素Ｅ１伍用的新型免疫抑制方案，预防小肠移植排斥反应取得满意效果。病人存活３１０ｄ。经验表明，通过内窥镜和肠粘膜组织病理检查，监测排斥反应简便实用有效。利用聚合酶链反应（ＰＣＲ）技术研究发现，移植术后供肠细胞向受体组织移居嵌合，而临床无移植物抗宿主病（ＧＶＨＤ）发生。促进细胞移居嵌合可能有利于防止排斥反应的发生。     

Serial evaluation of left ventricular function by radionuclide ventriculography at rest and during exercise after orthotopic heart transplantation

Discrepant results have previously been reported concerning long-term left ventricular function in the human transplanted heart as assessed by radionuclide ventriculography. In this study, radionuclide ventriculograms were obtained at rest and during exercise in 19 patients <6 months, 7–12 months, 13–24 months and >24 months after transplantation. Ejection fraction decreased significantly from <6 months to 13–24 months after transplantation (rest: 69.1%±9.7% to 56.7%±8.3%, P<0.05; exercise: 70.4%±11.3% to 59%±8%, P<0.05). Heart rate increased significantly during exercise after >2 years (90.2±10.5 beats/min to 103.5±15 beats/min, P<0.05) but not within 6 months after transplantation (98.5±12.8 beats/min to 99.07±15.8 beats/min). Left ventricular end-diastolic volume remained unchanged. Peak filling rate at rest decreased significantly from 4.2±0.96 edv/s <6 months after transplantation to 3.3±0.66 edv/s (P<0.05) 13–24 months and 3.3±0.64 edv/s (P<0.05)>24 months after cardiac transplantation. Exercise peak filing rate did not change significantly. It is concluded that radionuclide ventriculography demonstrates a decrease in systolic left ventricular function in the long-term course after cardiac transplantation. A significant increase in exercise peak heart rate may be due to autonomic reinnervation. Differences in the literature concerning left ventricular function may be due to different observation intervals following cardiac transplantation.