title: Cardiac allograft acceptance after localized bone marrow transplantation by isolated limb perfusion in nonmyeloablated recipients.
abstract: Donor-specific tolerance to cardiac grafts may be induced by hematopoietic chimerism. This study evaluates the potential of localized bone marrow transplantation (BMT) performed by isolated limb (IL) perfusion to induce tolerance to secondary cardiac grafts without myeloablative conditioning. BALB/c recipients (H2d) preconditioned with lethal and sublethal doses of busulfan were injected i.v. and IL with 10(7) whole bone marrow cells (wBMCs) from B10 donors (H2(b)). Two hours after IL infusion of PKH-labeled wBMCs into myeloablated hosts, there were few labeled cells in the host peripheral blood (p < 0.001 versus i.v.) and femurs of the infused limb contained 57% +/- 7% PKH-labeled blasts (p < 0.001 versus 8% +/- 0.6% after i.v.). Femurs of the noninfused limbs contained 60-70 PKH-labeled blasts (p < 0.001 versus i.v.-BMT) after 2 days and 47% +/- 5% of 0.32 x 10(7) donor cells (p < 0.001 versus 78% +/- 4% of 1.2 x 10(7) donor cells in infused femurs) after 4 weeks. The survival rates of myeloablated hosts were 90% and 80% after i.v. and IL infusion, respectively, and the chimeras had 78%-84% donor peripheral blood cells. In recipients conditioned with 35 mg/g busulfan, the levels of donor chimerism in peripheral blood were 33% +/- 4% and 21% +/- 4% at 3 weeks after i.v.- and IL-BMT, respectively. Transplantation of donor-matched (H2(b)) secondary vascularized hearts in these chimeras after 3 weeks resulted in graft survival for periods exceeding 8 weeks, while third-party (H2(k)) allografts were acutely rejected (p < 0.001 versus H2(b)). These data indicate that IL perfusion is a reliable alternative procedure for establishment of hematopoietic chimerism and donor-specific tolerance without myeloablative conditioning.
authors.affiliation: Frankel Laboratory of Bone Marrow Transplantation, Schneider Children's Medical Center of Israel, Petach Tikva, Israel. anadir@012.net.il
authors.forename: Nadir
authors.initials: N
authors.lastname: Askenasy
authors.forename: Esma S
authors.initials: ES
authors.lastname: Yolcu
authors.forename: Haval
authors.initials: H
authors.lastname: Shirwan
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Wang
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Farkas
authors.forename: Esma S
authors.initials: ES
authors.lastname: Yoleuk
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002066:Busulfan / Q000494:pharmacology*; D005263:Femoral Artery; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology* / Q000401:mortality; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015996:Survival Rate; D018183:Transplantation Chimera / Q000276:immunology; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D002066:Busulfan