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transplant (VWF, thrombomodulin, and soluble intercellular adhesion mol-
ecule-1) is predictive for the development of veno-occlusive disease
[22]
.
Taken together these preclinical and clinical results demonstrate consid-
erable toxic effects of conditioning regimens and of immunosuppressive
drugs on the endothelium.
Endothelial dysfunction caused by alloreactivity of
donor leukocytes
Endothelial damage is not exclusively a characteristic effect of the con-
ditioning regimen but also occurs during GVHD. Endothelial activation
and endothelial cell death may be caused by donor T cells recognizing
host HLA molecules on ECs. In murine models it was shown that the
transfer of allogeneic lymphocytes primarily leads to disseminated ECs
apoptosis
[23]
. To dissect the toxic effects of the conditioning regimen
on ECs and endothelial damage by alloreactivity, experiments in acute
GVHD models without conditioning treatment were performed. Interest-
ingly, in the absence of chemotherapy or radiation, the earliest detect-
able oral mucosa lesion was endothelial damage. Epithelial injury, which
is generally considered a benchmark of acute GVHD, was a secondary
event subsequent to endothelial cell death and lymphocytic inflamma-
tion
[24]
. As mentioned before, circulating ECs are often used as a marker
for endothelial injury. In an HLA-mismatch mouse allogeneic bone mar-
row transplantation model with radiation, the time course of endothelial
injury during conditioning and GVHD was demonstrated: circulating ECs
peaked the first time from radiation injury and a second time with GVHD
progression
[25]
. If GVHD persists over a longer period the progressive
destruction of the vasculature leads to rarefaction of blood vessels in tar-
get organs. In murine models of GVHD, we found that during intestinal
GVHD the vascular density in the intestines decreased in later stages of
GVHD (unpublished observation).
482
One study in humans investigated the endothelium in intestinal biopsies of
patients with GVHD. Biopsies of patients with severe hemorrhagic entero-
colitis (grade IV intestinal GVHD) showed vast areas with endothelial cell
lesions leading to pericapillary hemorrhage
[26]
. Most human studies, how-
ever, focus on the skin as the GVHD target organ, because of the availabil-
ity of biopsies. Most study results support the view that the endothelium is
damaged during cutaneous GVHD. Santos and co-workers
[27]
found endo-
thelial pathological changes, such as intimal lymphocytic infiltrate, von Wil-
lebrand factor extravasation, and perivascular nuclear dust, in skin biopsies
of patients with acute GVHD. During sclerotic chronic GVHD of the skin
destruction of microvessels and reduction of vascular density were found
[28]
. In biopsies taken at relatively early time points during chronic GVHD,
areas of microvascular endothelial proliferation were present, whereas dur-
ing later time points microvessel loss prevailed
[29]
. Furthermore it was
demonstrated that the number of circulating endothelial progenitor cells
(EPCs) is decreased during chronic GVHD, suggesting that neovasculariza-
tion may be reduced during chronic GVHD
[30]
. In summary these studies
in preclinical models, as well as in humans, demonstrate that GVHD is asso-
ciated with damage of host ECs by donor T cells.
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