Chemokines and graft-versus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 407

that did not overexpress CXCR3. Importantly, these effects were associated
with significantly reduced GVHD in the liver, lung, and intestine.

Collectively, these studies suggest a paradigm for the function of chemo-
kine receptors in the migration of Tregs. Migration to lymphoid tissue is
important in the function of regulatory T cells. However, it appears that
after conditioning therapy, lymphopenic-driven expansion of donor Tregs
may allow for their migration to lymphoid tissue in the absence of critically
important chemokine receptors such as CCR7. Furthermore, an important
longitudinal role for CCR7 is suggested, in that Tregs lacking CCR7 over time
cannot protect against a syndrome that appears similar to chronic GVHD.
This would suggest that persistent blockade of CCR7 may be problematic as
a means to decrease effector T cell function. However, short-term blockade
(1-2 months) may not mediate substantial inflammation. Published data
also suggest that optimal protection from GVHD may require the migration
of Tregs directly to target organs. In sum, there is still much that we need to
learn regarding the function of migratory proteins in the function of Tregs
during GVHD.

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TISSUE-SPECIFIC HOMING

The potential roles of other chemokine receptor:ligand interactions in the
development of GVHD, and particularly those involved in tissue-selective
trafficking of memory and effector T cells, deserve mention. Interactions
between CCR9 and CCL25 (TECK) are unique in that outside of the thy-
mus, they specifically contribute to intestinal homing of T cells. CCR9 is
expressed at high levels by essentially all lymphocytes in the small intes-
tine [91] , whereas lymphocytes from other secondary lymphoid and non-
lymphoid tissues are universally CCR9 negative [51] . CCL25 is selectively
expressed by endothelial cells of gut-associated tissues and, via CCR9,
attracts a subset of intestinal (α4β7 hi ) memory cells but not cutaneous or
other systemic memory cells [92] . In this context, Inamoto and colleagues
recently evaluated the impact a single-nucleotide polymorphism (SNP) in
the CCR9 gene of HCT donors had on the incidence of GVHD [93] . The SNP,
rs1272497, which codes for a G-to-A change at position 926, was evaluated
in 186 consecutive patients transplanted in Nagoya First Hospital using an
HLA-matched sibling donor over a 20-year period. Unfortunately, only 10
(6%) donors had the 926AG genotype and frequencies for the other alleles
were 926AA (94%) and 926GG (0%). Surprisingly, the 926AG genotype was
not associated with grade II-IV GVHD overall, or disease in other target tis-
sues, but did significantly associate with acute stage II-IV skin GVHD (haz-
ard ratio of 3.2) and chronic GVHD (cGVHD; hazard ratio of 4.1). In vitro
evaluations demonstrated that CCR9-926G-expressing cells migrated more
robustly to CCL25 compared to CCR9-926A cells.

Similarly, T-cell homing to the skin involves a variety of chemokine
receptor:ligand interactions including CCL17 (TARC, or thymus- and activa-
tion-regulated chemokine) and CCL22 (MDC, or macrophage-derived che-
mokine), which bind to CCR4, and CCL27 (CTACK), which binds to CCR10.
Faaij and colleagues [94] evaluated the function of the CCL27/CCR10 path-
way in the pathogenesis of acute GVHD in pediatric patients. Fifteen of 23
patients analyzed developed skin GVHD [94] . When chemokine receptor