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Microchimerism, Donor Dendritic Cells, and Alloimmune Reactivity in Recipients of Flt3 Ligand-Mobilized Hemopoietic Cells: Modulation by Tacrolimus¹

Adrian E. Morelli^2,*, Mary A. Antonysamy^2,*, Takuya Takayama^*, Holger Hackstein^*, Zongyou Chen^*, Shiguang Qian^*, Nancy B. Zurowski^* and Angus W. Thomson^3,*,

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

Flt3 ligand (FL) is a potent hemopoietic growth factor that strikingly enhances stem cells and dendritic cells (DC) in vivo. We examined the impact of infusing FL-mobilized bone marrow (BM) cells on microchimerism and anti-donor reactivity in normal and tacrolimus-immunosuppressed, noncytoablated allogeneic recipients. BM from B10 (H2^b) mice given FL (10 µg/day; days 0–8; FL-BM) contained a 7-fold higher incidence of potentially tolerogenic immature CD11c⁺ DC (CD40^low, CD80^low, CD86^low, MHC II^low) that induced alloantigen-specific T cell hyporesponsiveness in vitro. C3H (H2^k) mice received 50 x 10⁶ normal or FL-BM cells (day 0) and tacrolimus (2 mg/kg/day; days 0–12). On day 15, enhanced numbers of donor (IA^b+) cells were detected in the thymi and spleens of FL-BM recipients. Tacrolimus markedly enhanced microchimerism, which declined as a function of time. Ex vivo splenocyte proliferative and CTL responses and Th1 cytokine (IFN-) production in response to donor alloantigens were augmented by FL-BM infusion, but reduced by tacrolimus. Systemic infusion of purified FL-BM immature DC, equivalent in number to that in corresponding whole BM, confirmed their capacity to sensitize, rather than tolerize, recipient T cells in vivo. In vitro, tacrolimus suppressed GM-CSF-stimulated growth of myeloid DC from normal BM much more effectively than from FL-BM without affecting MHC class II or costimulatory molecule expression. Infusion of normal B10 BM cells at the time of transplant prolonged C3H heart allograft survival, whereas FL-BM cells did not. A therapeutic effect of tacrolimus on graft survival was observed in combination with normal, but not FL-BM cells. These findings suggest the need for alternative immunosuppressive strategies to calcineurin inhibition to enable the engraftment, survival, and immunomodulatory function of FL-enhanced, immature donor DC.

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