A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody.
A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody.
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DOI：
10.1111/j.1600-6143.2011.03836.x
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Colvin RB
中科院分区：
文献类型：
--
作者：
Hirohashi T;Chase CM;Della Pelle P;Sebastian D;Alessandrini A;Madsen JC;Russell PS;Colvin RB
慢性同种异体移植物血管病变（CAV）可以通过供体特异性抗体（DSA）对I类MHC抗原的过继性转移而引起，并且不依赖补体。在这里，我们讨论DSA引起CAV的机制。B6。RAG1−/−或B6。RAG1−/−C3−/−(H-2b)小鼠接受B10。BR （H-2k）心脏异体移植和重复剂量IgG2a、IgG1或F(ab ')2片段IgG2a DSA（抗H-2k）。完整的DSA在28天内经常引起明显狭窄的CAV。相反，通过形态计量学判断，用抗nk1.1耗尽NK细胞可显著降低dsa诱导的CAV。成熟NK细胞基因缺陷受体（γ链敲除）也显示dsa诱导的CAV严重程度降低。NK对移植物的直接反应不是必需的。F(ab ')2 DSA片段，即使剂量是完整DSA的两倍，也没有活性。在体内，移植物微血管内皮细胞对DSA的反应是通过增加磷酸化细胞外信号调节激酶（pERK）的表达，而不是由F(ab ')2 DSA引起的反应。我们得出结论，抗体以Fc依赖的方式通过NK细胞介导CAV。这一新途径增加了慢性排斥反应的可能机制，并可能与最近描述的c4d阴性慢性抗体介导的人类排斥反应有关。
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-2b) mice received B10.BR (H-2k) heart allografts and repeated doses of IgG2a, IgG1 or F(ab’)2 fragments of IgG2a DSA (anti-H-2k). 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.
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