Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen.
Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen.
复制标题
由非致死性准备方案诱导的混合嵌合和永久特异性移植耐受。
DOI：
10.1084/jem.169.2.493
复制
发表时间：
1989-02-01
影响因子：
15.3
通讯作者：
Sachs, D H
中科院分区：
文献类型：
--
作者：
Sharabi, Y;Sachs, D H
异基因骨髓移植作为一种诱导供体特异性耐受的方法，可以为器官移植提供一种免疫特异性的预处理方案。然而，这种方法的一个主要限制是目前用于消除宿主抗性和允许骨髓移植的全身照射的毒性。本研究描述了消除宿主抗性和允许骨髓移植而不需要致死辐射的方法。我们的制备方案包括体内施用抗-CD 4和抗-CD 8 mAb，300-rad WBI，700-rad胸腺照射，和未操作的完全MHC不同的骨髓。通过该方案制备的B10小鼠产生稳定的混合淋巴造血嵌合体，而没有任何移植物抗宿主疾病植入伴随着对供体皮肤移植物的特异性耐受的诱导（B10.D2），而第三方皮肤移植物（B10.BR）被迅速排斥。接受完整方案治疗而不进行骨髓移植的小鼠看起来很健康，并且可以长期存活.因此，这项研究表明，稳定的混合嵌合体与供体特异性耐受性，可以诱导跨越MHC屏障后，非致死性的准备方案，没有临床GVHD和再生障碍性贫血的风险。
The use of allogeneic bone marrow transplantation as a means of inducing donor-specific tolerance across MHC barriers could provide an immunologically specific conditioning regimen for organ transplantation. However, a major limitation to this approach is the toxicity of whole body irradiation as currently used to abrogate host resistance and permit marrow engraftment. The present study describes methodology for abrogating host resistance and permitting marrow engraftment without lethal irradiation. Our preparative protocol involves administration of anti-CD4 and anti-CD8 mAbs in vivo, 300-rad WBI, 700-rad thymic irradiation, and unmanipulated fully MHC-disparate bone marrow. B10 mice prepared by this regimen developed stable mixed lymphohematopoetic chimerism without any clinical evidence of graft-vs.- host disease. Engraftment was accompanied by induction of specific tolerance to donor skin grafts (B10.D2), while third-party skin grafts (B10.BR) were promptly rejected. Mice treated with the complete regimen without bone marrow transplantation appeared healthy and enjoyed long- term survival. This study therefore demonstrates that stable mixed chimerism with donor-specific tolerance can be induced across an MHC barrier after a nonlethal preparative regimen, without clinical GVHD and without the risk of aplasia.