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Localized Bone Marrow Transplantation Leads to Skin Allograft Acceptance in Nonmyeloablated Recipients: Comparison of Intra-Bone Marrow and Isolated Limb Perfusion

Center for Light Microscope, Imaging and Biotechnology, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA; Institute for Cellular Therapeutics, University of Louisville, Louisville, Kentucky, USA; Present address: Frankel Laboratory of Bone Marrow Transplantation, Center of Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel

Key Words. Bone marrow transplantation • Intra-bone marrow • Isolated limb perfusion • Hematopoietic chimerism • Skin grafts • Tolerance

Nadir Askenasy, Ph.D., Frankel Laboratory of Bone Marrow Transplantation, Center of Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, 14 Kaplan Street, Petach Tikva, 49202, Israel. Telephone: 9-723-925-3669; Fax: 9-723-925-3042; e-mail: anadir{at}012.net.il

It has been shown that engraftment of allogeneic bone marrow cells (BMC) induces tolerance to antigen-matched organs, and infusion of a megadose of cells improves the success of engraftment of T-cell-depleted BMC. This study explores intra-bone marrow injection (IB) and isolated limb perfusion (IL) as means of localized bone marrow transplantation (BMT) and assesses their tolerogenic effect. Intravenous (i.v.), IB, and IL infusion of syngeneic and allogeneic whole BMC rescued 90%-100% of myeloablated recipients. Tracing of PKH-labeled cells revealed early systemic dissipation after IB injection, indicating that it was equivalent to i.v. transplantation. In contrast, IL perfusion led to initial localization of donor BMC. BALB/c recipients conditioned with 70 µg/g busulfan had 58% ± 5% and 44% ± 4% donor lymphocytes at 4 weeks after i.v. and IL infusion, respectively, of 10⁷ whole BMC from B10 donors. This suggests that cells migrated out of the IL femur and seeded other bones. All recipients accepted donor-matched skin grafts and acutely rejected third party grafts. T-cell depletion lowered the engraftment efficiency of i.v.-BMT by 35% (p < 0.001 versus whole BMC), but not when infused IL (p < 0.001). It is concluded that IL-BMT is a procedure for initial localization of donor cells, which is as efficient as i.v.- and IB-BMT in rescue of myeloablated mice, induction of hemopoietic chimerism, and donor-specific immune nonresponsiveness to secondary skin grafts without myeloablative conditioning. The megadose effect achieved by inoculation of a small hemopoietic space improved engraftment of T-cell-depleted BMC. This approach may have clinical applications.

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