Flt-3 ligand increases microchimerism but can prevent the therapeutic effect of donor bone marrow in transiently immunosuppressed cardiac allograft recipients.
C3H (H2k) mice received 50 x 10(6) B10 (H2b) bone marrow (BM) cells either alone or with flt-3 ligand (FL) (10 microg/day), tacrolimus (2 mg/kg/day), or both agents for 7 days. Donor MHC class II+ (IAb+) cells were quantitated in spleens by immunohistochemical analysis, and donor 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 + tacrolimus led to a further eightfold increase in donor cells and enhanced donor DNA compared with the BM + tacrolimus group. This increase in donor cells was almost 500-fold compared with BM alone. C3H recipients of B10 heart allografts given perioperative B10 BM and tacrolimus (days 0-13) exhibited a markedly extended median graft survival time (MST, 42 days) compared with those given tacrolimus alone (MST, 22 days). Addition of FL (10 microg/day; 7 days) to BM + tacrolimus prevented the beneficial effect of donor BM (MST, 18 days). BM alone or BM + FL resulted in uniform early heart graft failure (MST < 8 days). Functional studies revealed maximal antidonor MLR and CTL activities in the BM- and BM + FL-treated groups, with minimal activity in the tacrolimus-treated groups. Thus, dramatic growth factor-induced increases in chimerism achieved under cover of immunosuppression may result in augmented antidonor T cell reactivity and reduced graft survival after immunosuppressive drug withdrawal. With FL, this may reflect striking augmentation of immunostimulatory dendritic cells.
Antonysamy
M A
MA
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, PA 15213, USA.
Steptoe
R J
RJ
Khanna
A
A
Rudert
W A
WA
Subbotin
V M
VM
Thomson
A W
AW
D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002678:Chimera / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D005802:Genes, MHC Class II; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods; D014185:Transplantation, Isogeneic
D017931:DNA Primers; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; C084881:flt3 ligand protein; D016559:Tacrolimus