Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Heart Lung Transplant. 2012 Nov;31(11):1214-22. doi: 10.1016/j.healun.2012.08.011. Epub 2012 Sep 11.
The role of non-complement activating antibodies (ncAbs) to mismatched donor human leukocyte antigen (HLA) in the pathogenesis of chronic lung rejection is not known. We used a murine model of obliterative airway disease (OAD) induced by Abs to major histocompatibility major histocompatibility complex (MHC) class I and serum from donor-specific Abs developed in human lung transplant (LTx) recipients to test the role of ncAbs in the development of OAD and bronchiolitis obliterans syndrome (BOS).
Anti-MHC ncAbs were administered intrabronchially in B.10 mice or in C3 knockout (C3KO) mice. Lungs were analyzed by histopathology. Lymphocytes secreting interleukin (IL)-17, interferon-γ, or IL-10 to collagen V and K-α1 tubulin (Kα1T) were enumerated by enzyme-linked immunospot assay. Serum antibodies to collagen V and Kα1T were determined by enzyme-linked immunosorbent assay. Cytokine and growth factor expression in lungs was determined by real-time polymerase chain reaction. Donor-specific Abs from patients with BOS and control BOS-negative LTx recipients were analyzed by C1q assay.
Administration of ncAbs in B.10 mice or C3KO resulted in OAD lesions. There were significant increases in IL-17- and interferon-γ-secreting cells to collagen V and Kα1T, along with serum Abs to these antigens. There was also augmented expression of monocyte chemotactic protein-1, IL-6, IL-1β, vascular endothelial growth factor, transforming growth factor-β, and fibroblastic growth factor in mice administered ncAbs by Day 3. Among 5 LTx recipients with BOS, only 1 had C1q binding donor-specific Abs.
Complement activation by Abs to MHC class I is not required for development of OAD and human BOS. Therefore, anti-MHC binding to epithelial and endothelial cells can directly activate pro-fibrotic and pro-inflammatory cascades leading to immune response to self-antigens and chronic rejection.
针对 mismatched donor 人类白细胞抗原 (HLA) 的非补体激活抗体 (ncAb) 在慢性肺排斥反应发病机制中的作用尚不清楚。我们使用了一种由针对主要组织相容性复合物 (MHC) Ⅰ类的 Abs 和人肺移植 (LTx) 受者中产生的供体特异性 Abs 诱导的闭塞性气道疾病 (OAD) 的小鼠模型，以测试 ncAb 在 OAD 和闭塞性细支气管炎综合征 (BOS) 发展中的作用。
ncAb 通过支气管内给药于 B.10 小鼠或 C3 敲除 (C3KO) 小鼠。通过组织病理学分析肺。通过酶联免疫斑点测定法计数分泌白细胞介素 (IL)-17、干扰素-γ 或 IL-10 至胶原蛋白 V 和 K-α1 微管蛋白 (Kα1T) 的淋巴细胞。通过酶联免疫吸附测定法测定血清抗胶原蛋白 V 和 Kα1T 抗体。通过实时聚合酶链反应测定肺中的细胞因子和生长因子表达。通过 C1q 测定分析来自 BOS 患者和对照 BOS 阴性 LTx 受者的供体特异性 Abs。
在 B.10 小鼠或 C3KO 中给予 ncAb 导致 OAD 病变。对胶原蛋白 V 和 Kα1T 分泌 IL-17 和干扰素-γ 的细胞有显著增加，同时伴有这些抗原的血清 Abs。在给予 ncAb 的第 3 天，小鼠还表达了单核细胞趋化蛋白-1、IL-6、IL-1β、血管内皮生长因子、转化生长因子-β 和成纤维细胞生长因子。在 5 名患有 BOS 的 LTx 受者中，只有 1 名具有 C1q 结合的供体特异性 Abs。
针对 MHC Ⅰ类的 Abs 引起的补体激活不是 OAD 和人类 BOS 发展所必需的。因此，针对上皮细胞和内皮细胞的抗 MHC 结合可以直接激活促纤维化和促炎级联反应，导致对自身抗原的免疫反应和慢性排斥反应。
