Transplantation Division, Department of Surgery of the Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
Am J Transplant. 2012 Feb;12(2):313-21. doi: 10.1111/j.1600-6143.2011.03836.x. Epub 2011 Nov 9.
Chronic allograft vasculopathy (CAV) in murine heart allografts can be elicited by adoptive transfer of donor specific antibody (DSA) to class I MHC antigens and is independent of complement. Here we address the mechanism by which DSA causes CAV. B6.RAG1(-/-) or B6.RAG1(-/-)C3(-/-) (H-2(b)) mice received B10.BR (H-2(k)) heart allografts and repeated doses of IgG2a, IgG1 or F(ab')(2) fragments of IgG2a DSA (anti-H-2(k)). Intact DSA regularly elicited markedly stenotic CAV in recipients over 28 days. In contrast, depletion of NK cells with anti-NK1.1 reduced significantly DSA-induced CAV, as judged morphometrically. Recipients genetically deficient in mature NK cells (γ-chain knock out) also showed decreased severity of DSA-induced CAV. Direct NK reactivity to the graft was not necessary. F(ab')(2) DSA fragments, even at doses twofold higher than intact DSA, were inactive. Graft microvascular endothelial cells responded to DSA in vivo by increased expression of phospho-extracellular signal-regulated kinase (pERK), a response not elicited by F(ab')(2) DSA. We conclude that antibody mediates CAV through NK cells, by an Fc dependent manner. This new pathway adds to the possible mechanisms of chronic rejection and may relate to the recently described C4d-negative chronic antibody-mediated rejection in humans.
慢性同种异体移植物血管病（CAV）可通过同种异体抗体（DSA）对 I 类 MHC 抗原的被动转移在小鼠心脏移植物中诱发，且不依赖于补体。在这里，我们探讨了 DSA 导致 CAV 的机制。B6.RAG1(-/-)或 B6.RAG1(-/-)C3(-/-)（H-2(b)) 小鼠接受 B10.BR（H-2(k)) 心脏移植物和重复剂量的 IgG2a、IgG1 或 IgG2a DSA（抗-H-2(k)) 的 F(ab')(2)片段。完整的 DSA 通常在 28 天内引发明显狭窄的 CAV。相比之下，用抗 NK1.1 耗尽 NK 细胞会大大减少 DSA 诱导的 CAV，从形态学上判断。成熟 NK 细胞（γ链敲除）遗传缺陷的受体也显示出 DSA 诱导的 CAV 严重程度降低。直接 NK 对移植物的反应不是必需的。即使 F(ab')(2) DSA 片段的剂量是完整 DSA 的两倍，也没有活性。移植物微血管内皮细胞在体内对 DSA 的反应是磷酸化细胞外信号调节激酶（pERK）表达增加，而 F(ab')(2) DSA 不会引起这种反应。我们得出结论，抗体通过 NK 细胞介导 CAV，通过 Fc 依赖性方式。这条新途径增加了慢性排斥的可能机制，并可能与最近描述的人类 C4d 阴性慢性抗体介导排斥反应有关。
