Research ArticleTransplantation

Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy

Science Translational Medicine  10 Aug 2016:
Vol. 8, Issue 351, pp. 351ra105
DOI: 10.1126/scitranslmed.aae0501

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Make way for stem cells

Current conditioning regimens to prepare the host bone marrow for transplantation of donor hematopoietic stem cells (HSCs) can have toxic effects on the patient. As an alternative to chemotherapy or radiation, Chhabra et al. describe a new immunotherapy strategy that clears out host HSCs from the bone marrow in preparation for a transplant. Blockade of the surface antigen CD47 allows phagocytic myeloid cells to engulf host HSCs displaced by antibody targeting, effectively depleting HSCs from the bone marrow of immunocompetent mice. This led to improved engraftment of donor HSCs, with fewer toxic effects for the mice receiving the transplant.

Abstract

Hematopoietic stem cell (HSC) transplantation can cure diverse diseases of the blood system, including hematologic malignancies, anemias, and autoimmune disorders. However, patients must undergo toxic conditioning regimens that use chemotherapy and/or radiation to eliminate host HSCs and enable donor HSC engraftment. Previous studies have shown that anti–c-Kit monoclonal antibodies deplete HSCs from bone marrow niches, allowing donor HSC engraftment in immunodeficient mice. We show that host HSC clearance is dependent on Fc-mediated antibody effector functions, and enhancing effector activity through blockade of CD47, a myeloid-specific immune checkpoint, extends anti–c-Kit conditioning to fully immunocompetent mice. The combined treatment leads to elimination of >99% of host HSCs and robust multilineage blood reconstitution after HSC transplantation. This targeted conditioning regimen that uses only biologic agents has the potential to transform the practice of HSC transplantation and enable its use in a wider spectrum of patients.

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