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

Nat Commun. 2019 Feb 6;10(1):616. doi: 10.1038/s41467-018-08202-w.

Abstract

Hematopoietic 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / drug effects
  • Bone Marrow Transplantation / methods*
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control
  • Graft Survival*
  • Hematopoietic Stem Cell Transplantation / methods*
  • Hematopoietic Stem Cells
  • Immune Tolerance
  • Immunoconjugates / pharmacology*
  • Immunosuppression / methods
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Models, Animal
  • Proto-Oncogene Proteins c-kit / immunology*
  • Skin / pathology
  • Skin Transplantation / methods
  • Transplantation Chimera
  • Transplantation Tolerance / drug effects*
  • Transplantation, Homologous

Substances

  • Immunoconjugates
  • Proto-Oncogene Proteins c-kit