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antiangiogenic therapy. Several inhibitors of neovascularization, including
anginex, endostatin, and angiostatin, were found to stimulate leukocyte-
vessel wall interactions and increase leukocyte infiltration in tumor tissues
[86]
. Dings, Mayo, and co-workers
[87]
used various solid-tumor mouse
models to show that the expression of endothelial adhesion molecules, as
well as T-cell infiltration in tumors, is very low early after adoptive T-cell
therapy. The authors found that the administration of various inhibitors of
neovascularization enhanced extravasation of immune cells to the tumor
tissue. The combination of angiostatic therapy and adoptive T-cell transfer
led to improved anti-tumor immune effects resulting in inhibition of tumor
growth
in vivo.
[87]
A third mechanism that could explain increased GVL effects due to inhi-
bition of neovascularization is the reduction of cancer-related systemic
immunosuppression as a result of antiangiogenic therapy. The close con-
nection of immunosuppression and angiogenesis has been demonstrated
by several groups and results support the view that the inhibition of neovas-
cularization potentially reduces cancer-induced immunosuppression by
various mechanisms, as reviewed by Motz and Coukos
[88]
. Data from our
own allo-HSCT mouse models, however, demonstrate not only increased
GVL effects, but also reduced GVHD as a result of the inhibition of neovas-
cularization. Our results suggest that reduced systemic immunosuppres-
sion might not be the main mechanism for enhanced GVL effects due to the
inhibition of neovascularization.
488
Conclusions and perspectives
There is an increasing body of evidence demonstrating that the endothe-
lium is involved in GVHD as well as GVL activity after allo-HSCT. Initially
endothelial activation and endothelial damage is caused by the condition-
ing regimen. Subsequently, recruitment of inflammatory cells and neo-
vascularization may occur, leading to the clinical manifestation of acute
GVHD. In the course of GVHD, the endothelium is targeted by alloreactive
donor T cells, resulting in destruction of blood vessels and vascular rarefac-
tion. Recent evidence shows that hematologic malignancies, which are the
most frequent indications for allo-HSCT, require neovascularization for
growth and survival. Therefore, the inhibition of neovascularization after
allo-HSCT is an interesting novel therapeutic approach with potential ben-
eficial effects on acute GVHD and tumor relapse after allo-HSCT. The first
animal studies demonstrated the feasibility and efficacy of the inhibition of
neovascularization to ameliorate acute GVHD and decrease tumor growth.
Future preclinical research should focus on finding the optimal substances
as well as the best timing to inhibit neovascularization after HSCT.
References
[1] Carreras E, Diaz-Ricart M. The role of the endothelium in the short-term complications
of hematopoietic SCT. Bone Marrow Transplant 2011;46:1495-502.
[2] Penack O, Socie G, van den Brink MR. The importance of neovascularization and its in-
hibition for allogeneic hematopoietic stem cell transplantation. Blood 2011;117:4181-9.
[3] Al-Lamki RS, Bradley JR, Pober JS. Endothelial cells in allograft rejection. Transplanta-
tion 2008;86:1340-8.
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