异基因造血干细胞移植患者血清抗内皮细胞抗体的临床意义及机制研究
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摘要
摘要：抗内皮细胞抗体(AECA)是众所周知的内皮细胞(ECs)损伤的生物学指标之一；移植物抗宿主病(GVHD)作为异基因造血干细胞移植(allo-HSCT)的主要并发症,与ECs损伤关系密切。但AECA与GVHD是否相关尚未见文献报道。为探讨allo-HSCT后患者体内是否存在AECA及其与GVHD的关系,我们以小血管内皮细胞系HMEC-1及大血管内皮细胞系EA.hy926为检测底物,采用细胞酶联免疫吸附法(cyto-ELISA)检测了急、慢性GVHD(aGVHD、cGVHD)患者血浆AECA。结果发现：II-IV度aGVHD患者anti-HMEC-1AECA(以下简称anti-HMEC)和anti-EA.hy926AECA(以下简称anti-EAHY)阳性率显著高于0-I度aGVHD (42.9vs.20.7%, P=0.049;52.4vs.22.4%, P=0.011)。有、无cGVHD患者AECA阳性率无统计学差异。移植后早期anti-EAHY阳性患者cGVHD发生率显著增高(59.6±1.4vs.33.4±0.5%,P=0.044)。0-I度aGVHD组中,AECA阳性患者总体生存(OS)率及无病生存(DFS)率显著高于AECA阴性患者(P<0.05),且复发率及移植相关死亡(TRM)率较低。我们的结果说明AECA在GVHD发生过程中起着重要作用。
摘要：异基因造血干细胞移植(allo-HSCT)过程中,血管内皮细胞(ECs)损伤是移植物抗宿主病(GVHD)的重要病理生理机制。我们的前期工作发现：aGVHD患者存在抗内皮细胞抗体(AECA)并与aGVHD的严重程度相关,但具体机制尚未明确。为探讨AECA介导的ECs损伤在GVHD中的病理生理机制,我们收集了allo-HSCT后患者的血清,将纯化后的IgG型免疫球蛋白与人脐静脉内皮细胞(HUVEC)共培养,观察HUVEC的功能变化及凋亡情况。结果发现：]HUVEC与AECA阳性的IgG共培养后,粘附分子(sICAM-1、sVCAM-1)表达显著增高(P<0.05),凝血活性因子(vWF、TM)显著升高(P<0.05),但并不影响炎性因子(IL-1β、IL-6、IL-8及ANG2)分泌(P>0.05)。此外,AECA并不诱导HUVEC凋亡(P>0.05)。我们通过体外实验证明allo-HSCT患者血清AECA能引起ECs功能发生显著变化,对于阐明AECA及ECs损伤在GVHD等移植相关并发症的病理机制有重要意义。
Abstract:Anti-endothelial cell antibody (AECA) has been well known to reflect endothelial injury. Meanwhile, graft-versus-host disease (GVHD), a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), is also closely associated with endothelial injury. We assume that AECA might be associated with GVHD. To investigate the clinical significance of AECA in allo-HSCT recipients with GVHD, we detected AECA by cyto-enzyme linked immunosorbent assay (cyto-ELISA) in allo-HSCT recipients with acute and/or chronic GVHD (aGVHD and cGVHD), with small vascular endothelial cell line HMEC-1and large vessel endothelial cell line EA.hy926as substrate, respectively. Incidences of anti-HMEC-1AECA (anti-HMEC) and anti-EA.hy926AECA (anti-EAHY) were significantly higher in patients with grade II-IV than grade0-1aGVHD (42.9vs.20.7%, P=0.049;52.4vs.22.4%, P=0.011, respectively). There was no difference of incidences of AECA between patients with or without cGVHD. Patients with anti-EAHY positive results early post transplant demonstrated a higher incidence of cGVHD (59.6±1.4vs.33.4±0.5%, P=0.044). In patients with grade0-1aGVHD, AECA positive patients had higher overall survival (OS) and disease free survival (DFS)(P<0.05), and tended to have lower incidences of relapse and transplant related mortality (TRM). Our data suggested that AECA played an important role in the pathogenesis of GVHD.
Abstract:During the procedure of allogeneic hematopoietic stem cell transplantation (allo-HSCT), endothelial injury is a critical pathogenesis of graft-versus-host disease (GVHD). Our previous work demonstrated that incidence of anti-endothelial cell antibody (AECA) was closely correlated with severity of acute GVHD, but the underlying mechanism of AECA remained unclear. To clarify the role of AECA in the pathogenesis of GVHD, we purified immunoglobulin (IgG) from sera of allo-HSCT recipients and incubated with human umbilical vein vascular endothelium (HUVEC) in vitro, then tested the functional changes and cell apoptosis. After incubation with AECA positive IgG, soluble adhesion molecules (sICAM-1and sVCAM-1) and clotting activity factors (vWF and TM) significantly elevated in culture supernatant (P <0.05), but inflammatory factors (IL-1β,IL-6, IL-8and ANG2) were not different from AECA negative samples (P>0.05). Additionally, AECA from AECA positive samples did not induce apoptosis. Our investigation demonstrates that AECA from allo-HSCT recipients dysregulates ECs' function in vitro, and is of importance to reveal AECA and endothelial injury in the pathophysiology of GVHD and other transplant-related complications after allo-HSCT.
摘要：异基因造血干细胞移植(allo-HSCT)过程中,血管内皮细胞(ECs)损伤是移植物抗宿主病(GVHD)的重要病理生理机制。我们的前期工作发现：aGVHD患者存在抗内皮细胞抗体(AECA)并与aGVHD的严重程度相关,但具体机制尚未明确。为探讨AECA介导的ECs损伤在GVHD中的病理生理机制,我们收集了allo-HSCT后患者的血清,将纯化后的IgG型免疫球蛋白与人脐静脉内皮细胞(HUVEC)共培养,观察HUVEC的功能变化及凋亡情况。结果发现：]HUVEC与AECA阳性的IgG共培养后,粘附分子(sICAM-1、sVCAM-1)表达显著增高(P<0.05),凝血活性因子(vWF、TM)显著升高(P<0.05),但并不影响炎性因子(IL-1β、IL-6、IL-8及ANG2)分泌(P>0.05)。此外,AECA并不诱导HUVEC凋亡(P>0.05)。我们通过体外实验证明allo-HSCT患者血清AECA能引起ECs功能发生显著变化,对于阐明AECA及ECs损伤在GVHD等移植相关并发症的病理机制有重要意义。
Abstract:Anti-endothelial cell antibody (AECA) has been well known to reflect endothelial injury. Meanwhile, graft-versus-host disease (GVHD), a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), is also closely associated with endothelial injury. We assume that AECA might be associated with GVHD. To investigate the clinical significance of AECA in allo-HSCT recipients with GVHD, we detected AECA by cyto-enzyme linked immunosorbent assay (cyto-ELISA) in allo-HSCT recipients with acute and/or chronic GVHD (aGVHD and cGVHD), with small vascular endothelial cell line HMEC-1and large vessel endothelial cell line EA.hy926as substrate, respectively. Incidences of anti-HMEC-1AECA (anti-HMEC) and anti-EA.hy926AECA (anti-EAHY) were significantly higher in patients with grade II-IV than grade0-1aGVHD (42.9vs.20.7%, P=0.049;52.4vs.22.4%, P=0.011, respectively). There was no difference of incidences of AECA between patients with or without cGVHD. Patients with anti-EAHY positive results early post transplant demonstrated a higher incidence of cGVHD (59.6±1.4vs.33.4±0.5%, P=0.044). In patients with grade0-1aGVHD, AECA positive patients had higher overall survival (OS) and disease free survival (DFS)(P<0.05), and tended to have lower incidences of relapse and transplant related mortality (TRM). Our data suggested that AECA played an important role in the pathogenesis of GVHD.
Abstract:During the procedure of allogeneic hematopoietic stem cell transplantation (allo-HSCT), endothelial injury is a critical pathogenesis of graft-versus-host disease (GVHD). Our previous work demonstrated that incidence of anti-endothelial cell antibody (AECA) was closely correlated with severity of acute GVHD, but the underlying mechanism of AECA remained unclear. To clarify the role of AECA in the pathogenesis of GVHD, we purified immunoglobulin (IgG) from sera of allo-HSCT recipients and incubated with human umbilical vein vascular endothelium (HUVEC) in vitro, then tested the functional changes and cell apoptosis. After incubation with AECA positive IgG, soluble adhesion molecules (sICAM-1and sVCAM-1) and clotting activity factors (vWF and TM) significantly elevated in culture supernatant (P <0.05), but inflammatory factors (IL-1β,IL-6, IL-8and ANG2) were not different from AECA negative samples (P>0.05). Additionally, AECA from AECA positive samples did not induce apoptosis. Our investigation demonstrates that AECA from allo-HSCT recipients dysregulates ECs' function in vitro, and is of importance to reveal AECA and endothelial injury in the pathophysiology of GVHD and other transplant-related complications after allo-HSCT.
引文
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5 Zeng L, Yan Z, Ding S, at al. Endothelial injury, an intriguing effect of methotrexate and cyclophosphamide during hematopoietic stem cell transplantation in mice. Transplant Proc,2008,40(8):2670-2673.
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9 Fujino M, Kim Y, Ito M. Intestinal thrombotic microangiopathy induced by FK506 in rats. Bone Marrow Transplant,2007,39(6):367-372.
10 Eyrich M, Burger G, Marquardt K,et al. Sequential expression of adhesion and costimulatory molecules in graft-versus-host disease target organs after murine bone marrow transplantation across minor histocompatibility antigen barriers. Biol Blood Marrow Transplant, 2005,11(5):371-382.
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12 Jevtic D, Zecevic Z, Veljkovic D,et al. Veno-occlusive disease in pediatric patients after hematopoietic stem cell transplantation:relevance of activated coagulation and fibrinolysis markers and natural anticoagulants. J Pediatr Hematol Oncol,2011,33(3):227-234.
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