Department of Surgery, Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Ann Thorac Surg. 2010 Oct;90(4):1094-101. doi: 10.1016/j.athoracsur.2010.06.009.
Primary graft dysfunction (PGD) is a known risk factor for bronchiolitis obliterans syndrome (BOS) after lung transplantation. Here, we report that preformed antibodies to self-antigens increase PGD risk and promote BOS.
Adult lung transplant recipients (n = 142) were included in the study. Primary graft dysfunction and BOS were diagnosed based on International Society for Heart and Lung Transplantation guidelines. Antibodies to self-antigens k-alpha-1 tubulin, collagen type V, and collagen I were quantitated using standardized enzyme-linked immunosorbent assays, and cytokines were analyzed using Luminex immunoassays (Biosource International, Camirillo, CA). Human leukocyte antigen (HLA) antibodies were measured using Flow-PRA (One Lambda, Canoga Park, CA).
Lung transplant recipients with pretransplant antibodies to self-antigens had increased risk of PGD (odds ratio 3.09, 95% confidence interval: 1.2 to 8.1, p = 0.02) compared with recipients without. Conversely, in patients with PGD, 34.7% were positive for pretransplant antibodies whereas in the PGD negative group, only 14.6% had antibodies (p = 0.03). Antibody positive patients demonstrated high levels of proinflammatory cytokines interleukin (IL)-1β (2.1-fold increase), IL-2 (3.0), IL-12 (2.5), IL-15 (3.0), and chemokines interferon-inducible protein-10 (3.9) and monocyte chemotactic protein-1 (3.1; p < 0.01 for all). On 5-year follow-up, patients without antibodies showed greater freedom from development of HLA antibodies compared with patients who had antibodies (class I: 67% versus 38%, p = 0.001; class II: 71% versus 41%, p < 0.001). Patients with pretransplant antibodies were found to have an independent relative risk of 2.3 (95% confidence interval: 1.7 to 4.5, p = 0.009) for developing BOS.
Presence of antibodies to self-antigens pretransplant increases the risk of PGD immediately after transplant period and BOS on long-term follow-up. Primary graft dysfunction is associated with an inflammatory cascade that augments the alloimmune (anti-HLA) response that predisposes to BOS.
原发性移植物功能障碍（PGD）是肺移植后发生闭塞性细支气管炎综合征（BOS）的已知危险因素。在这里，我们报告说，针对自身抗原的预先形成的抗体增加了 PGD 的风险，并促进了 BOS 的发生。
纳入了 142 名成人肺移植受者进行研究。根据国际心肺移植协会的指南诊断原发性移植物功能障碍和 BOS。使用标准化酶联免疫吸附测定法定量检测针对自身抗原 k-α-1 微管蛋白、胶原类型 V 和胶原 I 的抗体，并使用 Luminex 免疫测定法（Biosource International，Camirillo，CA）分析细胞因子。使用 Flow-PRA（One Lambda，Canoga Park，CA）测量人类白细胞抗原（HLA）抗体。
与无抗体的受者相比，移植前存在针对自身抗原抗体的肺移植受者发生 PGD 的风险增加（优势比 3.09，95%置信区间：1.2 至 8.1，p=0.02）。相反，在 PGD 患者中，34.7%为移植前抗体阳性，而在 PGD 阴性组中，只有 14.6%有抗体（p=0.03）。抗体阳性患者表现出高水平的促炎细胞因子白细胞介素（IL）-1β（增加 2.1 倍）、IL-2（3.0）、IL-12（2.5）、IL-15（3.0）和趋化因子干扰素诱导蛋白-10（3.9）和单核细胞趋化蛋白-1（3.1；所有 p<0.01）。在 5 年的随访中，无抗体的患者与有抗体的患者相比，发展 HLA 抗体的自由度更大（I 类：67%对 38%，p=0.001；II 类：71%对 41%，p<0.001）。研究发现，移植前存在抗体的患者发生 BOS 的独立相对风险为 2.3（95%置信区间：1.7 至 4.5，p=0.009）。
移植前针对自身抗原的抗体的存在增加了移植后立即发生 PGD 和长期随访时发生 BOS 的风险。原发性移植物功能障碍与炎症级联反应相关，该级联反应增强了有利于 BOS 的同种免疫（抗 HLA）反应。
