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

通过胸腺内接种同种异体胸腺基质细胞克隆诱导耐受

基本信息

批准号：
07671286
负责人：
DOI Hideyuki
金额：
$ 1.41万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

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.

建立胸腺基质细胞克隆在诱导移植耐受的作用进行了分析与小鼠胸腺嵌合模型。将BALB/c小鼠胸腺上皮细胞（TEC）和胸腺来源的成纤维细胞克隆经胸腺内接种和抗淋巴细胞血清（ALS）腹腔注射三次。来自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，尽管持续表达MHC供体抗原。用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，具有永久的胰岛同种异体移植物存活（>200天），而不需要进一步的免疫抑制，而皮肤同种异体移植物存活延长（120天相对于对照20天），但仍然被排斥。与此相反，A/J胰岛和C57 BL/6皮肤同种异体移植迅速排斥胸腺嵌合体小鼠。接受胰岛同种异体移植的嵌合体，允许他们随后接受供体皮肤移植，而不诉诸免疫抑制治疗。胸腺内接种TEC联合ALS后，65%的C3 H/He小鼠也诱导了供体特异性耐受，然而，胸腺内接种成纤维细胞或PAM 212，胸腺外经纵隔内、腹腔内或静脉内注射TEC和/或成纤维细胞在类似免疫抑制的受体中均不能有效延长供体胰岛移植物的存活。这些发现表明TEC的接种物必须存在于胸腺中以促进无反应性。我们在此证明，胸腺基质细胞克隆可以通过胸腺嵌合体诱导完全免疫活性的成年小鼠对同种异体供体的耐受。