Chemokines and graft-versus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 409

expression of CCL17, CCL18, CCL27, and CCR2 was observed. Immunostain-
ing revealed that dendritic-like cells and endothelial cells generated CXCL9,
while conjunctival epithelial cells appeared to be the source of the majority
of CXCL10. CXCR3 was expressed by all leukocytes infiltrating the conjunc-
tivae, suggesting that CXCR3 receptor:ligand interactions are operative dur-
ing the development of chronic, conjunctival GVHD. Arpinati and colleagues
[100] evaluated chemokine receptor expression on myeloid cells from HCT
recipients. They found that, compared to controls, patients with cGVHD had
a greater number of monocytes in the bone marrow and peripheral blood
and had an increased expression of CXCR4 [100] . Finally, a retrospective
patient study carried out by Kim et al. [101] showed that an SNP in the CCL5
promoter gene of HCT recipients was associated with a higher incidence and
severity of cGVHD. Correspondingly, Morita et al. suggested a role for CCR5
expression on lymphocytes in the development of cGVHD of the skin [102] .

Chemokines and GVT responses

Allogeneic HCT is used extensively in the treatment of hematologic malig-
nancies. While GVHD remains a significant cause of morbidity following
allogeneic HCT, relapse from the original malignancy remains a serious con-
cern. The therapeutic potential of allogeneic HCT resides in the presence
of GVT effects, which are closely linked to acute GVHD. Not surprisingly,
chemokines have been shown to play a role in tumorigenesis and these
interactions must be taken into consideration when attempting to clini-
cally exploit the actions of chemokines after HCT. In particular, chemokines
are known to play a significant role in tumor angiogenesis ( Table 17.2 ), and
chemokine neutralization strategies have been used in an attempt to gen-
erate anti-tumor effects. It is therefore attractive to envision an approach
wherein the neutralization of select chemokine receptor:ligand interactions

414

Table 17.2 Selected Chemokines and Possible Roles in Cancer and GVT

Chemokine Receptor Possible Role in Cancer and GVT

CC family

CCL1 CCR8 Induction of tumor immune response

CCL2 CCR2 Angiogenesis

CCL5 CCR1, 3, 5 Promotion of late stage of tumor growth

CCL11 CCR3 Angiogenesis

CCL21 CCR7, CXCR3 Promotion of anti-tumor immunity

CXC family

CXCL1 CXCR2 Angiogenesis

CXCL2 CXCR2 Autocrine tumor growth factor

CXCL4 Unknown Inhibition of angiogenesis

CXCL8 CXCR1 Angiogenesis

CXCL9 Promotion of tumor immune response

CXCL10 CXCR3 Inhibition of angiogenesis

CXCL12 CXCR4 Angiogenesis, inhibition of immune function,

promotion of metastasis