Soleimani B, Katopodis A, Wieczorek G, George A J T, Hornick P I, Heusser C
Department of Cardiac Surgery, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.
Clin Exp Immunol. 2006 Dec;146(3):509-17. doi: 10.1111/j.1365-2249.2006.03237.x.
Transplant coronary artery disease is the pre-eminent cause of late cardiac allograft failure. It is primarily characterized by a concentric intimal hyperplasia, which we designate transplant intimal hyperplasia (TIH). Although the pathogenesis of TIH is predominately immune driven, the specific role of alloantibodies in the disease process remains undefined. In this study we investigated the contribution of alloantibodies to the development of TIH in a murine model. Orthotopic, carotid artery transplantation was performed between B10A(2R) (H-2(h2)) donor mice and B-cell deficient muMT(-/-) knockout or wild-type C57BL/6 (H-2(b)) recipients in the absence of immunosuppression. Grafts were harvested at 35 days and subjected to planimetry and immunohistochemistry. Alloantibodies were detectable in wild-type recipients within 7 days of transplantation and recipients developed marked TIH at 35 days. Allografts harvested from B-cell deficient recipient mice also developed TIH, which was comparable in severity with wild-type recipients. However, whereas allografts from wild-type recipients showed marked intimal smooth muscle cell (SMC) proliferation, the neointima in B-cell deficient recipients lacked SMCs. Post-transplantation administration of anti-donor serum to muMT(-/-) recipients restored neointimal SMC population but did not influence the severity of TIH. Significant neointimal formation occurs in the absence of alloantibodies but lacks a SMC component. Therefore, SMC migration and proliferation is antibody dependent.
移植冠状动脉疾病是心脏同种异体移植晚期失败的首要原因。其主要特征是同心性内膜增生，我们将其称为移植内膜增生（TIH）。尽管TIH的发病机制主要由免疫驱动，但同种异体抗体在疾病过程中的具体作用仍不明确。在本研究中，我们在小鼠模型中研究了同种异体抗体对TIH发生发展的作用。在未进行免疫抑制的情况下，将B10A(2R)（H-2(h2)）供体小鼠的颈动脉原位移植到B细胞缺陷的muMT(-/-)基因敲除小鼠或野生型C57BL/6（H-2(b)）受体小鼠体内。在35天时采集移植物并进行面积测量和免疫组织化学分析。野生型受体在移植后7天内可检测到同种异体抗体，且在35天时受体出现明显的TIH。从B细胞缺陷受体小鼠采集的同种异体移植物也出现了TIH，其严重程度与野生型受体相当。然而，野生型受体的同种异体移植物显示出明显的内膜平滑肌细胞（SMC）增殖，而B细胞缺陷受体的新生内膜中缺乏SMC。给muMT(-/-)受体移植后给予抗供体血清可恢复新生内膜SMC数量，但不影响TIH的严重程度。在没有同种异体抗体的情况下会发生显著的新生内膜形成，但缺乏SMC成分。因此，SMC的迁移和增殖依赖于抗体。
