The endothelium in graft-versushost disease and graft-versusleukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 477

A study by Luft et al [31] . highlights the role of the endothelium in GVHD
refractory to immunosuppressive treatment by measuring markers of endo-
thelial dysfunction in the serum of patients with steroid-refractory GVHD.
Severe refractory GVHD was associated with increased levels of angiopo-
etin-2 (ANG2), which is involved in the detachment of pericytes and loosen-
ing of the matrix, as well as in the recruitment of myeloid cells. Interestingly,
ANG2 levels were already elevated before allo-HSCT in patients with ste-
roid-refractory GVHD [31] . These results suggest that EC vulnerability and
dysfunction may be critical to the pathophysiology of GVHD that progresses
despite intensive immunosuppression.

Antigen presentation and T-cell activation by
endothelial cells during GVHD

There is increasing evidence highlighting the importance of ECs for
antigen presentation and alloactivation during GVHD. Early after allo-
HSCT allogeneic donor T cells primarily interact with circulating hema-
topoietic host antigen-presenting cells (APCs) and with host ECs. If host
hematopoietic APCs, such as dendritic cells, persist after radiation and/
or chemotherapy they may play an important role in the alloactivation
of donor T cells [32] . However, in the clinical situation after allo-HSCT,
host dendritic cells may not be the most important APCs because they
are very sensitive to both radiation and chemotherapy. The sensitivity to
the conditioning regimen results in low numbers of circulating dendritic
cells in peripheral blood in the early phase after allo-HSCT [33,34] . Of
note, host hematopoietic APCs are not required for activation of donor
T cells because ECs are able to present antigens to T cells potently. Vas-
cularized cardiac allografts can be rejected via direct allorecognition
mediated by CD8 + T cells in the absence of antigen presentation by hema-
topoietic cells [35] . Similar to dendritic cells, ECs present antigens to
T cells through cross-presentation [36] . Cross-presentation by ECs is a fast
and efficient process that results in the loading of major histocompati-
bility complex (MHC) class I molecules with exogenous antigens. Inter-
estingly ECs need only relatively low antigen concentrations (≤1 nM) for
cross-presentation, while macrophages and dendritic cells require higher
antigen concentrations (≥20 μM) [36] . Antigen presentation by ECs to cir-
culating CD4 + effector T cells may also initiate transendothelial migration
and inflammation in peripheral tissues [37] . Taken together these results
demonstrate that host ECs exhibit important functions as APCs during
alloactivation of donor T cells in the HLA-mismatched setting. However,
the efficacy of T-cell activation by ECs in HLA-matched allo-HSCT is sub-
ject to further scientific debate, as preclinical models showed that CD8 +
T-cell responses against minor antigens were not initiated by ECs in the
absence of dendritic cells [38] .

483

Neovascularization during GVHD

Endothelial damage by the conditioning regimen is likely to contribute to
the initiation of processes that result in neovascularization and inflamma-
tion characterizing GVHD ( Figure 20.1 ). It was discovered more than 40 years