Hematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation

• DOI: 10.1038/s41467-018-08202-w
• Publication Date: 2019-02-06T11:04:47Z
• Authors: Zhanzhuo Li; Agnieszka Czechowicz; Amelia Scheck; Derrick J. Rossi; Philip M. Murphy
• Keywords: Graft Rejection; Male; 0301 basic medicine; Immunoconjugates; Science; Bone Marrow Cells; Article; Mice; 03 medical and health sciences; Immune Tolerance; Animals; Bone Marrow Transplantation; Skin; Immunosuppression Therapy; Mice, Inbred BALB C; Transplantation Chimera; Q; Graft Survival; Hematopoietic Stem Cell Transplantation; Skin Transplantation; Hematopoietic Stem Cells; 3. Good health; Mice, Inbred C57BL; Proto-Oncogene Proteins c-kit; Models, Animal; Transplantation Tolerance

AbstractHematopoietic chimerism after allogeneic bone marrow transplantation may establish a state of donor antigen-specific tolerance. However, current allotransplantation protocols involve genotoxic conditioning which has harmful side-effects and predisposes to infection and cancer. Here we describe a non-genotoxic conditioning protocol for fully MHC-mismatched bone marrow allotransplantation in mice involving transient immunosuppression and selective depletion of recipient hematopoietic stem cells with a CD117-antibody-drug-conjugate (ADC). This protocol resulted in multilineage, high level (up to 50%), durable, donor-derived hematopoietic chimerism after transplantation of 20 million total bone marrow cells, compared with ≤ 2.1% hematopoietic chimerism from 50 million total bone marrow cells without conditioning. Moreover, long-term survival of bone marrow donor-type but not third party skin allografts is achieved in CD117-ADC-conditioned chimeric mice without chronic immunosuppression. The only observed adverse event is transient elevation of liver enzymes in the first week after conditioning. These results provide proof-of-principle for CD117-ADC as a non−genotoxic, highly-targeted conditioning agent in allotransplantation and tolerance protocols.