FLT-3 LIGAND INCREASES MICROCHIMERISM BUT CAN PREVENT THE THERAPEUTICEFFECT OF DONOR BONE-MARROW IN TRANSIENTLY IMMUNOSUPPRESSED CARDIAC ALLOGRAFT RECIPIENTS

C3H (H2(k)) mice received 50 x 10(6) B10 (H2(b)) bone marrow (BM) cell s either alone or with fit-3 ligand (FL) (10 mu g/day), tacrolimus (2 mg/kg/day), or both agents for 7 days, Donor MHC class II+ (IA(b+)) ce lls were quantitated in spleens by immunohistochemical analysis, and d onor class II DNA detected in BM by PCR, Donor cells were rare in the BM alone and BM + FL groups, whereas there was a substantial increase in chimerism in the BM + tacrolimus group, Addition of FL to BM + tacr olimus led to a further eightfold increase in donor cells and enhanced donor DNA compared with the BM + tacrolimus group, This increase in d onor cells was almost 500-fold compared with BM alone, C3H recipients of B10 heart allografts given perioperative B10 BM and tacrolimus (day s 0-13) exhibited a markedly extended median graft survival time (MST, 42 days) compared with those given tacrolimus alone (MST, 22 days), A ddition of FL (10 mu g/day; 7 days) to BM + tacrolimus prevented the b eneficial effect of donor BM (MST, 18 days), BM alone or BM + FL resul ted in uniform early heart graft failure (MST < 8 days), Functional st udies revealed maximal antidonor MLR and CTL activities in the BM- and BM + FL-treated groups, with minimal activity in the tacrolimus-treat ed groups, Thus, dramatic growth factor-induced increases in chimerism achieved under cover of immunosuppression may result in augmented ant idonor T cell reactivity and reduced graft survival after immunosuppre ssive drug withdrawal, With FL, this map reflect striking augmentation of immunostimulatory dendritic cells.