Homing of human cells in the fetal sheep model: Modulation by antibodies activating or inhibiting very late activation antigen-4-dependent function

The mechanisms by which intravenously (IV)-administered homing, we also pre treated human donor cells with an hematopoietic cells home to the bone marr ow (BM) are activating antibody to pi integrins. This treatment resulted po orly defined. Although insightful information has been obtained in mice, ou r knowledge about homing of human cells is very limited. In the present stu dy, 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 th at preincubation of donor cells with anti-VLA-4 blocking antibodies resulte d 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 cell s in the peripheral circulation. Furthermore, IV infusion of the anti-VLA-4 antibody at later times (posttransplantation days 21 to 24) resulted in re distribution or mobilization of human progenitors from the BM to the periph eral blood. In an attempt to positively modulate in increased lodgment of d onor cells in the fetal liver, presumably for hemodynamic reasons, at the e xpense of the BM, Given previous involvement of the VLA-4/vascular cell adh esion 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 conservatio n of molecular mechanisms of homing and mobilization across disparate speci es barriers. Thus, information from xenogeneic models of human hematopoiesi s and specifically, the human/sheep model of in utero transplantation, may provide valuable insights into human hematopoietic transplantation biology. (C) 1999 by The American Society of Hematology.