A case of acute humoral rejection with various depositions of C4d, IgG, IgM, and C3c in peritubular capillaries and/or glomerular capillaries

Abstract:  A 41-year-old Japanese male patient with end-stage renal disease received ABO compatible living related kidney transplantation from his sister on April 2003. The kidney functioned immediately after kidney transplantation. Protocol allograft biopsy at 1 yr after kidney transplantation was performed on April 2004. His serological data was not particular and he did not suffer with chronic inflammation. The allograft biopsy specimen revealed moderate accumulations of polymorphonuclear leukocytes in peritubular capillaries (PTCs), dilatation of PTCs and moderate infiltrations of polymorphonuclear and/or mononuclear cell in glomeruli (Transplant glomerulitis, moderate). Immunofluorescent study (IF) of a frozen section of the allograft biopsy specimen showed a strong, diffusely distributed endothelial-staining pattern in PTCs for C4d. The C4d was also strongly detected in a linear glomerular basement membrane (GBM) pattern. And widespread moderate C3c deposits, weak IgM, and IgG deposits were also seen in PTCs. Immunofluorescent study also showed granularly peripheral and mesangial deposits of strong IgM, C1q, and moderate IgG in glomeruli, IgA and C3c were faintly positive. The panel reactive antibody, which had been negative before transplantation, was positive for both HLA classes I and II at that time. We diagnosed as acute humoral rejection (AHR) and he was treated with course of steroid pulses and 5 d of gusperimus (DSG); and a total of three times Plasma exchange (PE) treatment was added. The level of serum creatinine, once increased to 1.7 mg/dL, decreased gradually to 1.4 mg/dL. He has a stable graft function. This is the only case of various depositions of immunoglobulins and complements in PTC and/or glomerular capillaries during AHR.     

移植肾动脉内膜炎的细胞类型及其与管周毛细血管C4d沉积的关系

目的 研究同种异体肾移植术后急性血管性排斥患者动脉内膜炎的细胞类型及其与管周毛细血管（PTC）C4d沉积的关系。 方法 共纳入20例自2006年6月至2008年6月在本中心行同种异体肾移植手术后肾功能异常且病理证实为急性血管性排斥受者的21份肾活检组织。免疫组化方法检测同一活检标本连续切片内T细胞表面标记物CD3、巨噬细胞表面标记物CD68及体液性排斥特异性标记物C4d的表达情况。根据PTC C4d的沉积情况将患者分为C4d阳性（C4d+）组和C4d阴性（C4d-）组,定量计数中动脉内膜阳性细胞数,并计算每个中动脉横切面的平均细胞数。 结果 急性血管性排斥患者动脉内膜都以巨噬细胞浸润为主;C4d+组和C4d-组患者的动脉内膜都以巨噬细胞浸润为主,与浸润的T淋巴细胞数相比差异均有统计学意义[（12.45±9.86）个/ 中动脉横切面比（3.91±3.03）个/中动脉横切面,P = 0.007;（3.47±1.89）个/中动脉横切面比（1.45±1.37）个/中动脉横切面,P = 0.006],且C4d+组患者动脉内膜巨噬细胞浸润数量显著多于C4d-组（P = 0.007）。 结论 肾移植术后急性血管性排斥患者动脉内膜以巨噬细胞浸润为主,且与PTC C4d的沉积有相关性。C4d+患者动脉内膜巨噬细胞数显著多于C4d-患者。     

Clinicopathological relevance of granular C4d deposition in peritubular capillaries of kidney allografts

While linear C4d staining in peritubular capillaries (PTC) is established as a marker of antibody‐mediated rejection, the significance of a distinct granular C4d deposition pattern has not yet been clarified. In this study, 329 renal allograft recipients who underwent indication biopsies were analysed for immunohistochemical C4d staining characteristics. Fifty‐six (17%) recipients showed granular C4d in PTC, without any relationship to conventional risk factors and morphological features of rejection. We found a strong association with long‐term overall graft survival (7‐year survival: 41% vs. 66% in granular C4d‐negative subjects, P = 0.001), which was mainly driven by a greater risk of mortality [hazard ratio: 3.12 (95% confidence interval: 1.23–7.94); P = 0.02]. Granular C4d was associated with delayed graft function [39% vs. 22% (C4d‐negative subjects), P = 0.007], higher 1‐year serum creatinine [median 2.1 (interquartile range: 1.7–2.6) mg/dl vs. 1.6 (1.3–2.0) mg/dl, P = 0.001] and a trend towards worse death‐censored graft survival (P = 0.07). In support of a role of capillary immune complex formation, granular C4d was associated with electron‐dense deposits in PTC basement membranes, which were occasionally accompanied by focally distributed capillary IgG deposits. In conclusion, our study suggests clinical relevance of detecting capillary granular C4d deposition. Our results point to a pathogenetic role of alloimmune‐independent immune complex deposition.     

Acute graft dysfunction after viral enteritis in a patient with cadaveric kidney transplantation: Norovirus infection is a possible cause of linear deposition of C4d in peritubular capillaries of renal allograft

Abstract:  We describe a cadaveric kidney transplant recipient with graft dysfunction after Norovirus infection. The graft biopsy specimen revealed no acute rejection findings, including antibody-mediated rejection in light microscopy. However, immunofluorescent study showed the linear and bright deposition of C4d along peritubular and glomerular capillaries. Norovirus brings formation of infection by binding to the histo-blood group antigens in epithelial cells of small intestine, and uses secretory H-antigen or A-antigen as a receptor. The recipient and donor had blood type A; the virus possibly bound to the histo-blood A-antigen in endothelial cells of vasculature in his graft after viremia. We consider Norovirus infection a possible cause of linear deposition of C4d in peritubular capillaries as a result of activation of complement pathways in endothelial cells of graft vasculature.     

Clinical significance of C4d deposition in stable renal allografts in the early post‐transplantation period

Abstract: The clinical significance of C4d positivity in patients with stable graft function is undetermined. This study evaluated the clinical outcome of protocol biopsy‐proven C4d‐positive renal transplants with stable graft function in the early post‐transplantation period. Protocol biopsies (n = 79) were performed on stable allografts on the 14th post‐transplant day, and indication biopsies (n = 74) were performed on dysfunctioning allografts within one yr after transplantation. Clinical and histological findings, graft function and graft survival rates were compared between C4d‐positive and C4d‐negative grafts in each group. The incidence of C4d positivity was 5.1% in protocol biopsies and 9.5% in indication biopsies. In protocol biopsies, C4d‐positive allografts showed minimal tubulointerstitial inflammation, and the graft function and graft survival rate did not differ from C4d‐negative allografts. All C4d‐positive allografts maintained stable graft function without anti‐rejection therapy, and follow‐up biopsies of two patients showed no C4d deposition or evidence of rejection. On the other hand, C4d‐positive allografts in indication biopsies showed severe tissue injury, and the graft survival rate was significantly lower than C4d‐negative allografts. In conclusion, C4d‐positive allografts with stable graft function in the early post‐transplantation period take an indolent course.     

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.     

C4d deposition in allograft renal biopsies is an independent risk factor for graft failure

Aim:   Association between C4d deposition and renal allograft survival is still uncertain. We retrospectively evaluated the clinical outcome of C4d deposition in allograft renal biopsies.
Methods:   One hundred and fifty biopsies from 150 patients with a histological diagnosis of acute rejection from December 1997 to March 2007 were included. Paraffin-embedded sections were stained with a polyclonal antibody using an immunoperoxidase technique. Detailed clinical data were obtained by retrospective review.
Results:   C4d was stained positively in 74 (49.3%) of 150 cases: 47 (61.5%) biopsies showed diffuse C4d deposition and 27 (38.5%) showed focal C4d deposition. During follow up, significantly more C4d-positive patients (24/74 patients, 32.4%) lost their grafts, compared with the C4d-negative group (10/76 patients, 13.2%) ( P  = 0.005). After a Kaplan–Meier analysis, grafts from the C4d-negative group had a markedly higher survival as compared with the C4d-positive group ( P  = 0.003, log–rank test). Graft survival among C4d-negative, C4d diffuse-positive, and C4d focal-positive groups was significantly different ( P  = 0.007, log–rank test). The graft survival rate among C4d-negative patients in early (<6 months) and later biopsies (>6 months), and C4d-positive patients in early and in later biopsies was different ( P  = 0.028, log–rank test). The adjusted risk ratio of graft failure after Cox proportional hazards multivariate analyses for C4d-positive patients was 3.309 (95% confidence interval, 1.413–6.537; P  = 0.004).
Conclusion:   Patients with C4d deposition had an inferior graft survival, especially with diffused C4d deposition, and later experienced acute rejection. C4d deposition was an independent risk factor for graft survival.     

补体裂解片断C4d在移植肾急性排斥反应中的临床意义

目的探讨肾小管周围毛细血管补体裂解片断(C4d)沉积在移植肾急性排斥反应中的临床意义。方法对肾移植后发生急性排斥反应的78例受者进行移植肾活体穿刺检查,共获取移植肾活检穿刺标本86份。根据Banff97病理分型将86份活检标本分为BanffⅠ型32份,Ⅱ型51份,Ⅲ型3份。应用免疫组织化学法检测出86份标本中有30份出现肾小管周围毛细血管C4d沉积,阳性率为34.9%。分析C4d阳性其与Banff97分型、术前一般情况、抗排斥治疗、移植肾功能及移植肾预后的关系。结果BanffⅠ和Ⅱ型受者移植肾中C4d阳性率分别为21.9%和39.2%,两者相比差异无统计学意义(P=0.101)。有妊娠史、术前群体反应性抗体(PRA)>30%和再次移植的受者C4d阳性率较高。C4d阳性的受者发生排斥反应时血肌酐较阴性受者高,分别为(312.56±196.26)μmol/L和(210.97±136.59)μmol/L,两组差异有统计学意义(P=0.0115)。C4d阳性受者对激素和ATG冲击治疗与阴性受者比较,敏感率明显降低。C4d阳性的受者移植肾1年生存率较阴性受者低,分别为64.3%和90.0%,两组间差异有统计学意义(P=0.006)。结论移植肾C4d阳性的受者发生排斥反应时,对常规的激素冲击和ATG抗排斥治疗不敏感,血肌酐明显升高,移植肾1年存活率下降,受者预后较差。     

Focal peritubular capillary C4d deposition in acute rejection.

BACKGROUND: Diffuse peritubular capillary (PTC) C4d deposition has been shown to be associated with relatively poor graft outcome. The significance of focal PTC C4d staining in the early post-transplant period is uncertain. METHODS: Sixty-five biopsies from 53 patients with acute rejection were graded (Banff '97 criteria), stained for C4d, monocytes and T cells, and divided into three groups according to PTC C4d: (i) focal C4d (F) (14 biopsies, 14 patients), (ii) diffuse C4d (D) (23 biopsies, 15 patients) and (iii) no C4d (N) (28 biopsies, 24 patients). The three groups were compared with respect to a variety of biopsy and clinical parameters including outcome. RESULTS: The incidence of transplant glomerulitis and glomerular monocyte infiltration were significantly greater in F (64% and 2.0+/-2.0) and D (57% and 3.4+/-2.0) than in N (11% and 0.2+/-0.2). A significantly higher proportion of F (93%) demonstrated acute cellular rejection (Banff '97 grade > or = 1A) than did D (35%). The F and D groups included significantly more females (50 and 67%, respectively) than did N (21%). The percentage of patients with a second or third transplant was higher in F (29%) and D (40%) than in N (8%) (P = 0.0589). The proportion of patients with glomerular filtration rate < 30 ml/min at 12, 24 and 48 months was higher in the D and F groups than in the N, and there was a statistically significant increasing trend in odds of this outcome occurring at 48 months across the three groups (D > F > N group) (P = 0.0416). CONCLUSION: The results suggest that the biopsy findings and clinical course in patients with focal PTC C4d staining are similar to those associated with diffuse C4d.     

移植肾切除标本中C4d表达分析

目的 检测C4d在难治性排斥反应移植肾组织中的表达情况,分析体液免疫参与难治性排斥反应与移植肾长期存活的相关性.方法 以40例难治性排斥反应致移植肾切除患者为研究组(A组),20例移植术后因移植肾功能一过性异常行穿刺活检患者作为对照组(B组);应用C4d多克隆抗体对移植肾组织的石蜡切片行免疫组织化学染色,检测C4d在切除移植肾中的表达情况,分析2组标本中C4d的表达差异.结果 A组中检测到C4d阳性17例(42.5%),17例C4d阳性患者中存活时间＜5年的移植肾12例(70.6%),明显多于存活时间＞5年者的阳性数(5例,29.4%);B组中C4d阳性2例(10.0%),2组比较P=0.024.A组中受者男28例,女12例;年龄27～67岁,平均(39±10)岁;冷缺血时间6～12 min,热缺血时间170～720 min;免疫抑制方案为吗替麦考酚酯加环孢素加糖皮质激素19例、吗替麦考酚酯加他克莫司加糖皮质激素7例、硫唑嘌呤加环孢素加糖皮质激素14例;二次移植4例;31例术后仍有高血压.经t检验与X2检验,以上各因素与移植.肾C4d的阳性沉积无明显相关(P＞0.05).结论 体液免疫参与的难治性排斥反应是影响移植物长期存活的危险因素.     

C4d deposition in peritubular capillary and alloantibody in the allografted kidney suffering severe acute rejection

Abstract:  Background: Alloantibodies and C4d deposition in peritubular capillaries (PTCs) are thought to be related to antibody-mediated acute rejection. The purpose of this study was to evaluate the relationship between C4d deposition in PTCs and alloantibodies at various days after allograft dysfunction due to severe acute rejection. Method: There were 620 renal transplantations (Tx) performed. Forty patients diagnosed with acute humoral and/or vascular rejection showed graft dysfunction with anuria or dysuria. The patients were divided into four groups by ABO compatibility and clinical course after graft dysfunction: compatible recipients with graft loss (c-GL ; n  = 6); compatible recipients with recovery from graft dysfunction (c-RE; n  = 10); incompatible recipients with graft loss (i-GL; n  = 9); and incompatible recipients with recovery from graft dysfunction (i-RE; n  = 15). Results: C4d depositions in 4/6 c-GL recipients increased, and those in 8/10 c-RE recipients decreased after graft dysfunction. These changes in C4d deposition between the c-GL and the c-RE groups were significantly different ( P  < 0.01). These titres of anti-A/B IgG antibody in 7/9 i-GL recipients increased and those in 8/15 i-RE recipients decreased after graft dysfunction. These changes in titre between the i-GL and the i-RE groups were significantly different ( P  < 0.01). All c-GL recipients and 4/10 c-RE recipients had anti-HLA antibody at the last biopsy. There was a significant difference in the number of recipients who had anti-HLA antibody between the c-GL and the c-RE groups ( P  < 0.05). Conclusions: These results indicate that changes in C4d deposition in PTCs in the c-ABO group and titre of anti-A/B IgG antibody in the ABO-incompatible groups exert a strong impact on graft survival after dysfunction in the early period after Tx.     

An ABO-incompatible renal transplant patient who developed severe antibody-mediated vascular rejection 36 days after transplantation

Abstract:  A 44-yr-old man had an ABO-incompatible renal transplantation from his 41-yr-old wife. He was diagnosed with IgA nephropathy at the age of 31 and began hemodialysis to treat chronic renal failure at the age of 39. Preoperative flow panel reactive antibody was negative. An episode biopsy on post-operative day (POD) 18 showed mild infiltrative vasculopathy (v1, g2, ptc1, TMA, PTC+). The serum creatinine (sCr) was 2.26 mg/dL. Anti-A antibody was x32. Double filtration plasmapheresis and plasma exchange were performed. A second episode biopsy was performed on POD 36. The Cr was 3.73 mg/dL. Anti-A antibody was x32. Histologically, antibody-mediated vascular rejection with severe fibrinoid necrosis in the lobular arteries was detected (v3, g2, ptc2, TMA, PTC+). Steroid pulse therapy was performed, and OKT-3 was administered for 10 d. The anti-A antibody titer was x128 on POD 47. A biopsy specimen obtained on POD 55 showed severe vascular rejection with stenosis of the vascular lumen and fibrinoid necrosis (v3, cv2, g1, cg2, ptc1, TMA, PTC+). The sCr was 7.09 mg/dL. Despite double-filtration plasmapheresis, the patient was reintroduced to hemodialysis. Here, we report a case showing the typical histological features of antibody-mediated vascular rejection.     

Renal allograft C4d deposition in Chinese: Hong Kong perspective

Background: Acute rejection constitutes a significant proportion of renal allograft loss. Peritubular capillary deposition of C4d has been recognized as the footprint of humoral alloimmunity and proven to be a sensitive and specific marker for humoral rejection in the appropriate clinical context. Its presence in indication biopsies is the most important independent risk factor for graft failure. Data are, however, scarce among Chinese subjects. Methods: We retrospectively reviewed all renal graft biopsies performed from 1 April 2002 to 31 March 2006 for unexplained acute renal dysfunction or delayed graft function. Renal outcomes were assessed at the time of renal biopsy and at 1 month, 3 months, 6 months and 1 year afterwards. Survival was assessed by Kaplan–Meier analysis. Multivariate analysis was used to determine if C4d positivity is an independent risk factor for poor renal outcome. Results: Fifty‐two biopsies were included, of which 16 were positive for peritubular capillary C4d. Peritubular capillary C4d was associated with lower glomerular filtration rate and higher serum creatinine at 6 and 12 months after renal biopsies. The C4d‐positive group fares worse in terms of death‐censored graft failure, doubling of serum creatinine and reaching 50% of glomerular filtration rate at the end of the study. Peritubular capillary C4d deposition was the only significant risk factor that predicts graft failure in multivariate analysis. Conclusion: Our findings confirmed the independent prognostic value of peritubular capillary C4d staining on renal allograft survival in Chinese.     

Peritubular capillary C4d deposition and renal outcome in post-transplant IgA nephropathy

BACKGROUNDS: Immunological staining of the transplanted kidney for C4d in peritubular capillaries (C4d(PTC)) has emerged as a useful method to detect antibody-mediated rejection in situ. In this retrospective study, we evaluated the prevalence of C4d(PTC) deposition in allograft renal biopsies diagnosed of IgA nephropathy (IgAN) and analysed its clinical significance. METHOD: Sixty-six biopsy specimens of post-transplant IgAN, which were obtained to evaluate azotemia and/or heavy proteinuria, were examined by immunohistochemical staining of the paraffin sections with polyclonal antibody for C4d. RESULTS: C4d was stained positively in peritubular capillaries in 16 (24%) of the 66 cases. The C4d(PTC)-negative (n=50) and C4d(PTC)-positive groups (n=16) were not different in recipient gender, age, donor age, type of donor (living vs. cadaveric), interval from transplantation to graft biopsy (41.6+/- 21.8 vs. 48.3+/-26.1 months) and post-biopsy follow-up period (60.3+/-23.3 vs. 56.9+/-25.4 months). During the follow-up period, 12 of 50 (24%) although the incidence of graft failure was not different by the C4d deposition in peritubular capillaries, intervals from renal biopsy to graft failure tended to be shorter in C4d(PTC)-positive cases than C4d(PTC)-negative cases. In Kaplan-Meier analysis, the renal allograft function of the C4d(PTC)-positive group deteriorated more rapidly than that of the C4d(PTC)-negative group (p<0.05). Histologically, the C4d(PTC)-positive group had findings suggestive of acute cellular rejection more commonly than the C4d(PTC)-negative group (p<0.01). CONCLUSIONS: Evidence of humoral rejection, as demonstrated by C4d(PTC) deposition, was concurrently present in significant portions of post-transplant IgAN biopsy specimens and was associated with more rapid deterioration of renal function. These results suggest that C4d(PTC) positivity needs to be determined at the time of biopsy even in cases of post-transplant glomerulonephritis and immunosuppression may need to be modified accordingly.     

C4d deposition in the glomeruli and peritubular capillaries associated with transplant glomerulopathy

Transplant glomerulopathy (TGP) is a unique disease entity with characteristic pathological findings. Although ultrastructural studies for TGP have been performed, histogenesis of TGP is not fully understood. The present study was designed to investigate the relation of complement fragment C4d to the histogenesis of TGP. Nine cases of isolated TGP were randomly selected. A commercially available monoclonal antibody against complement fragment C4d was used in allograft biopsies. To evaluate the extent and severity of deposition of the C4d complement in the glomerular and peritubular capillaries, indirect immunofluoresce method was performed on frozen sections. Intense deposition of C4d in the glomerular basement membrane and peritubular capillaries was found in association with morphological appearance of TGP. Peritubular capillaries were affected in all the patients, showing splitting and multilayering of peritubular capillary basement membrane. These changes, which diffusely affect most capillaries, and their severity pattern were quite similar in each patient. In early stages of all patients with cellular rejection, C4d was not detected in the glomerular and peritubular capillaries. In addition, no C4d deposition was detected in all zero-hour biopsies without diagnostic abnormality. These findings suggest that C4d deposition in the glomerular and peritubular capillaries might be associated with the pathogenesis of TGP in renal transplantation.     

C4d as a significant predictor for humoral rejection in renal allografts

OBJECTIVE: To determine the diagnostic and clinical significance of C4d accumulation in renal allografts followed by acute rejection. METHODS: A total of 158 graft biopsies performed from December 1997 to December 2002 were classified, according to the Banff-97 criteria, into hyperacute rejection (HAR, three cases), acute vascular rejection (AVR, 27), acute cellular rejection (ACR, 24), borderline rejection (BR, 38), acute tubular necrosis (ATN, five), stable graft function (SGF, 30) and baseline kidney (31). Immunohistochemical technique was used to determine the C4d deposition level. RESULTS: The percentages of C4d positive in HAR, AVR, ACR, BR, ATN, SGF and baseline kidney groups were 100% (3/3), 77.8% (21/27), 37.5% (9/24), 23.7% (9/38), 0% (0/5), 3.3% (1/30), 0% (0/31), respectively. In acute rejection patients, the peak serum creatinine (sCr) level in C4d(ptc)-positive group (41 cases) was 334.82 +/- 238.37 micromol/L, with that of C4d(ptc)-negative group (47 cases) being 220.20 +/- 176.94 micromol/L (p < 0.01). After treatment, the trough sCr level in C4d(ptc)-positive group and C4d(ptc)-negative group were 176.87 +/- 111.80 and 121.75 +/- 34.59 micromol/L (p < 0.01), respectively. In each AVR, ACR and BR subgroups, the peak sCr level, the trough sCr level, after 3 or 6 months of AR, the sCr level in C4d(ptc)-positive subgroup was higher than that of C4d(ptc)-negative subgroup. There were more resistance against steroid therapy [65.9% (27/41) vs. 36.2% (17/47), p = 0.005] and a higher rate of graft loss [29.3% (12/41) vs. 6.4% (3/47), p = 0.001] in C4d(ptc)-positive group than those of C4d(ptc)-negative group. In each C4d(ptc)-positive subgroup of AVR, ACR and BR the complete reversion was 57.1, 56 and 66.7%, respectively, it is almost same. CONCLUSION: The C4d deposition level is of great value in diagnosis of acute rejection caused by humoral immune components. It is a significant predictor of graft survival and will be of great help when treating acute rejection.     

Rejection of peritubular capillaries in renal allo- and xeno-graft

The microvasculature plays an important role in the pathogenesis of humoral- and cell-mediated renal allo- and xeno-graft rejection. Peritubular capillary (PTC) endothelium expresses the major histocompatibility complex (MHC) class I and II antigens in the resting phase, as does the glomerular capillary endothelium, suggesting that these cells may be major immune targets. However, the role of PTCs in renal allo- and xeno-graft rejection is unclear. In this review, we discuss injury and subsequent remodeling of PTCs in both humoral- and cell-mediated rejection in allo- and xeno-grafts. Recent evidence suggests that PTC injury and endothelial cell death occur during both cell- and humoral-mediated rejection. Severe PTC rejection contributes to deterioration of graft function and acute graft loss. The mild but recurrent form of PTC rejection is associated with progressive interstitial fibrosis and chronic rejection. Following endothelial injury, the remaining PTC endothelium activates with up-regulation of allo-antigens and adhesion molecules, and down-regulation of anti-coagulant proteins. Subsequent to this, more severe rejection and graft dysfunction occur. Therefore, a careful analysis of cellular- and antibody-mediated rejection in PTCs is important in the diagnosis of rejection, prediction of graft prognosis, and in further development of new anti-rejection therapies.     

移植肾小球炎的细胞类型及其与管周毛细血管C4d沉积的关系

目的 研究同种异体肾移植术后急性排斥患者肾小球炎的细胞类型及其与管周毛细血管（PTC）C4d沉积的关系。 方法 2006年6月至2009年6月在本中心行同种异体肾移植手术后,肾功能异常且病理证实为急性排斥并发小球炎受者51例的肾活检组织为研究对象。免疫组化方法检测同一活检标本连续切片内T细胞表面标记物CD3、巨噬细胞表面标记物CD68、体液性排斥特异性标记物C4d、细胞毒T淋巴细胞标记物颗粒酶B及调节性T淋巴细胞标记物Foxp3的表达情况。根据PTC有无C4d沉积将受者分为C4d阳性组和C4d阴性组,定量计数小球内阳性细胞数,并计算每个小球的平均细胞数。 结果 C4d阳性与C4d阴性的急性排斥受者小球内浸润的炎细胞数分别为17.79±7.70和8.17±3.80,差异有统计学意义（P < 0.01）。C4d阳性急性排斥受者小球内以巨噬细胞浸润为主,与C4d阴性者差异有统计学意义（13.73±7.03 比2.57±1.22,P < 0.01）。C4d阴性急性排斥受者小球内以T淋巴细胞为主,与C4d阳性者差异有统计学意义（5.60±2.81比4.05±2.60,P = 0.023）。C4d阴性与C4d阳性急性排斥受者小球内T淋巴细胞都以细胞毒细胞为主 （3.37±2.34比4.27±2.41,P = 0.141）,而没有调节性T淋巴细胞的浸润。 结论 肾移植术后急性排斥患者小球内炎细胞浸润总数与PTC的C4d沉积有关。C4d阳性患者小球炎细胞数多于C4d阴性患者。C4d阳性患者小球炎细胞以巨噬细胞浸润为主;C4d阴性患者小球炎细胞以T淋巴细胞浸润为主。两组患者小球内T淋巴细胞都以细胞毒细胞为主。     

Rejection of peritubular capillaries in renal allo- and xeno-grafts

The microvasculature plays an important role in the pathogenesis of humoral- and cell-mediated renal allo- and xeno-graft rejection. Peritubular capillary (PTC) endothelium expresses the major histocompatibility complex (MHC) class I and II antigens in the resting phase, as does the glomerular capillary endothelium, suggesting that these cells may be major immune targets. However, the role of PTCs in renal allo- and xeno-graft rejection is unclear. In this review, we discuss injury and subsequent remodeling of PTCs in both humoral- and cell-mediated rejection in allo- and xeno-grafts. Recent evidence suggests that PTC injury and endothelial cell death occur during both cell- and humoral-mediated rejection. Severe PTC rejection contributes to deterioration of graft function and acute graft loss. The mild but recurrent form of PTC rejection is associated with progressive interstitial fibrosis and chronic rejection. Following endothelial injury, the remaining PTC endothelium activates with up-regulation of allo-antigens and adhesion molecules, and down-regulation of anti-coagulant proteins. Subsequent to this, more severe rejection and graft dysfunction occur. Therefore, a careful analysis of cellular- and antibody-mediated rejection in PTCs is important in the diagnosis of rejection, prediction of graft prognosis, and in further development of new anti-rejection therapies.