AN ESSENTIAL ROLE FOR FAS LIGAND IN TRANSPLANTATION TOLERANCE INDUCEDBY DONOR BONE-MARROW

Medawar and co-workers originally demonstrated that injection of donor bone marrow (DBM) into immune-incompetent neonatal rodents could indu ce tolerance to grafts from animals of the same strain as the bone mar row donor(1). Induction of tolerance in this manner can also be accomp lished in mature mice, dogs and monkeys if the resident T-cell populat ions in the recipient are depleted by a polyclonal antithymocyte globu lin or an anti-T cell immunotoxin(2-4.) The molecular mechanisms by wh ich bone marrow cells mediate the induction of tolerance remain uncert ain. Here we examined a well-established adult mouse model of antithym ocyte globulin and DBM treatment and show that expression of functiona l pas ligand (Fast, also CD95L) an the injected bone marrow cells is r equired for tolerance induction. The results indicate that a state of microchimerism per se is insufficient for the induction of tolerance i n T cell-depleted transplant recipients. Moreover, the results are con sistent with the hypothesis that tolerance induced by DBM involves an apoptotic process leading to deletion of graft-reactive cells.