The endothelium in graft-versushost disease and graft-versusleukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 478

ago that local graft-versus-host (GVH) reactions after injection of allogeneic
lymphocytes are associated with increased neovascularization [39-41] .

The role of neovascularization in systemic GVHD, however, has not been
studied systematically until recently. Neovascularization and its inhibi-
tion became a major focus of interest because antiangiogenic substances
were found to be active as a treatment for a variety of malignant diseases
and inflammatory disorders [42-45] . Since inflammation (GVHD) as well
as tumor relapse is a major clinical problem after allo-HSCT we decided to
study the role of neovascularization in murine allo-HSCT models [46] . Dur-
ing GVHD, we found increased vessel density in GVHD target organs. Using
MHC class I molecules as donor-host markers and green fluorescence
protein-positive donor cells we demonstrated that neovascularization was
mainly due to an increase in donor-derived ECs. The predominant role that
donor ECs play in the formation of neovasculature (vasculogenesis) after
HSCT in our murine models is probably due to damage of host ECs by the
radiation used as conditioning [9,47,48] .

Clinical results are in line with the experimental data and demonstrate neo-
vascularization in target organs during the early phase of GVHD. Increased
vascular density and vascular proliferation were found in skin and gas-
tric biopsies during acute GVHD [27,49] . Given that vascular endothelial
growth factor (VEGF) plays a major role in neovascularization, several stud-
ies investigated VEGF levels and VEGF single-nucleotide polymorphisms in
allo-HSCT recipients. Clinical results suggest a positive correlation between
low VEGF production and increased severity of GVHD in HSCT recipients
[50-52] . However, the mechanism of this correlation as well as its implica-
tion for the clinical use of anti-VEGF drugs after allo-HSCT remains to be
determined.

484

Several human studies addressed the question regarding the relative con-
tribution of vasculogenesis versus angiogenesis for neovascularization dur-
ing GVHD. In sex-mismatched transplants the contribution of donor bone
marrow-derived ECs to neovascularization in the skin and the intestines
during GVHD was demonstrated [53-56] . However, the amount of the con-
tribution of donor-derived ECs versus host-derived ECs (vasculogenesis
versus angiogenesis) was variable, which is probably due to differences in
the conditioning regimens and patient-related factors as well as method-
ological difficulties in assessing vasculogenesis.

In summary, results from preclinical models as well as clinical studies dem-
onstrate that neovascularization occurs during the early phase of GVHD.

Inhibition of neovascularization during GVHD

Based on encouraging study results on the inhibition of neovascularization
as a therapy for inflammatory diseases of the skin, joints, and intestines,
we were interested in testing it as a novel approach to ameliorate GVHD
[42-44] . To specifically inhibit vasculogenesis in murine models of allo-
HSCT, we used an antibody (E4G10) that recognizes vascular endothelial
cadherin (VE-cadherin) monomers on EPCs [46] . We observed that admin-
istration of E4G10 was associated with inhibition of neovascularization in