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GIT. Neither group could demonstrate IL-17A-expressing cells in the skin
or GIT using either
ex vivo
stimulation and flow cytometric assays or
immunohistochemical methods
[166,167]
. The studies of IL-17 in human
GVHD remain extremely limited at this time, with small sample sizes and
limited clinical contexts, and further work is needed to clarify its role in
the coming years.
In addition to assessing the presence of the cytokine itself, the gene
expression of IL-17 has been assessed by a number of groups interested
in SNP profiles and their role in GVHD/GVL. The IL-17 promoter poly-
morphism (197A type) leads to higher IL-17 production by PBMC and is
correlated with worse aGVHD survival
[168]
. Patients in this study were
followed only to day 140, however, so long-term outcomes are not clear
as yet. IL-23 has also been studied from a genetic point of view and a
strong association between an SNP present in the IL-23R and Crohn's
disease (G to A substitution at position 1142, leading to the substitution
of a glycine in place of an arginine residue), and this polymorphism was
subsequently examined in a 221-patient cohort of transplant recipients
and their HLA-identical donors
[169]
. Interestingly, grade III-IV aGVHD
was found less frequently in recipients transplanted with donor cells
with the IL-23R SNP (22% versus 4%). In a subsequent cohort, patients
transplanted with donors possessing the IL-23R SNP had a significant
decrease in grade III-IV aGVHD compared with those receiving donor
cells with the wild-type gene (3.8% versus 25.5%), but they did not report
a benefit in overall mortality. Subsequent studies by different groups
have reported differing results, with a decrease in overall GVHD seen,
but no change in severe GVHD
[170]
reported in one study, and no asso-
ciation between gene expression and either GVHD incidence or sever-
ity seen in another study
[171]
. Given these promising, yet conflicting,
results, it remains unclear from an SNP point of view whether IL-17 and
IL-23 genetic signatures are truly biomarkers for GVHD, and this remains
to be clarified.
376
IL-21
IL-21, like IL-2, is a member of the common-γ-chain family of cytokines and
is produced predominantly by CD4
+
T cells and NKTs (reviewed in
[172]
).
IL-21 has a broad range of functions and can have an impact on the prolifer-
ation, differentiation, and effector functions of B, T, NK, and DCs. It can also
act as a proapoptotic factor, thus contributing to AICD. As well as these acti-
vating properties, it is also a strong inducer of IL-10 and therefore has the
capacity to take on a regulatory role depending on the surrounding cyto-
kine milieu. The functional receptor for IL-21 is the unique IL-21R molecule
coupled with the γ
c
[173,174]
. The IL-21R is expressed in lymphoid tissues,
including spleen, thymus, and peripheral blood cells
[175,176]
.
IL-21R activates the JAK/STAT family of signal transducers upon ligand
binding, and signal transduction has been demonstrated to have strong
anti-tumor activity due to its stimulatory effect on NK and CD8
+
T cells.
Several studies have now demonstrated that IL-21 has an important patho-
genic role in GVHD, using both IL-21R-deficient animals and specific
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