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Flt-3 Ligand Increases Microchimerism But Can Prevent the Therapeutic Effect of Donor Bone Marrow in Transiently Immunosuppressed Cardiac Allograft Recipients¹

Mary A. Antonysamy^*, Raymond J. Steptoe^*, Ajai Khanna^*, William A. Rudert, Vladimir M. Subbotin^* and Angus W. Thomson^2,*,

^* Thomas E. Starzl Transplantation Institute and Departments of Surgery, Pediatrics, and Molecular Genetics and Biochemistry, University of Pittsburgh, PA 15213

C3H (H2^k) mice received 50 x 10⁶ B10 (H2^b) bone marrow (BM) cells either alone or with flt-3 ligand (FL) (10 µg/day), tacrolimus (2 mg/kg/day), or both agents for 7 days. Donor MHC class II⁺ (IA^b+) 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 µg/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.

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