Allogeneic reconstitution after nonmyeloablative conditioning: mitigation of graft-versus-host and host-versus-graft reactivity by anti-CD44v6

T-cell maturation is accelerated in transgenic mice expressing rat CD44v4-v7 on T cells, the effect being blocked by anti-CD44v6. This finding suggested functional activity of CD44v6 in thymocyte development. We tested the hypothesis by antibody blocking and using mice with targeted deletion of CD44v6/v7 exon products (CD44v6/v7(-/-)). When lethally irradiated CD44v6/v7-competent (CD44v6/v7(+/+)) mice were reconstituted syngeneically, higher numbers of CD44v6/v7(-/-) than CD44v6/v7(+/+) BMC were required for survival, the period of reconstitution was prolonged, and regain of immunocompetence was delayed. Similar findings were observed in lethally irradiated, anti-CD44v6-treated syngeneic CD44v6/v7(+/+) hosts. Thus, CD44v6/v7 supports maturation and expansion of hematopoietic progenitor cells. Surprisingly, reconstitution with CD44v6/v7(-/-) BMC or anti-CD44v6 treatment of the nonlethally irradiated allogeneic CD44v6/v7(+/+) host had only a minor impact on survival rates. When nonlethally irradiated CD44v6/v7(-/-) hosts received an allogeneic graft, survival rates were improved. These phenomena have been a result of reduced GvH reactivities when the donor was CD44v6/v7(-/-) and reduced HvG reactivities in the CD44v6/v7(-/-) host. Thus, although a deficit or blockade of CD44v6/v7 has a negative impact on hematopoietic reconstitution, a transient blockade will be of benefit for the allogeneically reconstituted host because of a strong reduction in GvH and HvG reactivities.