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

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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.