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Cardiac Allograft Acceptance after Localized Bone Marrow Transplantation by Isolated Limb Perfusion in Nonmyeloablated Recipients

^a Frankel Laboratory of Bone Marrow Transplantation, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel;
^b Institute for Cellular Therapeutics, and Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA;
^c The Starzl E. Thomas Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
^d Minimally Invasive Surgical Technologies Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA

Key Words. Bone marrow transplantation • Isolated limb perfusion • Hematopoietic chimerism • Heart grafts • Tolerance

Nadir Askenasy, M.D., Frankel Laboratory of Bone Marrow Transplantation, Center for Stem Cell Research, National Center of Pediatric Hematology Oncology, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, Petach Tikva 49202 Israel. Telephone: 972-3-641-1475; Fax: 972-3-641-1475; e-mail: anadir{at}012.net.il

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 10⁷ 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 10⁷ donor cells (p < 0.001 versus 78% ± 4% of 1.2 x 10⁷ 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.

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