Xenogenic smooth muscle cell immunization reduces neointimal formation in balloon-injured rabbit carotid arteries.
Xenogenic smooth muscle cell immunization reduces neointimal formation in balloon-injured rabbit carotid arteries.
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DOI：
10.1016/j.cardiores.2005.06.016
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发表时间：
2005-11
影响因子：
10.8
通讯作者：
M. Shinohara;S. Kawashima;T. Yamashita;Tomofumi Takaya;R. Toh;T. Ishida;T. Ueyama;N. Inoue;K. Hirata;M. Yokoyama
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文献类型：
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作者：
M. Shinohara;S. Kawashima;T. Yamashita;Tomofumi Takaya;R. Toh;T. Ishida;T. Ueyama;N. Inoue;K. Hirata;M. Yokoyama
目的：内膜增生在多种类型的血管重塑中起重要作用，尤其是血管损伤后管腔狭窄。新生内膜区的血管平滑肌细胞(VSMCs)是一种合成表型，与正常中膜中的VSMCs具有不同的表位。新生内膜中合成的VSMCs含有免疫系统可以靶向的各种可能的抗原。在本研究中，我们试图建立一种新的免疫疗法，以人工合成的VSMCs为靶点，预防血管成形术后新生内膜的形成。方法和结果：以固定的异种培养的VSMCs作为免疫原，或以佐剂和磷酸盐缓冲盐水(PBS)或大鼠肝细胞为对照，重复免疫兔3次。最后一次免疫/注射1周后，球囊损伤左侧颈总动脉。伤后4周处死动物，观察新生内膜病变的形成情况。未免疫组和对照组新生内膜面积分别为0.339±0.036和0.350±0.041 mm~2，差异无统计学意义(P=NS)。然而，大鼠血管平滑肌细胞免疫显著缩小了血管内膜损伤面积(0.219±0.0286 mm~2；P<；0.05与注射PBS、未免疫组和大鼠肝细胞免疫组相比。)VSMC免疫可抑制新生内膜增殖的增殖细胞(1.34±0.49%vs.5.78±0.47%；P<0.05 vs.PBS未免疫组)。大鼠VSMC免疫诱导的抗体与兔合成的VSMC有较强的交叉反应。在体外实验中，从VSMC免疫的兔血浆中提取的免疫球蛋白对血清、血管紧张素II、血小板衍生生长因子BB、成纤维细胞生长因子和佛波酯PMA刺激的兔VSMCs的增殖和迁移有明显的抑制作用，提示该免疫球蛋白对VSMC具有一定的整体作用。大鼠血管平滑肌细胞免疫的兔免疫球蛋白与兔AT1a受体蛋白结合，通过转染兔AT1a受体pcDNA3在COS7细胞中表达。这种与AT1a受体的结合可能是VSMC免疫免疫球蛋白作用的机制之一。结论：异种、合成大鼠VSMC免疫在兔体内诱导了抗合成兔VSMC自身抗体的交叉反应。诱导的抗合成VSMCs的自身抗体可能为形成新生内膜病变的血管重塑提供新的免疫治疗的可能性。
Objective:Intimal hyperplasia plays an important role in a variety of types of vascular remodeling, particularly luminal narrowing after vascular injury. The vascular smooth muscle cells (VSMCs) in the neointimal area are a synthetic phenotype and have different epitopes from VSMCs in the normal media. The synthetic VSMCs in the neointima contain various possible antigens that can be targeted by the immune system. In this study, we tried to develop a new immunotherapy, which targets the synthetic VSMCs, for prevention of neointimal formation after angioplasty.Method and results:Rabbits were repeatedly immunized with fixed xenogenic rat cultured VSMCs suspended in adjuvant as immunogens or injected with adjuvant and phosphate-buffered saline (PBS) or rat hepatocytes as controls every 2 weeks for 3 times. One week after the last immunization/injection, balloon injury of the left common carotid artery was performed. Four weeks after the injury, rabbits were euthanized and the neointimal lesion formation was assessed. The mean neointimal area of the PBS-injected, non-immunized group and the rat hepatocyte-immunized, control group was not statistically different (0.339 ± 0.036 and 0.350 ± 0.041 mm2,P= NS). However, immunization with rat VSMCs significantly reduced the intimal lesion area (0.219 ± 0.0286 mm2;P<0.05 vs. PBS-injected, non-immunized group and rat hepatocyte-immunized group.) PCNA-immunopositive proliferating VSMCs in the neointima were suppressed by the rat VSMC immunization (1.34 ± 0.49% vs. 5.78 ± 0.47%;P<0.05 vs. PBS-injected, non-immunized group). Rat VSMC immunization induced antibodies which had strong cross-reactivity against rabbit synthetic VSMCs. In experiments in vitro, proliferation and migration of rabbit VSMCs that were stimulated by serum, angiotensin (AT) II, platelet-derived growth factor (PDGF)-BB, fibroblast growth factor (FGF), and the phorbol ester PMA were significantly suppressed by treatment with immunoglobulin extracted from the VSMC-immunized rabbit plasma, implying that the immunoglobulin had some global effects on VSMCs. The rat VSMC-immunized rabbit immunoglobulin bound the rabbit AT1a receptor protein, which was expressed in COS7 cells by transfection of rabbit AT1a receptor pcDNA3. This binding to AT1a receptor may be one of mechanisms of the effects of VSMC-immunized immunoglobulin.Conclusion:Xenogenic, synthetic rat VSMC immunization in rabbits induced auto-antibodies against synthetic rabbit VSMCs in a cross-reaction. The induced auto-antibodies against synthetic VSMCs may provide a possibility of new immunotherapy for vascular remodeling that forms neointimal lesions.