Reap before sowing: depleting host Hematopoetic Stem Cells improves transplantation

Hematopoetic stem cells (HSC) can generate all the cells of the blood, including the myeloid (erythrocytes, neutrophils, etc.) and lymphoid (B, T, and NK cells) lineages. HSC transplantation would be a valuable therapy for many conditions, including reconstitution of immune deficiencies and following radiation.

HSCs transplanted by intravenous injection efficiently home to the bone marrow. However, transplanted HSCs are only transiently productive, with donor cell frequencies in the blood reduced to < 1% within months, unless the host is “conditioned” by toxic regimens that are thought to work by depleting host HSC occupying a limiting number of niches in the bone marrow.

Here, Czechowicz and colleagues tested a targeted depletion with ACK2, an antibody that blocks the cytokine stem cell factor (SCF) receptor CD117 (c-kit). They report that ACK2 treatment of immunodeficient mice led to the transient removal of >98% of HSCs. (Using immunodeficient hosts avoided host-vs.-graft immune responses that would complicate the interpretation. Rag2-knockout mice lack mature B and T cell lineages due to failure to recombine V(D)J regions of immunoglobulin and T cell receptor genes. Common-gamma-chain-knockout mice are severely immunodeficient due to the failure to signal IL2, IL4, IL7, IL9, and IL15. ) Moreover, they show that donor HSC in ACK2-treated immunodeficient host mice produced up to 90% of the blood cells months after transplantation (figure 3a). This result demonstrates that host HSC must be depleted from a limiting number of niches to allow donor HSC to stably reconstitute an immunodeficent host.

Czechowicz et al. "Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches". Science. 2007 Nov 23;318(5854):1296-9.