Anergic lymphocytes generated by blocking CD28 and ICOS pathways in vitro prolong rat cardiac graft survival
Anergic lymphocytes generated by blocking CD28 and ICOS pathways in vitro prolong rat cardiac graft survival
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DOI：
10.1016/j.intimp.2006.02.008
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发表时间：
2006-07-01
影响因子：
5.6
通讯作者：
Li, Xiao-Kang
中科院分区：
文献类型：
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作者：
Hara, Yoshiaki;Kitazawa, Yusuke;Li, Xiao-Kang
调节细胞可能在诱导和维持移植耐受中起关键作用。我们研究了通过ICOS和CD 28共刺激阻断体外产生的具有调节细胞潜能的无反应性淋巴细胞作为治疗同种异体移植排斥反应的细胞疗法来源的机制。在抗ICOS mAb和rCTLA-41 g存在下，通过由作为刺激物的DA脾细胞和作为应答物的刘易斯脾细胞组成的混合淋巴细胞反应产生无反应性淋巴细胞。这些淋巴细胞的免疫调节作用通过二次MLR和使用其他各种刺激来评价。静脉注射这些细胞和/或刘易斯脾淋巴细胞后，将DA心脏移植到7.5Gy照射的刘易斯大鼠体内。我们观察到这些淋巴细胞不仅对同种异体抗原和多克隆刺激无反应性，而且还表现出抑制同种异体反应性T细胞反应的调节活性。我们的过继移植研究显示，接受麻醉性淋巴细胞和幼稚刘易斯淋巴细胞的受者与仅接受刘易斯淋巴细胞的受者相比（平均10. 5天），DA心脏移植物存活时间显著延长（平均17. 5天）。8天）。此外，一些接受者在接受无反应性淋巴细胞后无限期地接受移植物（> 100天）。这些结果表明，通过同时阻断CD 28和ICOS共刺激信号，在体外可以产生具有调节活性的无反应性淋巴细胞，为器官移植中预防排斥反应提供了一种新的免疫调节策略。(c)2006 Elsevier B. V.保留所有权利。
Regulatory cells may play a pivotal role in inducing and maintaining transplantation tolerance. We investigated the mechanism of anergic lymphocytes with regulatory cell potential generated in vitro by ICOS and CD28 co-stimulatory blockades as a source of cellular therapy for treating allograft rejection. Anergic lymphocytes were generated by a mixed lymphocyte reaction consisting of DA splenocytes as the stimulator and Lewis splenocytes as the responder in the presence of anti-ICOS mAb and rCTLA-41g. Immunoregulatory effects of these lymphocytes were evaluated by secondary MLR and using other various stimulations. DA heart was transplanted into 7.5 Gy-irradiated Lewis rat after intravenous administration of these cells and/or Lewis spleen lymphocytes. We observed that these lymphocytes were not only anergic to alloantigen and polyclonal stimulations but also exhibited regulative activity to inhibit the alloreactive T-cell response. Our adoptive transfer studies revealed that irradiated recipients that received both aneygic lymphocytes and naive Lewis lymphocytes had significantly prolonged DA cardiac graft survival (mean 17.5days) compared with a group that received Lewis lymphocytes alone (mean 10. 8 days). Furthermore, some of the recipients accepted the graft indefinitely after receiving anergic lymphocytes alone (> 100 days). These results demonstrated that anergic lymphocytes with regulatory activities can be generated through blocking co-stimulatory signals, CD28 and ICOS, simultaneously in vitro, and may advance a new immumomodulatory strategy for preventing allorejection in organ transplantation. (c) 2006 Elsevier B.V. All rights reserved.