STRIKING AUGMENTATION OF HEMATOPOIETIC-CELL CHIMERISM IN NONCYTOABLATED ALLOGENEIC BONE-MARROW RECIPIENTS BY FLT3 LIGAND AND TACROLIMUS

The influence of granulocyte-macrophage colony-stimulating factor (GM- CSF) and the recently identified hematopoietic stem-progenitor cell mo bilizing factor flt3 ligand (FL) on donor leukocyte microchimerism in noncytodepleted recipients of allogeneic bone marrow (BM) was compared , B10 mice (H2(b)) given 50 x 10(6) allogeneic (B10.BR [H2(k)]) BM cel ls also received either GM-CSF (4 mu g/day s.c.), FL (10 mu g/day i.p. ), or no cytokine, with or without concomitant tacrolimus (formerly FK 506; 2 mg/kg) from day 0, Chimerism was quantitated in the spleen 7 da ys after transplantation by both polymerase chain reaction (donor DNA [major histocompatibility complex class II; I-E-k]) and immunohistoche mical (donor [I-Ek+] cell) analyses, Whereas GM-CSF alone significantl y augmented (fivefold) the level of donor DNA in recipients' spleens, FL alone caused a significant (60%) reduction. Donor DNA was increased 10-fold by tacrolimus alone, whereas coadministration of GM-CSF and t acrolimus resulted in a greater than additive effect (28-fold increase ), A much more striking effect was observed with FL + tacrolimus (> 12 5-fold increase in donor DNA compared with BM alone), These findings w ere reflected in the relative numbers of donor major histocompatibilit y complex class II+ cells (many resembling dendritic cells) detected i n spleens, although quantitative differences among the groups were les s pronounced, Evaluation of cytotoxic T lymphocyte generation by BM re cipients' spleen cells revealed that FL alone augmented antidonor immu nity and that this was reversed by tacrolimus. Thus, although FL may p otentiate antidonor reactivity in nonimmunosuppressed, allogeneic BM r ecipients, it exhibits potent chimerism-enhancing activity when coadmi nistered with recipient immunosuppressive therapy. This property of FL may offer considerable potential for the augmentation of microchimeri sm, with therapeutic implications for organ allograft survival and tol erance induction.