Establishing hematopoietic chimerism enables donor-specific allograft tolerance; however, chimerism protocols typically require either genotoxic conditioning or mega-doses of donor bone marrow cells (BMC), impeding clinical translation. Previously, we developed anti-CD117-saporin for non-genotoxic conditioning in syngeneic BM transplantation (BMT) acting through recipient HSC depletion (Czechowicz, Science 2007 and ASH Abstract, 2016). Here we test the safety and efficacy of this immunotoxin in fully MHC-mismatched sequential BM and skin transplantation. C57Bl/6 mice received one dose of anti-CD117-saporin 6 days before BALB/c BMT plus 3 doses of anti-T cell antibody cocktail and 2 doses of rapamycin. Mice then received dual BALB/c and CBA/Ca skin grafts twice, ~150 and 240 days after BMT. Donor chimerism in peripheral blood ranged from 0.44 to 2.15% in mice receiving 5[times]10⁷ BMC without immunotoxin, and 0 to 0.24%in mice receiving 2[times]10⁷ BMC with a nonspecific immunotoxin. In contrast, durable donor chimerism up to 45.6% for up to 624 days after BMT was observed in mice receiving 2[times]10⁷ BMC after anti-CD117 immunotoxin. Multi-lineage chimerism was also observed in lymphoid organs, ranging from 13.8 to 28.0%; donor B cell chimerism was the most prominent. In addition, chimeric mice accepted BALB/c skin grafts without further immunosuppression but rejected third party CBA/Ca skin allografts. Our results provide proof-of-principle for a safe and effective method for establishing persistent high-level mixed hematopoietic chimerism and donor-specific organ allograft tolerance that obviates both genotoxic conditioning and long-term immunosuppression by selectively depleting host HSCs in BM with an anti-CD117 immunotoxin. Since anti-CD117 antibodies are currently in development and in clinical trials, anti-CD117 immunotoxin may be rapidly translatable as a general method of allo-transplantation.

CITATION INFORMATION: Li Z., Czechowicz A., Scheck A., Rossi D., Murphy P. Robust Hematopoietic Mixed Chimerism and Donor-Specific Skin Allograft Tolerance after Non-Genotoxic Anti-CD117 Immunotoxin Conditioning and Donor Bone Marrow Allotransplantation Am J Transplant. 2017;17 (suppl 3).

« Back to 2018 American Transplant Congress