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.
Christ
Oliver
O
Department of Tumor Progression and Immune Defense, German Cancer Research Center, Heidelberg, Germany.
Günthert
Ursula
U
Schmidt
Dirk-Steffen
DS
Zöller
Margot
M
D000818:Animals; D003114:Colony-Forming Units Assay; D006023:Glycoproteins / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology*; D006410:Hematopoiesis / Q000276:immunology*; D006789:Host vs Graft Reaction / Q000276:immunology*; D018960:Hyaluronan Receptors / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D013950:Thymus Gland / Q000276:immunology; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
C112697:CD44v6 antigen; D006023:Glycoproteins; D018960:Hyaluronan Receptors