De novo development of circulating anti-endothelial cell antibodies rather than pre-existing antibodies is associated with post-transplant allograft rejection
2010; Elsevier BV; Volume: 79; Issue: 6 Linguagem: Inglês
10.1038/ki.2010.437
ISSN1523-1755
AutoresQiquan Sun, Zhen Cheng, Dongrui Cheng, Jinsong Chen, Shuming Ji, Jiqiu Wen, Qian Zheng, Zhihong Liu,
Tópico(s)Vasculitis and related conditions
ResumoAnti-endothelial cell antibodies (AECAs) are thought to be involved in the development of renal allograft rejection. To explore this further, we determine whether AECAs play a role both in predicting the incidence of allograft rejection and long-term outcomes by analysis of serum samples from 226 renal allograft recipients for AECAs pre- and post-transplant. Surprisingly, the presence of pre-existing AECAs was not associated with either an increased risk of rejection or a detrimental impact on recipient/graft survival. Subsequent de novo AECAs, however, were associated with a significantly increased risk of early acute rejection. Moreover, these rejections tended to be more severe with a significantly increased incidence of both steroid-resistant and multiple episodes of acute rejection. The acute rejections associated with de novo AECAs did not correlate with C4d deposition at the time of renal biopsy, but did demonstrate an association with the presence of glomerulitis and peritubular capillary inflammation. Significantly more patients with de novo AECAs developed graft dysfunction. Thus, our prospective study suggests the emergence of de novo AECAs is associated with transplant rejection that may lead to allograft dysfunction. Anti-endothelial cell antibodies (AECAs) are thought to be involved in the development of renal allograft rejection. To explore this further, we determine whether AECAs play a role both in predicting the incidence of allograft rejection and long-term outcomes by analysis of serum samples from 226 renal allograft recipients for AECAs pre- and post-transplant. Surprisingly, the presence of pre-existing AECAs was not associated with either an increased risk of rejection or a detrimental impact on recipient/graft survival. Subsequent de novo AECAs, however, were associated with a significantly increased risk of early acute rejection. Moreover, these rejections tended to be more severe with a significantly increased incidence of both steroid-resistant and multiple episodes of acute rejection. The acute rejections associated with de novo AECAs did not correlate with C4d deposition at the time of renal biopsy, but did demonstrate an association with the presence of glomerulitis and peritubular capillary inflammation. Significantly more patients with de novo AECAs developed graft dysfunction. Thus, our prospective study suggests the emergence of de novo AECAs is associated with transplant rejection that may lead to allograft dysfunction. It is well recognized that antibodies against human leukocyte antigens (HLAs), particularly those directed toward donor antigens, can elicit an acute humoral rejection response resulting in severe damage to the renal allograft. It has been suggested that non-HLA antibodies might also have an important role in the pathogenesis of allograft rejection.1.Zou Y. Stastny P. Susal C. et al.Antibodies against MICA antigens and kidney-transplant rejection.N Engl J Med. 2007; 357: 1293-1300Crossref PubMed Scopus (336) Google Scholar,2.Dragun D. Muller D.N. Brasen J.H. et al.Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.N Engl J Med. 2005; 352: 558-569Crossref PubMed Scopus (603) Google Scholar Vascular endothelial cells express tissue-specific antigens and, given their critical location in any perfused organ, would serve as first-line targets for an immune response during allograft rejection.3.Sis B. Jhangri G.S. Bunnag S. et al.Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining.Am J Transplant. 2009; 9: 2312-2323Crossref PubMed Scopus (355) Google Scholar,4.Breimer M.E. Rydberg L. Jackson A.M. et al.Multicenter evaluation of a novel endothelial cell crossmatch test in kidney transplantation.Transplantation. 2009; 87: 549-556Crossref PubMed Scopus (94) Google Scholar It has been suggested that anti-endothelial cell antibodies (AECAs) have an important clinical role in organ transplantation5.Cerilli J. Brasile L. Galouzis T. et al.The vascular endothelial cell antigen system.Transplantation. 1985; 39: 286-289Crossref PubMed Scopus (97) Google Scholar, 6.Paul L.C. Baldwin III, W.M. van Es L.A. Vascular endothelial alloantigens in renal transplantation.Transplantation. 1985; 40: 117-123Crossref PubMed Scopus (66) Google Scholar, 7.Sun Q. Liu Z. Yin G. et al.Detectable circulating antiendothelial cell antibodies in renal allograft recipients with C4d-positive acute rejection: a report of three cases.Transplantation. 2005; 79: 1759-1762Crossref PubMed Scopus (19) Google Scholar, 8.Sun Q. Liu Z. Chen J. et al.Circulating anti-endothelial cell antibodies are associated with poor outcome in renal allograft recipients with acute rejection.Clin J Am Soc Nephrol. 2008; 3: 1479-1486Crossref PubMed Scopus (30) Google Scholar, 9.Glotz D. Lucchiari N. Pegaz-Fiornet B. et al.Endothelial cells as targets of allograft rejection.Transplantation. 2006; 82: S19-S21Crossref PubMed Scopus (46) Google Scholar and have been implicated as a cause of hyper-acute rejection leading to immediate graft loss.10.Ferry B.L. Welsh K.I. Dunn M.J. et al.Anti-cell surface endothelial antibodies in sera from cardiac and kidney transplant recipients: association with chronic rejection.Transpl Immunol. 1997; 5: 17-24Crossref PubMed Scopus (61) Google Scholar, 11.Jordan S.C. Yap H.K. Sakai R.S. et al.Hyperacute allograft rejection mediated by anti-vascular endothelial cell antibodies with a negative monocyte crossmatch.Transplantation. 1988; 46: 585-587Crossref PubMed Scopus (48) Google Scholar, 12.Perrey C. Brenchley P.E. Johnson R.W. et al.An association between antibodies specific for endothelial cells and renal transplant failure.Transpl Immunol. 1998; 6: 101-106Crossref PubMed Scopus (57) Google Scholar, 13.Sumitran-Karuppan S. Tyden G. Reinholt F. et al.Hyperacute rejections of two consecutive renal allografts and early loss of the third transplant caused by non-HLA antibodies specific for endothelial cells.Transpl Immunol. 1997; 5: 321-327Crossref PubMed Scopus (102) Google Scholar, 14.Grandtnerova B. Mackova N. Hovoricova B. et al.Hyperacute rejection of living related kidney grafts caused by endothelial cell-specific antibodies: case reports.Transplant Proc. 2008; 40: 2422-2424Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 15.Alvarez-Marquez A. Aguilera I. Blanco R.M. et al.Positive association of anticytoskeletal endothelial cell antibodies and cardiac allograft rejection.Hum Immunol. 2008; 69: 143-148Crossref PubMed Scopus (25) Google Scholar Increasing evidence suggests a correlation with both acute and chronic rejection.7.Sun Q. Liu Z. Yin G. et al.Detectable circulating antiendothelial cell antibodies in renal allograft recipients with C4d-positive acute rejection: a report of three cases.Transplantation. 2005; 79: 1759-1762Crossref PubMed Scopus (19) Google Scholar, 8.Sun Q. Liu Z. Chen J. et al.Circulating anti-endothelial cell antibodies are associated with poor outcome in renal allograft recipients with acute rejection.Clin J Am Soc Nephrol. 2008; 3: 1479-1486Crossref PubMed Scopus (30) Google Scholar, 10.Ferry B.L. Welsh K.I. Dunn M.J. et al.Anti-cell surface endothelial antibodies in sera from cardiac and kidney transplant recipients: association with chronic rejection.Transpl Immunol. 1997; 5: 17-24Crossref PubMed Scopus (61) Google Scholar In the Banff (2001) working classification of renal allograft pathology, AECAs were proposed as one cause of antibody-mediated rejection in addition to antibodies directed against donor HLA.16.Racusen L.C. Colvin R.B. Solez K. et al.Antibody-mediated rejection criteria – an addition to the Banff 97 classification of renal allograft rejection.Am J Transplant. 2003; 3: 708-714Crossref PubMed Scopus (905) Google Scholar Despite increasing evidence suggesting their participation in the host response to the allograft,11.Jordan S.C. Yap H.K. Sakai R.S. et al.Hyperacute allograft rejection mediated by anti-vascular endothelial cell antibodies with a negative monocyte crossmatch.Transplantation. 1988; 46: 585-587Crossref PubMed Scopus (48) Google Scholar, 17.Fredrich R. Toyoda M. Czer L.S. et al.The clinical significance of antibodies to human vascular endothelial cells after cardiac transplantation.Transplantation. 1999; 67: 385-391Crossref PubMed Scopus (110) Google Scholar, 18.Toyoda M. Petrosian A. Jordan S.C. Immunological characterization of anti-endothelial cell antibodies induced by cytomegalovirus infection.Transplantation. 1999; 68: 1311-1318Crossref PubMed Scopus (41) Google Scholar, 19.Pober J.S. Orosz C.G. Rose M.L. et al.Can graft endothelial cells initiate a host anti-graft immune response?.Transplantation. 1996; 61: 343-349Crossref PubMed Scopus (141) Google Scholar, 20.Smith J.D. Crisp S.J. Dunn M.J. et al.Pre-transplant anti-epithelial cell antibodies and graft failure after single lung transplantation.Transpl Immunol. 1995; 3: 68-73Crossref PubMed Scopus (15) Google Scholar, 21.Rose M.L. Smith J.D. Lawson C. Antibody formation and its impact on long-term graft outcome.Transplant Proc. 2001; 33: 2411-2413Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar the exact role of AECAs is not known. Specifically, there have been conflicting reports as to the value of pre-existing AECAs in the prediction of post-transplant rejection.22.Le Bas-Bernardet S. Hourmant M. Coupel S. et al.Non-HLA-type endothelial cell reactive alloantibodies in pre-transplant sera of kidney recipients trigger apoptosis.Am J Transplant. 2003; 3: 167-177Crossref PubMed Scopus (88) Google Scholar Our earlier studies suggested that AECA-positive acute rejections are associated with poor graft outcomes with a high risk of recurrent episodes of rejection within the year following the inciting event.7.Sun Q. Liu Z. Yin G. et al.Detectable circulating antiendothelial cell antibodies in renal allograft recipients with C4d-positive acute rejection: a report of three cases.Transplantation. 2005; 79: 1759-1762Crossref PubMed Scopus (19) Google Scholar,8.Sun Q. Liu Z. Chen J. et al.Circulating anti-endothelial cell antibodies are associated with poor outcome in renal allograft recipients with acute rejection.Clin J Am Soc Nephrol. 2008; 3: 1479-1486Crossref PubMed Scopus (30) Google Scholar Unfortunately, AECAs were not tested for a priori in the earlier study and, therefore, it is not known whether AECAs were present before transplantation or developed de novo following exposure to foreign antigens. In this study, serum samples were analyzed before and at different time points post-transplantation for the presence of AECAs and we examined the correlation between these results and clinical outcome. A total of 226 deceased-donor renal allograft recipients were enrolled in this study. Among them, 52 recipients had pre-existing AECAs (AECA Pre+ group) before transplantation and 22 developed de novo AECAs during the course of the study (AECA pre−/post+ group). In 5 (9.62%) of the 52 patients with pre-existing AECAs, the antibodies were negative post-renal transplantation. However, AECAs in the other 47 (91.4%) patients were consistently positive (at 3 days and at 3 months post-transplantation). The significance of pre-existing and de novo AECAs for clinical outcome was studied separately: The 174 patients without pre-existing AECAs (AECA Pre− group) and the 152 recipients with continuously negative AECAs (AECA pre−/post− group) served as controls (Figure 1). Demographic data for the patients in this study are given in Table 1. All patients received their first renal allograft. All transplants were carried out between ABO-compatible pairs with a negative pre-transplant complement-dependent lymphocytotoxicity (CDC) crossmatch (patients with positive CDC crossmatch were not preferred to receive renal transplantation in our Center). The panel-reactive antibody was positive in three (5.8%) patients before transplantation in the AECA Pre+ group; their HLA-I and II antibodies were 25/17, 42/25, and 32/9.59. One patient had an acute rejection but recovered rapidly. In the control group, the panel-reactive antibody was positive in two patients (1.15%, P=0.081) and one of them had a recoverable acute rejection, but died from pneumonia complications after 2 years. There was no significant difference between the two groups with regard to the age of recipients, the incidence of underlying autoimmune diseases, donor age, or the cold/warm ischemia time. There were significantly more females than males with pre-existing circulating AECAs (34.2% (27/79) vs 17.0% (25/147), P=0.005).Table 1Basic data of renal allograft recipients before transplantationAECA(+) (n=52)AECA(−) (n=174)P-valueAge (years)39.2±9.9238.6±10.30.685Gender (male/female)25/27122/520.005Autoimmune diseases1 (1.92%)4 (2.30%)1.000PRA positive3 (5.8%)2 (1.15%)0.081Age of donor (years)30.2±7.3629.8±7.960.722Previous renal transplantation00—Cold ischemia time (h)17.5±6.9517.2±6.530.801Warm ischemia time (min)6.54±1.266.66±1.200.534Baseline immunosuppressants MMF+CsA+Pred4 (7.7%)38 (21.8%)0.024 MMF+Tac+Pred48 (92.3%)136 (78.2%)0.024 Aza+CsA+Pred00— IL-2 mAb induction49 (94.2%)163 (93.7%)1.000Abbreviations: AECA, anti-endothelial cell antibody; AZA, azathioprine; CsA, cyclosporine A; IL, interleukin; mAb, monoclonal antibody; MMF, mycophenolate mofetil; PRA, panel-reactive antibody; Pred, prednisone; Tac, tacrolimus. Open table in a new tab Abbreviations: AECA, anti-endothelial cell antibody; AZA, azathioprine; CsA, cyclosporine A; IL, interleukin; mAb, monoclonal antibody; MMF, mycophenolate mofetil; PRA, panel-reactive antibody; Pred, prednisone; Tac, tacrolimus. Interestingly, the incidence of positive panel-reactive antibody after transplantation and acute rejection, including early acute rejection (within the first 2 weeks) and steroid-resistant rejection, was similar in the two groups. Furthermore, no difference was noted in the severity of rejection episodes as graded by the Banff (2001) working classification of renal allograft pathology. In fact, the incidence of recurrent acute rejections during the follow-up was higher (but not statistically significant) in the control group (Table 2). Protocol biopsies found no difference in the incidence of C4d deposition. No significant correlation was found between the presence of pre-existing AECAs with graft or patient survival. When the patients with positive panel-reactive antibody were excluded, there was still no significant difference between the two groups regarding the incidence of acute rejection and allograft survival.Table 2Complications and outcome in AECA (+) group compared with AECA (−) groupAECA(+) (n=52)AECA(−) (n=174)P-valueAcute rejection18 (34.6%)61 (35.1%)1.000Early acute rejection ( 25% of parenchyma affected) and foci of tubulitis; Grade II: cases with intimal arteritis; Grade III: cases with 'transmural' arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation.16.Racusen L.C. Colvin R.B. Solez K. et al.Antibody-mediated rejection criteria – an addition to the Banff 97 classification of renal allograft rejection.Am J Transplant. 2003; 3: 708-714Crossref PubMed Scopus (905) Google Scholar Open table in a new tab Abbreviations: AECA, anti-endothelial cell antibody; PRA, panel-reactive antibody. Banff Grade I: cases with significant interstitial infiltration (>25% of parenchyma affected) and foci of tubulitis; Grade II: cases with intimal arteritis; Grade III: cases with 'transmural' arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation.16.Racusen L.C. Colvin R.B. Solez K. et al.Antibody-mediated rejection criteria – an addition to the Banff 97 classification of renal allograft rejection.Am J Transplant. 2003; 3: 708-714Crossref PubMed Scopus (905) Google Scholar Of the 174 patients without pre-existing AECAs, 22 developed de novo AECAs in the follow-up period post-transplantation. Among them, AECAs became positive in 7 patients within 3 days post-transplantation and in 15 patients thereafter (six patients at 3 months post-transplantation and the other nine patients during the rejection). Compared with the patients with continuously negative circulating AECAs, there was no significant difference between the two groups with regard to the recipient or donor age, recipient sex, incidence of underlying autoimmune diseases, or cold/warm ischemia time (Table 3). AECAs were consistently positive throughout the study period in most (17/22, 77.3%) of the patients. However, in five (22.7%) patients, AECAs became negative within 6 months.Table 3Basic data of renal allograft recipients in AECA (pre−/post+) group compared with AECA (pre−/post−) groupAECA (pre−/post+) (n=22)AECA (pre−/post−) (n=152)P-valueAge (years)38.1±8.6238.3±10.51.000Gender (male/female)15/7107/450.808PRA positive021.000Age of donor (years)29.5±4.8029.8±8.320.896Previous renal transplantation00—Cold ischemia time15.6±6.0017.5±6.590.207Warm ischemia time6.95±1.506.62±1.150.216Baseline immunosuppressants MMF+CsA+Pred038 (25%)0.005 MMF+Tac+Pred22 (100%)114 (75%)0.005 Aza+CsA+Pred00— IL-2 mAb induction22 (100%)141 (92.8%)0.363Abbreviations: AECA, anti-endothelial cell antibody; AzA, azathioprine; CsA, cyclosporine A; IL, interleukin; mAb, monoclonal antibody; MMF, mycophenolate mofetil; PRA, panel-reactive antibody; Pred, prednisone; Tac, tacrolimus. Open table in a new tab Abbreviations: AECA, anti-endothelial cell antibody; AzA, azathioprine; CsA, cyclosporine A; IL, interleukin; mAb, monoclonal antibody; MMF, mycophenolate mofetil; PRA, panel-reactive antibody; Pred, prednisone; Tac, tacrolimus. Eleven (50%) patients in the de novo AECAs group developed acute rejection during the follow-up (nine patients were positive during the rejection and two patients were positive before the rejection), compared with 32.9% in the control group (P=0.151). However, although the overall incidence of acute rejection is numerically higher in patients with de novo AECAs, this did not reach statistical significance (Table 4). In the patients with de novo AECAs, significantly more patients developed steroid-resistant acute rejection (22.7 vs 7.89%, P=0.045) and multiple rejection episodes (22.7 vs 5.92%, P=0.019). Furthermore, the incidence of early acute rejection (<2 weeks, 40.9 vs 15.8%, P=0.016) was also significantly higher in this group.Table 4Complications and outcome in AECA (pre−/post+) group compared with AECA (pre−/post−) groupAECA (pre−/post+) (n=22)AECA (pre−/post−) (n=152)P-valueAcute rejection11 (50.0%)50 (32.9%)0.151 Recovery of acute rejection10/11 (90.9%)42/50 (84.0%)1.000Early acute rejection ( 1.24 mg/dl)10 (45.5%)45 (29.6%)0.147Immunoadsorption3 (13.6%)7 (4.61%)0.117Loss of graft3 (13.6%)10 (6.58%)0.216Death2 (9.09%)4 (2.63%)1.000Abbreviations: AECA, anti-endothelial cell antibody; PRA, panel-reactive antibody. Open table in a new tab Abbreviations: AECA, anti-endothelial cell antibody; PRA, panel-reactive antibody. With regard to the pathological features of acute rejection (Table 5), the incidence of C4d deposition was similar in the two groups. The incidence of glomerulitis and peritubular capillary inflammation was higher in the de novo AECAs group, but the difference was not statistically significant. It appeared that acute rejection episodes experienced by patients in the de novo AECAs group might have a higher incidence of vascular injury. Significantly more patients demonstrated small vessel fibrinoid necrosis (18.2 vs 0%, P=0.030) on biopsy, as well as a slightly higher rate of intimal arteritis (45.5 vs 36.0%). Among the patients in the de novo AECAs group, the 45.5% who experienced acute rejection met the criteria of Banff grade II or III, compared with 36% in the control group but the difference was not statistically significant. There was no difference between the two groups in this cohort with regard to plasma cell infiltration.Table 5Histological lesion of acute rejection patients in AECA (pre−/post+) group and AECA (−/−) groupAECA (pre−/post+) (n=11)AECA (pre−/post−) (n=50)P-valueTransplant glomerulopathy, n (%)00Glomerulitis with neutrophils (n (%))5 (45.5)15 (30.0)0.479Glomerulitis with mononuclear cells (n (%))9 (81.8)27 (54.0)0.106Tubulitis, n (%)10 (90.9)46 (92.0)1.000Tubular atrophy, n (%)3 (27.3)9 (18.0)0.676Interstitial infiltrate, n (%)11 (100)50 (100)1.000Plasma cell infiltrate, n (%)3 (27.3)25 (50.0)0.201Interstitial hemorrhage, n (%)5 (45.5)12 (24.0)0.262Interstitial fibrosis, n (%)4 (36.4)13 (26.0)0.481Mononuclear cell infiltration in PTC, n (%)10 (90.9)34 (68.0)0.159Neutrophil infiltration in PTC, n (%)4 (36.4)12 (24.0)0.457Intimal arteritis, n (%)5 (45.5)18 (36.0)0.733Small vessel fibrinoid necrosis2 (18.2%)00.030Small vessel thrombi1 (9.10%)00.180Banff 97 grade I6 (54.5%)32 (64.0%)0.733 II3 (27.3%)18 (36.0%)0.733 IIA2 (18.2%)11 (22.0%)1.000 IIB1 (9.10%)7 (14.0%)1.000 III2 (18.2%)00.030Abbreviations: AECA, anti-endothelial cell antibody; PTC, peritubular capillaries.Banff Grade I: cases with significant interstitial infiltration (>25% of parenchyma affected) and foci of tubulitis; Grade IIA: cases with mild-to-moderate intimal arteritis; IIB: cases with severe intimal arteritis comprising >25% of the luminal area; Grade III: cases with 'transmural' arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation.39.Racusen L.C. Solez K. Colvin R.B. et al.The Banff 97 working classification of renal allograft pathology.Kidney Int. 1999; 55: 713-723Abstract Full Text Full Text PDF PubMed Scopus (2665) Google Scholar Open table in a new tab Abbreviations: AECA, anti-endothelial cell antibody; PTC, peritubular capillaries. Banff Grade I: cases with significant interstitial infiltration (>25% of parenchyma affected) and foci of tubulitis; Grade IIA: cases with mild-to-moderate intimal arteritis; IIB: cases with severe intimal arteritis comprising >25% of the luminal area; Grade III: cases with 'transmural' arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation.39.Racusen L.C. Solez K. Colvin R.B. et al.The Banff 97 working classification of renal allograft pathology.Kidney Int. 1999; 55: 713-723Abstract Full Text Full Text PDF PubMed Scopus (2665) Google Scholar With regard to overall outcome, there was no difference in 3-year survival in patients or renal allograft survival when comparing the AECA Pre− group with the AECA Pre+ group (Figure 2a and b). However, a similar analysis revealed a significantly higher patient and allograft survival in those persistently negative for AECAs (AECA pre−/post− group) compared with the AECA pre−/post+ group (90.9 vs 96.1% (P=0.034) and 94 vs 80.8% (P=0.044), respectively) (Figure 3a and b). As expected, the 3-year acute rejection-free survival and the number of patients without graft dysfunction (serum creatinine >1.24 mg/dl) was also superior for the AECA pre−/post− group compared with the AECA pre–/post+ group (66.1, and 70.4 vs 50.0 and 54.5%, P=0.044 and 0.042, respectively) (Figure 3c and d).Figure 3Impact of de novo anti-endothelial antibodies (AECAs) on outcome of renal transplantation. (a) Patient survival of AECA pre−/post+ group compared with AECA pre−/post− group (P=0.034 by log-rank test); (b) renal graft survival of AECA pre−/post+ group compared with AECA pre−/post− group (P=0.044 by log-rank test); (c) acute rejection-free survival of AECA pre−/post+ group compared with AECA pre−/post− group (P=0.044 by log-rank test); (d) graft dysfunction (serum creatinine >1.24 mg/dl)-free survival of AECA pre−/post+ group compared with AECA pre−/post− group (P=0.042 by log-rank test).View Large Image Figure ViewerDownload Hi-res image Download (PPT) AECAs have emerged as a potentially clinically important group of antibodies in organ transplantation. The results of this study suggest that when compared with pre-existing AECAs, the presence of de novo AECAs might have a much stronger correlation with the development of post-transplant rejection. Earlier studies provided conflicting information with regard to the value of pre-existing AECAs in predicting rejection,15.Alvarez-Marquez A. Aguilera I. Blanco R.M. et al.Positive association of anticytoskeletal endothelial cell antibodies and cardiac allograft rejection.Hum Immunol. 2008; 69: 143-148Crossref PubMed Scopus (25) Google Scholar, 23.Ismail A.M. Badawi R.M. El-Agroudy A.E. et al.Pretransplant detection of anti-endothelial cell antibodies could predict renal allograft outcome.Exp Clin Transplant. 2009; 7: 104-109PubMed Google Scholar, 24.Han F. Lv R. Jin J. et al.Pre-transplant serum concentrations of anti-endothelial cell antibody in panel reactive antibody negative renal recipients and its impact on acute rejection.Clin Chem Lab Med. 2009; 47: 1265-1269Crossref PubMed Scopus (14) Google Scholar, 25.Costa C. Touscoz G.A. Bergallo M. et al.Non-organ-specific and anti-endothelial antibodies in relation to CMV infection and acute rejection in renal transplant recipients.Clin Transplant. 2010; 24: 488-492Crossref PubMed Scopus (11) Google Scholar, 26.Nakagawa Y. Saito K. Morioka T. et al.The clinical significance of antibody to vascular endothelial cells after renal transplantation.Clin Transplant. 2002; 16: 51-57Crossref PubMed Scopus (13) Google Scholar and no such correlation was found in this study. The incidence of multiple acute rejections in this cohort was even lower than that in the AECA (−) group. AECAs represent a heterogeneous group of antibodies directed against a variety of antigenic determinants expressed on endothelial cells. Such antibodies can be detected in a variety of autoimmune and connective tissue diseases, especially in vascular disorder diseases.27.Youinou P. New target antigens for anti-endothelial cell antibodies.Immunobiology. 2005; 210: 789-797Crossref PubMed Scopus (27) Google Scholar Unlike other endothelial cells, human umbilical vein endothelial cells do not express ABO blood group antigens,28.O'Donnell J. Mille-Baker B. Laffan M. Human umbilical vein endothelial cells differ from other endothelial cells in failing to express ABO blood group antigens.J Vasc Res. 2000; 37: 540-547Crossref PubMed Scopus (40) Google Scholar and are better target cells for AECA detection. As AECA-positive sera usually are negative for the presence of anti-HLA-I antibodies, and HLA class II determinants are present only on activated endothelial cells,29.Belizna C. Tervaert J.W. Specificity, pathogenecity, and clinical value of antiendothelial cell antibodies.Semin Arthritis Rheum. 1997; 27: 98-109Abstract Full Text PDF PubMed Scopus (72) Google Scholar it is currently accepted that HLA class I and II are not targets for AECA,30.Ronda N. Meroni P.L. Raschi E. et al.Shoenfeld Y. Gershwin M.E. Meroni P.L. Autoantibodies. 2nd edn. Elsevier, Amsterdam, The Netherlands2006Google Scholar which is why AECAs are regarded as a group of non-HLA antibodies. If detected in pre-transplant sera, it is clearly not possible for AECAs to be donor specific and, therefore, it would be reasonable to assume that they would not trigger a donor-specific alloimmune response. In our study, females were found to have a higher incidence of pre-existing AECAs compared with males, which is consistent with that found in the general population, and it has been reported that the prevalence of AECAs is usually correlated with HLA alloimmunization,16.Racusen L.C. Colvin R.B. Solez K. et al.Antibody-mediated rejection criteria – an addition to the Banff 97 classification of renal allograft rejection.Am J Transplant. 2003; 3: 708-714Crossref PubMed Scopus (905) Google Scholar which could account for the observed relationship between pre-existing AECAs and rejection. The prevalence of allosensitization to HLA in our study was indeed slightly higher in the pre-existing AECA (+) group (5.8 vs 1.15%, P=0.081) compared with the AECA (−) group, although this did not reach statistical significance. In contrast, the emergence of de novo AECAs following transplantation might have a stronger relationship with acute rejection. Although the overall rates of rejection in these patients were not significantly different when compared with those who remained AECA (−), there was a statistically significantly higher incidence of early steroid-resistant and multiple acute re
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