Engraftment of allogeneic hematopoietic stem cells requires both inhibition of host-versus-graft responses and 'space' for homeostatic expansion.

BACKGROUND

The establishment of host-versus-graft (HvG) tolerance is the primary aim of reduced intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (SCT). It remains to be clarified to what extent recipient myeloablation is fundamental in the establishment of donor chimerism.

METHODS

We have addressed this question in a murine model of RIC SCT in which the donor-recipient combination produces HvG against the male specific minor histocompatibility antigen HY. In this system engraftment can be monitored by RT-PCR and HvG effectors enumerated by tetramer analysis.

RESULTS

We demonstrate that the dose of irradiation influences donor hemopoietic engraftment and affects generation of anti-donor specific T cells. Chimeric recipients do not mount a HvG immune response, becoming selectively tolerant, as demonstrated by the long term acceptance of skin grafts of donor but not third party origin. However, HvG tolerance is not sufficient to secure engraftment since, even in the absence of HvG, partial myeloablation was still required. The "space" produced by myeloablation and the consequent potential for donor cell expansion could also affect HvG tolerance, since its induction is severely impaired when donor hematopoietic cells have reduced proliferative capacity.

CONCLUSIONS

We conclude that both some degree of myeloablation and HvG tolerance are required for successful engraftment, and that the capacity of donor cells to proliferate influences the induction of HvG tolerance.