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Epitope Specificity of CD44 for Monoclonal Antibody-Dependent
Facilitation of Marrow Engraftment in a Canine Model
Brenda M. Sandmaier,
Rainer Storb,
Kelly L. Bennett,
Frederick R. Appelbaum, and
Erlinda B. Santos
From the Clinical Research Division, Fred Hutchinson Cancer Research
Center, Seattle; the Department of Medicine, University of Washington,
Seattle; and Bristol-Myers Squibb Pharmaceutical Research Institute,
Seattle, WA.
Primary graft rejection after marrow transplantation occurs more
frequently in patients receiving HLA-haploidentical compared with
HLA-identical sibling transplants. Both human and experimental animal
data suggest that the cells responsible for this phenomenon are either
host natural killer (NK) cells, T cells, or both. To investigate the mechanisms of graft rejection, we have developed a
canine model of marrow transplantation, which uses DLA-nonidentical unrelated donors in the absence of postgrafting immunosuppression. In
this model most animals rejected their marrow grafts after a
preparative regimen of 9.2 Gy total body irradiation (TBI). However,
engraftment of DLA-nonidentical marrow can be facilitated when the
recipients are pretreated with monoclonal antibody (MoAb) S5, which
recognizes CD44. In this report, we extended these observations by
first cloning the canine CD44 and, next, mapping the epitope recognized
by S5, which was located in a region conserved among human and canine
CD44 and was distinct from the hyaluronan binding domain. However, in
vitro binding of S5 caused a conformational change in CD44, which
allowed increased hyaluronan binding. Then, we reexamined the in vivo
model of marrow transplantation and compared results with MoAb S5 to
those with two other anti-CD44 MoAbs, IM7 and S3. Only MoAb S5
significantly increased the engraftment rate of DLA-nonidentical
unrelated marrow, whereas the two other anti-CD44 MoAbs were
ineffective. The enhanced in vivo effect was not related to differences
in the MoAbs' avidities, since both S5 and IM7 had equivalent binding
to CD44, but most likely related to the specific epitope that S5
recognizes. Thus, this study shows that the effect of the anti-CD44
MoAb S5 in facilitating engraftment is epitope specific and if one is
to use an anti-CD44 to facilitate engraftment of marrow in humans, one
cannot assume that any anti-CD44 would work.
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3494-3502
© 1998 by The American Society of Hematology.
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