Induction of tolerance by intrathymic inoculation of the allogeneic thymic stromal cell clone

用小鼠胸腺嵌合模型分析了已建立的胸腺基质细胞克隆在移植物耐受诱导中的作用。通过胸腺内接种加三次腹腔注射抗淋巴细胞血清（ALS），获得BALB/c胸腺上皮细胞（TEC）和胸腺源性成纤维细胞克隆。来源于BALB/c胸腺的胸腺基质细胞克隆在同种异体胸腺环境中存活，尽管MHC供体抗原继续表达。经TEC和成纤维细胞接种的胸腺嵌合体具有供体特异性耐受性，无需进一步免疫抑制，永久胰岛移植存活（bb0 200天），而皮肤移植存活时间延长（120天，对照组20天），但仍被排斥。相比之下，A/J胰岛和C57BL/6同种异体皮肤移植在胸腺嵌合体小鼠中迅速产生排斥反应。接受同种异体胰岛移植的嵌合体，允许他们随后接受供体皮肤移植，而不需要免疫抑制治疗。在胸腺内接种very TEC联合ALS后，65%的C3H/He小鼠也产生了供体特异性耐受性。然而，在同样免疫抑制的受体中，胸腺内注射成纤维细胞或PAM212，胸腺外注射TEC和/或成纤维细胞并不能有效延长供体胰岛移植物的存活时间。这些发现表明，TEC的接种必须存在于胸腺中，以促进无反应。我们在此证明胸腺基质细胞克隆可以通过实现胸腺嵌合诱导完全免疫胜任的成年小鼠对异体供体的耐受性。

The role of established thymic stromal cell clones in the induction of graft tolerance was analyzed with a murine thymic chimeric model. C3H/He adult mice were given BALB/c thymic epithelial cell (TEC) and thymus derived-fibroblast clones by intrathymic inoculation plus triple intraperitoneal injections of antilymphocyte serum (ALS). Thymic stromal cell clones, derived from BALB/c thymus, survived in an allogenic thymic enviroment despite the continued expression of MHC donor antigens. Thymic chimeras that were innoculated by TEC and fibroblast, had a donor specific tolerance with permanent pancreatic islet allograft survival (>200 days) without the need for further immunosuppression, while skin allograft survival was prolonged (120 days vs. control 20 days) but was still rejected. In contrast, A/J islet and C57BL/6 skin allografts were promptly rejected in thymic chimera mice. Chimeras that had accepted islet allograft, allowed their subsequent acceptance of donor skin grafts without resort to immunosupressive treatment. Donor specific tolerance was also induced in 65% of C3H/He mice following intrathymic innoculation of the very TEC combined with ALS.However, intrathymic innocuration of fibroblast or PAM212, and extrathymic injection of TEC and/or fibroblast by the intramediastinal, intraperitoneal, or intavenous routes in similarly immunosupressed recipients were not effective in prolonging survival of donor islet grafts. These finding suggested that the inoculum of TEC must be present in the thymus to promote unresponsiveness. We demonstrat here that thymic stroma cell clones can induce tolerance in fully immunocompetent adult mice to an allogeneic donor by achieving thymic chimerism.