Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2515-2522
Homing of Human Cells in the Fetal Sheep Model: Modulation by
Antibodies Activating or Inhibiting Very Late Activation
Antigen-4-Dependent Function
Esmail D. Zanjani,
Alan W. Flake,
Graça Almeida-Porada,
Nam Tran, and
Thalia Papayannopoulou
From the VA Medical Center, Reno, NV; Children's Hospital of
Philadelphia, Philadelphia, PA; and the University of Washington,
Seattle, WA.
The mechanisms by which intravenously (IV)-administered
hematopoietic cells home to the bone marrow (BM) are poorly defined. Although insightful information has been obtained in mice, our knowledge about homing of human cells is very limited. In the present
study, we investigated the importance of very late activation antigen
(VLA)-4 in the early phases of lodgment of human CD34+
progenitors into the sheep hematopoietic compartment after in utero
transplantation. We have found that preincubation of donor cells with
anti-VLA-4 blocking antibodies resulted in a profound reduction of
human cell lodgment in the fetal BM at 24 and 48 hours after
transplantation, with a corresponding increase of human cells in the
peripheral circulation. Furthermore, IV infusion of the anti-VLA-4
antibody at later times (posttransplantation days 21 to 24) resulted in
redistribution or mobilization of human progenitors from the BM to the
peripheral blood. In an attempt to positively modulate homing, we also
pretreated human donor cells with an activating antibody to 
1
integrins. This treatment resulted in increased lodgment of donor cells
in the fetal liver, presumably for hemodynamic reasons, at the expense
of the BM. Given previous involvement of the VLA-4/vascular cell
adhesion molecule (VCAM)-1 adhesion pathway in homing and
mobilization in the murine system, our present data suggest that
cross-reacting ligands (likely VCAM-1) for human VLA-4 exist in sheep
BM, thereby implicating conservation of molecular mechanisms of homing
and mobilization across disparate species barriers. Thus, information from xenogeneic models of human hematopoiesis and specifically, the
human/sheep model of in utero transplantation, may provide valuable
insights into human hematopoietic transplantation biology.
