Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion.
Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion.
复制标题
DOI：
10.1084/jem.178.5.1801
复制
发表时间：
1993-11-01
期刊：
影响因子：
--
通讯作者：
Turka LA
中科院分区：
文献类型：
--
作者：
Lin H;Bolling SF;Linsley PS;Wei RQ;Gordon D;Thompson CB;Turka LA
同种异体移植排斥反应是一个T细胞依赖的过程。抗原激活生产性T细胞需要抗原参与T细胞受体以及通过其他T细胞表面分子（如CD28）传递的共刺激信号。CD28与天然配体B7的结合可以通过可溶性重组融合蛋白CTLA4Ig阻断。CTLA4Ig在体外和体内阻断抗原特异性免疫反应，我们已经证明，在移植时给予大鼠7天的CTLA4Ig治疗可以延长同种异体心脏移植物的存活时间（平均30天），尽管大多数移植物最终会被排斥。在这里，我们探索了使用CTLA4Ig的其他策略，以实现同种异体移植物的长期存活。我们的数据表明，供体特异性输血（DST）加CTLA4Ig可以提供有效的抗原特异性免疫抑制。如果在移植时给予DST，然后在2天后给予单剂量CTLA4Ig，所有动物都有长期移植存活（> 60 d）。与对第三方皮肤移植的正常排斥反应相比，这些动物对供体型皮肤移植的反应延迟。此外，供体匹配的第二心脏异体移植物耐受性良好，组织学上的排斥证据很少。这些数据表明，移植周围使用DST，随后使用CTLA4Ig治疗，可以诱导长时间的，通常是不确定的心脏异体移植接受。这些结果对人体尸体器官和组织移植具有一定的临床应用价值。
Allograft rejection is a T cell-dependent process. Productive T cell activation by antigen requires antigen engagement of the T cell receptor as well as costimulatory signals delivered through other T cell surface molecules such as CD28. Engagement of CD28 by its natural ligand B7 can be blocked using a soluble recombinant fusion protein, CTLA4Ig. Administration of CTLA4Ig blocks antigen-specific immune responses in vitro and in vivo, and we have shown that treatment of rats with a 7-d course of CTLA4Ig at the time of transplantation leads to prolonged survival of cardiac allografts (median 30 d), although most grafts are eventually rejected. Here, we have explored additional strategies employing CTLA4Ig in order to achieve long-term allograft survival. Our data indicate that donor-specific transfusion (DST) plus CTLA4Ig can provide effective antigen-specific immunosuppression. When DST is administered at the time of transplantation followed by a single dose of CTLA4Ig 2 d later, all animals had long-term graft survival (> 60 d). These animals had delayed responses to donor-type skin transplants, compared with normal rejection responses to third-party skin transplants. Furthermore, donor-matched second cardiac allografts were well tolerated with minimal histologic evidence of rejection. These data indicate that peritransplant use of DST followed by subsequent treatment with CTLA4Ig can induce prolonged, often indefinite, cardiac allograft acceptance. These results may be clinically applicable for cadaveric organ and tissue transplantation in humans.