Chronic Kidney Isograft and Allograft Rejection

In this study antigen-independent factor in the pathogenesis of chronic rejection of organ transplants was examined.Kidney isografts and allografts were transplanted orthotopically into bilaterally nephroectomized rat recipients and studied functionaaly,morphologically and immunohistologically,at serial intervals up to 52 weeks after transplantation.Allograft recipients developed progressive proteinuria after 12 weeks,with gradual renal failure ultimately leading to death.At the same time,morphological changes,including progressive arteriosclerosis and glomerulosclerosis ,tubular atrophy and interstitial fibrosis,developed.Immunohistologically,macrophages infiltrated glomeruli during this period and cytokines became unregulated.Our results showed that antigen-independent functional and morphological changes occurred in long-tern kidney isografts and mimicked those appearing much earlier in allografts that reject chronically.Initial injury and extent of functioning renal mass is suggested to be important factor for such late changes.     

Expression of cell-matrix molecules and integrin receptors in human liver grafts during chronic rejection

Abstract The inflammatory response of immune cells to target cells and cell-matrix molecules is regulated by several receptor-ligand molecules. As fibrosis develops in ongoing chronic rejection after liver transplantation, it is of interest to analyze patterns of integrin receptors and cell-matrix molecules in order to study the relation between immune cells and the stromal and parenchymal cells. In the present study, we demonstrated the expression of these molecules in chronic rejected human liver grafts using immunohistochemical techniques. The results showed a differential expression and induction of integrin receptors and cell-matrix molecules on resident liver cells, especially on sinusoids, reflecting a state of chronic inflammation and a specific interaction between integrin receptors and cell-matrix molecules. The patterns of induced integrin receptors on graft-infiltrating cells was closely related to the local production of cell-matrix molecules and reflected the final sequence of a stepwise progress of the inflammatory reaction.     

IL-2R 在急性细胞性排异反应的同种异体尸体移植肾组织中的检测及意义

为探讨白介素－２受体（ＩＬ－２Ｒ，即ＣＤ２５）在同种异体肾移植急性细胞性排异（ＡＣＲ）临床诊断的作用，着重观察移植肾发生（ＡＣＲ）和无ＡＣＲ时，其间质浸润细胞中ＩＬ－２Ｒ阳性细胞数的变化，及其与间质浸润的淋巴细胞的关系。作者选择同期行异体肾移植，且无并发症患者１７例，采用ＰＡＰ四层免疫酶标法，检测移植肾组织中间质浸润细胞中ＩＬ－２Ｒ阳性细胞数的变化。结果显示：无ＡＣＲ的肾组织中，ＩＬ－２Ｒ阳性细胞仅轻度增加，当移植肾出现ＡＣＲ时，ＩＬ－２Ｒ阳性细胞数的增加十分显著，并与间质浸润的ＣＤ８密切相关。作者认为ＩＬ－２Ｒ对于ＡＣＲ的诊断及鉴别诊断具有一定的临床应用价值。     

Human chronic kidney allograft rejection is accompanied by increased intraglomerular cathepsin B and L activity

Abstract The major reason for late graft losses is chronic rejection. Recently, a large number of studies have indicated that proteolytic enzymes play an important role as mediators of glomerular injury. The cysteine proteinases cathepsins B and L degrade structural matrix proteins such as type I collagen and laminin. We investigated intraglomerular protease activities in 12 patients after kidney graftectomy because of end-tage renal disease following chronic rejection. A group of 12 patients undergoing nephrectomy because of cancer served as controls using only non-involved parts of the kidney. The activities of cathepsins B and L in homogenates of isolated glomeruli were measured fluorometrically methylcoumarylamidc substrates and related to DNA content. In rejected kidney allografts we observed significantly enhanced intraglomerular cathepsin B activity and cathepsin B + L activity.     

尿流式细胞学在诊断移植肾急性排斥反应中的应用价值

目的：探讨尿流式细胞学在诊断移植肾急性排斥反应中的临床应用价值。方法：对43例肾移植受者的116份尿样本进行尿流式细胞学分析，并将急性排斥组和肾功能稳定组的分析结果进行比较。结果：急性排斥反应组尿淋巴细胞总数以及HLA－DR^ 淋巴细胞数显著增多，与肾功能稳定组比较，P＜0．01，CD8^ 细胞亦增多（P＜0．05），而CD3^ ,CD4^ ,CD19^ 细胞数变化两组差异不显著（P＞0．05），在诊断移植肾急性排斥反应上，HLA－DR阳性样本和淋巴细胞数阳性样本的诊断敏感性和特异性分别达95．2％，90．5％，和92．6％，87．4％，结论：尿流式细胞学分析可反映移植肾内的免疫状态，尿淋巴细胞数的显著增多和尿HLA－DR^ 淋巴细胞增多可以作为诊断急性排斥反应的有意义指标。     

Reduction in acute rejections decreases chronic rejection graft failure in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

Chronic rejection accounted for 32% of all graft losses in 7123 pediatric transplants. In a previous study acute, multiple acute and late acute rejections were risk factors for the development of chronic rejection. We postulated that the recent decrease in acute rejections would translate into a lower risk for chronic rejection among patients with recent transplants. We reviewed our data on patients transplanted from 1995 to 2000, and using multivariate analysis and a proportional hazards model developed risk factors for patients whose grafts had failed due to chronic rejection. A late initial rejection increased the risk of chronic rejection graft failure 3.6-fold (p < 0.001), while a second rejection resulted in further increase of 4.2-fold (p < 0.001). Recipients who received less than 5 mg/kg of cyclosporine at 30 days post-transplant had a relative risk (RR) of 1.9 (p = 0.02). Patients transplanted from 1995 to 2000 had a significantly lower risk (RR = 0.54, p < 0.001) of graft failure from chronic rejection than those who received their transplants earlier (1987-94). Since we were able to demonstrate that there is a decreased risk of chronic rejection graft failure in our study cohort, we would conclude that the goal of future transplants should be to minimize acute rejections.     

心脏移植术后急性排异反应的监测

目的 总结原位心脏移植术后急性排异反应的监测。方法 2000－01／2002－04施行11例原位心脏移植手术，结合临床表现、心电图、超声心动图、化验检查及心内膜活栓等检查，对心脏移植术后急性排异反应的监测进行分析。结果 采用临床症状＋心电图＋超声心电图＋心肌血清学检测综合判断有6次急性排异反应，行心内膜活检证实Ⅰb级2次，Ⅲa级3次；术后常规行心内膜活检21次，仅发现急性排异反应Ⅰa或Ⅰb级5次。结论 急性排异反应是关系到心脏移植术后患者康复及愈后的重要因素，因此要及时、有效地进行监测；心内膜心肌活检是诊断急性排异反应敏感可靠的方法，但为有创性检查，有一定的并发症风险，其他多项无创性检查可作辅助指标，因此急性排异反应监测应把无创性检查与心内膜心肌活检有机地结合起来。     

Correlation between the intensity of cytomegalovirus infection and the amount of perivasculitis in aortic allografts

Abstract  We previously demonstrated that cytomegalovirus (CMV) infection enhanced perivascular inflammation in rat aortic allografts. In this study, we investigated the relationship between the CMV infection load and the magnitude of perivasculitis (chronic rejection) in aortic transplants. Rats received or-thotopic abdominal aortic grafts, different degrees of total body irradiation (TBI) for immunosuppres-sion and CMV inoculation. The spleens of the rats receiving 5 Gy of TBI contained more infectious virus and viral antigens than those of rats receiving 3 Gy of TBI or no TBI. Although the number of inflammatory cells infiltrating the perivascular area was decreased after TBI, CMV infection resulted in increased perivasculitis in rats that received 5 Gy of TBI as compared to non-infected animals. This virus-induced effect was characterized predominantly by an increased T-cell infiltration, including CD4 and CD8 T-cells. It is concluded that an enhanced systemic CMV infection during severe immunosuppressive therapy can accelerate the development of chronic rejection, which seems to be mediated mainly by T-cells.     

The value of serial determination of MEGX and hyaluronic acid early after orthotopic liver transplantation

Abstract. Post-transplant assessment of early graft function has become an essential part of monitoring, especially when deciding on retransplantation. If primary non-function is indicated, retransplantation is inevitable; early graft dysfunction may be related to subsequent complications. In a prospective study in 84 patients after orthotopic liver transplantation (OLT) we measured aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), bilirubin (BIL), prothrombin time, MEGX formation, hyaluronic acid (HA) and soluble interleukin-2 receptor (sIL-2R) concentrations during the first 2 postoperative weeks; graft outcome was followed over 4 months. The aim of this study was to determine whether graft survival could be predicted by such variables early after OLT. Compared with patients with stable graft function (n= 25), patients with post-transplant icteric cholestasis (n= 30) exhibited no difference in graft survival, despite a decrease in MEGX formation to a nadir median of 12 μgL^-1 on day 10. Patients with rejection (n= 8) and septicaemia (n= 6) showed a marked decrease in MEGX values and an increase in HA and sIL-2R concentrations between postoperative days 3 and 7. Patients with primary non-function (PNF; n= 5) were characterized by strongly reduced MEGX formation (median 4 μgL) and increased HA values (median 2300 μgL^-1) on day 3 after OLT. A total of 24/84 grafts were lost within 120 days. In a survival analysis using the Cox proportional hazards regression, HA and MEGX values on day 1 were the only independent variables entering the model that showed an adequate prognostic sensitivity. At cut-off points of 22 μgL^-1 (MEGX) and 730 μgL^-1 (HA) the combined use of these parameters in a parallel approach yielded a sensitivity of 58% with a corresponding specificity of 95% for 120-day graft survival. These findings suggest that the inclusion of MEGX and HA in postoperative monitoring of OLT patients may be helpful in the early prediction of graft survival.     

Lesions of T-Cell-Mediated Kidney Allograft Rejection in Mice Do Not Require Perforin or Granzymes A and B

Organ allograft rejection is strongly associated with the presence of alloreactive cytotoxic T cells but the role of cytotoxicity in the pathologic lesions is unclear. Previous studies showed that the principal lesions of kidney rejection - interstitial infiltration, tubulitis, and endothelial arteritis - are T-cell-dependent and antibody-independent. We studied the role of cytotoxic granule components perforin and granzymes A and B in the evolution of the T-cell-mediated lesions of mouse kidney transplant rejection. By real-time RT-PCR, allografts rejecting in wild-type hosts at days 5, 7, 21, and 42 showed massively elevated and persistent expression of perforin and granzymes A and B, but evolution of tubulitis and arteritis did not correlate with increasing granzyme or perforin expression. Allografts transplanted into hosts with disrupted genes for perforin or granzymes A and B showed no change in tubulitis, arteritis, or MHC induction. Thus the development of the histologic lesions diagnostic of T-cell-mediated kidney transplant rejection are associated with but not mediated by perforin or granzyme A or B. Together with previous graft survival studies, these results indicate that the granule-associated cytotoxic mechanisms of T cells are not the effectors of T-cell-mediated allograft rejection.