Chemokines and graft-versus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 408

expression was analyzed from T cells collected in the peripheral blood, no
differences in the expression of CCR4 or CCR8 on CD8 + T cells were detected.
However, a significant increase in the percentage of CD4 + T cells expressing
CCR10 in the bloodstream was observed in all patients with skin GVHD, and
the duration of cutaneous GVHD paralleled the increase in CCR10-express-
ing CD4 + T cells. A significant percentage of these T cells coexpressed the
cutaneous lymphoid antigen and CCR4 with little expression of CCR7 or
CD103, a gut-homing integrin. Immunohistochemical staining on biopsies
of skin GVHD revealed similar findings and also demonstrated increased
expression of CCL27 within the epidermis.

Th2 EFFECTOR CELLS AND THE DEVELOPMENT OF CHRONIC GVHD

This chapter has focused sharply on the role of Th1 effectors in the devel-
opment of acute GVHD. However, Th2 cells can also contribute to target
organ injury in the acute and chronic settings [95] . As noted above, Th1
cells preferentially express CCR5 and CXCR3, whereas CCR3, CCR4, and
CCR8 associate with Th2 and CCR6 with Th17 cells [15] . In particular, CCR3
is expressed on eosinophils, basophils, and polarized Th2 lymphocytes,
all of which are recruited to sites of allergic inflammation by the effects of
eotaxin. Eotaxin is believed to be one of the most relevant chemokines in the
pathophysiology of allergic conditions, but its expression is also increased
in the skin, liver, and lung during the induction of acute GVHD. However,
what role if any eotaxin plays in the recruitment of CCR3-expressing cells to
GVHD target organs, as well as potential roles in chronic GVHD, remains to
be determined.

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Studies on chemokines and their receptors in cGVHD are limited, perhaps
because of the heterogeneity of clinical disease and the lack of suitable
mouse models. However, fibrosis of the skin and other organs, one of the
key pathological findings of cGVHD, is reproducibly reflected in the sclero-
dermatous (Scl)-cGVHD mouse model [96] . Zhou et al. [97] analyzed mRNA
expression levels of chemokines and chemokine receptors in the skin of Scl-
cGVHD mice on day 7, 30, 60, and 120 after HCT. Measurable skin thick-
ening occurred after 3-5 weeks, and cytokine expression revealed a shift
toward a Th2 predominance during the course of skin fibrosis. Upregulated
chemokines included CCL2, CCL3, CCL5, and CCL7. In addition, the Th1-
associated IFN-γ-inducible chemokines CXCL9-11 and the Th2-associated
chemokines CCL17 and CCL22 were also increased. Another line of inves-
tigation demonstrated that analogs of SLC (CCRL21) block responses by
CCR7-expressing cells and reduce the autoimmune components of chronic
GVHD (host B-cell expansion, presence of anti-DNA antibodies) in an unir-
radiated murine model [98] . These data are suggestive that chemokine
antagonism may be of benefit in chronic GVHD.

A few studies have examined the role of chemokines in the development of
chronic GVHD from a clinical perspective. Westekemper and colleagues [99]
evaluated the expression of CXCR3 and its ligands in conjunctival biopsies
from 10 patients with chronic ocular GVHD and found marked increases
in the expression of CXCL9, CXCL10, and CXCL11 compared to controls.
There were no differences in the expression of CCL1, CCL2, or CXCL12 and
its receptor CXCR4 from these specimens, whereas a trend for increased