Sayegh M H, Zheng X G, Magee C, Hancock W W, Turka L A
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Transplantation. 1997 Dec 27;64(12):1646-50. doi: 10.1097/00007890-199712270-00003.
Optimal activation of T cells requires two signals: antigen engagement through the T cell receptor and a costimulatory signal. Previous studies have shown that blockade of the CD28:B7 costimulatory pathway using the soluble fusion protein CTLA4Ig can prevent acute rejection of organ and tissue allografts; however, long-term engraftment has not been seen universally. This study was undertaken to define the role of donor antigen in inducing long-term allograft survival in CTLA4Ig-treated recipients.
A murine cardiac allograft model was employed using BALB/c donors and C57BL/6 recipients. Additional donor antigen in the form of donor splenocytes was given at the time of transplantation. Recipients were treated with a single dose of CTLA4Ig 2 days after transplantation.
We find that a single dose of CTLA4Ig prolongs cardiac allograft survival, but permanent engraftment is not observed unless the recipients receive an injection of donor-type splenocytes. Treatment of the donor cells with CTLA4Ig does not by itself prolong allograft survival, which indicates the need for systemic treatment of the recipient. Allografts from animals not receiving donor cells show classic histologic changes of chronic rejection, and most cease function from 1 to 4 months after transplantation. Lethal irradiation of the donor cells does not appreciably affect their ability to prevent late allograft loss.
Donor cells are required to synergize with CTLA4Ig and prevent late cardiac allograft loss in the murine system. The fact that pretreatment of the donor cells alone is not effective suggests a role for antigen presentation by recipient antigen-presenting cells in the initiation of rejection. As lethal irradiation of the donor cells does not affect their ability to promote long-term engraftment, our data suggest that long-term microchimerism is not required to prevent chronic rejection in this model.
T细胞的最佳激活需要两个信号：通过T细胞受体进行抗原结合以及共刺激信号。先前的研究表明，使用可溶性融合蛋白CTLA4Ig阻断CD28:B7共刺激途径可预防器官和组织同种异体移植的急性排斥反应；然而，并非普遍能实现长期植入。本研究旨在确定供体抗原在CTLA4Ig治疗的受体中诱导同种异体移植长期存活的作用。
采用BALB/c供体和C57BL/6受体建立小鼠心脏同种异体移植模型。在移植时给予供体脾细胞形式的额外供体抗原。受体在移植后2天接受单剂量的CTLA4Ig治疗。
我们发现单剂量的CTLA4Ig可延长心脏同种异体移植的存活时间，但除非受体接受供体类型脾细胞的注射，否则不会观察到永久植入。用CTLA4Ig处理供体细胞本身并不能延长同种异体移植的存活时间，这表明需要对受体进行全身治疗。未接受供体细胞的动物的同种异体移植表现出慢性排斥的典型组织学变化，并且大多数在移植后1至4个月停止功能。对供体细胞进行致死性照射不会明显影响其预防晚期同种异体移植丢失的能力。
在小鼠系统中，需要供体细胞与CTLA4Ig协同作用以防止晚期心脏同种异体移植丢失。仅对供体细胞进行预处理无效这一事实表明受体抗原呈递细胞在排斥反应起始中的抗原呈递作用。由于对供体细胞进行致死性照射不会影响其促进长期植入的能力，我们的数据表明在该模型中预防慢性排斥不需要长期微嵌合体。
