Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts
Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts
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DOI：
10.1161/circulationaha.109.910703
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发表时间：
2010-03-30
期刊：
影响因子：
37.8
通讯作者：
Lemstrom, Karl B.
中科院分区：
文献类型：
--
作者：
Nykanen, Antti I.;Sandelin, Henrik;Lemstrom, Karl B.
背景：淋巴网络和趋化因子介导的信号在同种免疫反应的近端步骤中对白细胞运输至关重要。我们旨在确定淋巴管及其主要生长信号通路血管内皮生长因子(VEGF)-C/D/VEGFR-3在同种异体心脏移植急性和慢性排斥反应中的作用。方法与结果：对异位移植大鼠同种异体心脏的分析表明，慢性排斥反应增加了VEGF-C+炎症细胞和透明质酸受体-1 (LYVE-1)（+）淋巴管密度。同种异体淋巴管为VEGFR-3(+)，含有抗原呈递细胞，产生树突状细胞趋化因子CCL21。以VEGFR-3/LacZ小鼠或具有绿色荧光蛋白阳性骨髓细胞的小鼠作为心脏移植受体的实验表明，同种异体移植淋巴管几乎完全来自供体细胞。门静脉内腺病毒VEGFR-3-Ig。采用VEGFR-3- ig /VEGF-C/D- trap)灌注抑制VEGF-C/D/VEGFR-3信号传导。受体用Ad治疗。VEGFR-3-Ig延长大鼠同种异体心脏移植存活时间。广告。VEGFR-3-Ig不影响同种异体移植物的淋巴管生成，但与减少CCL21的产生和CD8（+）效应细胞进入同种异体移植物有关。与此同时,广告。VEGFR-3-Ig减少了OX62（+）树突状细胞的募集，增加了脾脏中转录因子Foxp3的表达。在单独的实验中，用中和性单克隆VEGFR-3抗体治疗可以减少动脉硬化，减少表达VEGFR-3和CCL21的激活淋巴管的数量，减少移植物浸润的CD4(+) T细胞。结论-这些结果表明，VEGFR-3通过调节异体移植物淋巴管CCL21的产生，参与免疫细胞从外周组织到次级淋巴器官的运输，提示抑制VEGFR-3可能是一种新的淋巴管靶向免疫调节治疗异体心脏移植排斥反应和动脉硬化的方法。（Circulation. 2010; 121: 1413-1422）
Background-Lymphatic network and chemokine-mediated signals are essential for leukocyte traffic during the proximal steps of alloimmune response. We aimed to determine the role of lymphatic vessels and their principal growth signaling pathway, vascular endothelial growth factor (VEGF)-C/D/VEGFR-3, during acute and chronic rejection in cardiac allografts.Methods and Results-Analysis of heterotopically transplanted rat cardiac allografts showed that chronic rejection increased VEGF-C+ inflammatory cell and hyaluronan receptor-1 (LYVE-1)(+) lymphatic vessel density. Allograft lymphatic vessels were VEGFR-3(+), contained antigen-presenting cells, and produced dendritic cell chemokine CCL21. Experiments with VEGFR-3/LacZ mice or mice with green fluorescent protein-positive bone marrow cells as cardiac allograft recipients showed that allograft lymphatic vessels originated almost exclusively from donor cells. Intraportal adenoviral VEGFR-3-Ig (Ad. VEGFR-3-Ig/VEGF-C/D-Trap) perfusion was used to inhibit VEGF-C/D/VEGFR-3 signaling. Recipient treatment with Ad. VEGFR-3-Ig prolonged rat cardiac allograft survival. Ad. VEGFR-3-Ig did not affect allograft lymphangiogenesis but was linked to reduced CCL21 production and CD8(+) effector cell entry in the allograft. Concomitantly, Ad. VEGFR-3-Ig reduced OX62(+) dendritic cell recruitment and increased transcription factor Foxp3 expression in the spleen. In separate experiments, treatment with a neutralizing monoclonal VEGFR-3 antibody reduced arteriosclerosis, the number of activated lymphatic vessels expressing VEGFR-3 and CCL21, and graft-infiltrating CD4(+) T cells in chronically rejecting mouse cardiac allografts.Conclusions-These results show that VEGFR-3 participates in immune cell traffic from peripheral tissues to secondary lymphoid organs by regulating allograft lymphatic vessel CCL21 production and suggest VEGFR-3 inhibition as a novel lymphatic vessel-targeted immunomodulatory therapy for cardiac allograft rejection and arteriosclerosis. (Circulation. 2010; 121: 1413-1422.)