Journal of Leukocyte Biology
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(Journal of Leukocyte Biology. 2002;71:33-46.)
© 2002 by Society for Leukocyte Biology

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

Oliver Christ*, Ursula Günthert{dagger}, Dirk-Steffen Schmidt* and Margot Zöller*,{ddagger}

* Department of Tumor Progression and Immune Defense, German Cancer Research Center, Heidelberg, Germany;
{dagger} Basel Institute for Immunology, Basel Switzerland; and
{ddagger} Department of Applied Genetics, University of Karlsruhe, Karlsruhe, Germany

Correspondence: Margot Zöller, Department of Tumor Progression and Immune Defense, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. E-mail: m.zoeller{at}dkfz.de

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.

Key Words: hematopoiesis • rodent • adhesion molecules • knockout • T lymphocytes






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