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Promotion of Skin Graft Tolerance Across MHC Barriers by Mobilization of Dendritic Cells in Donor Hemopoietic Cell Infusions¹

Masatoshi Eto^2,3,*, Holger Hackstein^2,*, Katsuhiko Kaneko^*, Kikuo Nomoto and Angus W. Thomson^4,*

^* Department of Surgery and Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Medical Center, Pittsburgh, PA 15213; and Department of Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

Flt3 ligand (FL) dramatically increases the number of immunostimulatory dendritic cells (DC) and their precursors in bone marrow (BM) and secondary lymphoid tissues. Herein we tested the ability of FL-mobilized donor hemopoietic cells to promote induction of skin graft tolerance across full MHC barriers. C57BL/10 (B10; H2^b, IE^-) mice were given 10⁸ spleen cells (SC) from normal or FL-treated, H-2-mismatched B10.D2 (H2^d, IE⁺) donors i.v. on day 0, 200 mg/kg i.p. cyclophosphamide on day 2, and 10⁷ T cell-depleted BM cells from B10.D2 mice on day 3. B10.D2 skin grafting was performed on day 14. Indefinite allograft survival (100 days) was induced in recipients of FL-SC, but not in mice given normal SC. Tolerance was associated with blood macrochimerism and was confirmed by second-set skin grafting with donor skin 100 days after the first graft. In tolerant mice, peripheral donor-reactive T cells expressing TCR V11 were deleted selectively. Immunocompetence of tolerant FL-SC-treated mice was proven by rapid rejection of third-party skin grafts. To our knowledge this is the first report that mobilization of DC in donor cell infusions can be used to induce skin graft tolerance across MHC barriers, accompanied by specific deletion of donor-reactive T cells.

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