Induction of immunologic tolerance to cardiac allograft by simultaneous blockade of inducible co-stimulator and cytotoxic T-lymphocyte antigen 4 pathway
Induction of immunologic tolerance to cardiac allograft by simultaneous blockade of inducible co-stimulator and cytotoxic T-lymphocyte antigen 4 pathway
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DOI：
10.1097/01.tp.0000061601.26325.82
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发表时间：
2003-04-27
期刊：
影响因子：
6.2
通讯作者：
Uede, T
中科院分区：
文献类型：
--
作者：
Kosuge, H;Suzuki, JI;Uede, T
背景。诱导共刺激因子 (ICOS) 是最近描述的 CD28 家族成员之一，它在免疫反应中发挥着重要作用。研究ICOS在同种异体移植中的作用；排斥反应，作者研究了小鼠心脏移植后的移植物存活率。方法。将 BALB/c 小鼠的心脏移植到 C3H/He 小鼠体内。进行免疫组织化学染色和流式细胞术。腹膜内注射针对 ICOS 的单克隆抗体或 ICOS-免疫球蛋白 (Ig)。作者进行了混合淋巴细胞反应（MLR）。结果。在同种异体移植物排斥过程中，移植物浸润细胞强烈表达 ICOS。与未治疗的小鼠相比，用抗ICOS抗体和ICOSIg阻断ICOS途径显着延长了移植物的存活时间；然而，所有同种异体心脏移植物最终都被单次治疗所排斥。使用ICOSIg和细胞毒性T淋巴细胞抗原4 (CTLA4) Ig治疗不仅诱导了对心脏同种异体移植物的长期接受，而且诱导了供体特异性耐受，这通过接受供体而不是第三方皮肤来证明。这些同种异体心脏移植物中的移植物动脉内膜增生明显低于用他克莫司治疗的同种异体心脏移植物。将抗ICOS抗体或ICOSIg添加至MLR导致T细胞增殖的抑制。结论。 ICOSIg 和 CTLA4Ig 抑制 T 细胞增殖比单独使用 ICOSIg 更有效。因此，ICOS似乎是T细胞活化的重要调节剂，并且可能是临床心脏移植的有效疗法。
Background. Inducible co-stimulator (ICOS) is one of the most recently described members of the CD28 family, and it plays an important role in immune responses. To investigate the role of ICOS in allograft; rejection, the authors studied graft survival after cardiac transplantation in mice.Methods. Hearts from BALB/c mice were transplanted into C3H/He mice. Immunohistochemical staining and flow cytometry were performed. Monoclonal antibody to ICOS or ICOS-immunoglobulin (Ig) was injected intraperitoneally. The authors performed mixed lymphocyte reaction (MLR).Results. ICOS was expressed strongly by graft-infiltrating cells during rejection of the allograft. Blockade of the ICOS pathway with anti-ICOS antibody and ICOSIg significantly prolonged graft survival time relative to that in untreated mice; however, all cardiac allografts were eventually rejected by a single treatment. Treatment with both ICOSIg and cytotoxic, T-lymphocyte antigen 4 (CTLA4) Ig induced not only long-term acceptance of the cardiac allograft but also donor-specific tolerance, which was shown by acceptance of donor but not third-party skin. Graft arterial intimal hyperplasia in these cardiac allografts was remarkably less than that in cardiac allografts treated with tacrolimus. Addition of anti-ICOS antibody or ICOSIg to MLR resulted in inhibition of T-cell proliferation.Conclusions. Inhibition of T-cell proliferation with ICOSIg and CTLA4Ig was more effective than that with ICOSIg alone. Thus, ICOS appears to be an important regulator of T-cell activation, and may be an effective therapy in clinical cardiac transplantation.