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transplantation, in particular the severity of GVHD. However, studies have
also demonstrated that non-HLA genes associated with immune func-
tion are also involved in determining clinical outcomes after transplan-
tation
[105]
. In this regard, single-nucleotide polymorphisms (SNPs) in
genes involved in the allogeneic immune response and the amplification
of inflammatory reactions have been identified as additional predictive
markers for the severity of GVHD. For example, polymorphisms of cytokine
genes including TNF-α, IL-10, IFN-γ, and IL-6 are associated with more
severe acute GVHD
[106-108]
. The potential role of Th17 cells in the patho-
physiology of GVHD has been studied by examining the SNPs of cytokines
that are crucial for Th17 differentiation and expansion. A polymorphism in
the promoter region of the IL-17 gene that is the result of an SNP rs2275913
(G197A) has been reported to be associated with susceptibility to rheu-
matoid arthritis
[109]
and ulcerative colitis
[110]
. Espinoza and colleagues
[111]
examined the impact of IL-17 gene polymorphism in a total of 510
recipients with hematologic malignancies and their unrelated donors on
GVHD in HLA-matched myeloablative and nonmyeloablative BMT. They
found that the 197A allele in the recipient was associated with an increased
incidence of acute GVHD (
Table 13.1
). A subsequent report also demon-
strated that the donor IL-17 197A allele was associated with a higher risk
of GVHD after unrelated fully HLA-matched BMT
[112]
. Peripheral blood
mononuclear cells (PBMCs) that were 197A allele- positive produced sig-
nificantly more IL-17 than 197A allele-negative PBMCs upon
in vitro
stimu-
lation, implying that the high production of IL-17 might be associated with
the development of acute GVHD. Furthermore, the 197A allele displayed
a higher affinity for nuclear factor-activated T cells, a critical transcription
factor involved in IL-17 regulation.
287
IL-23 is a key regulator of inflammation and influences the survival and/
or expansion of Th17 cells
in vivo,
and previous studies have demonstrated
that variants in the gene coding for IL-23R are strongly associated with
Table 13.1
IL-17 and IL-23R Single-Nucleotide Polymorphisms and Risk of GVHD
Single-Nucleotide
Polymorphism
Donor/Recipient
Histocompatibility
Study (reference)
No. of Patients
Comment
Espinoza et al.
[111]
IL-17 G197A (recipient)
510
URD
Increased incidence of acute
GVHD
Espinoza et al.
[112]
IL-17 G197A (donor)
438
URD
Increased incidence of acute
GVHD
Elmaagacli et al.
[114]
IL-23R 1142G
→
A (donor)
407
MSD, URD
Decreased incidence of acute
GVHD, decreased TRM, no
difference in survival
Gruhn et al.
[115]
IL-23R 1142G
→
A (donor)
231
MSD, URD, MMD
Decreased incidence of acute
GVHD, no difference in survival
Wermke et al.
[116]
IL-23R 1142G
→
A (donor)
304
MSD, URD
Decreased incidence of acute
GVHD, no difference in survival
Nguyen et al.
[117]
IL-23R 1142G
→
A (donor)
390
URD
No difference in acute GVHD or
survival
Abbreviations: URD, unrelated donor; MSD, HLA-identical sibling donor; MMD, mismatched family donor; TRM, transplant-related mortality.
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