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status, age of recipient and disease status). The only factor that remained
statistically significant was the HLA-G 14-bp ins/ins genotype. Given the
potential effect of MTX on HCT outcome in the context of HLA-G poly-
morphism
[105]
, the subgroup who received this drug for acute GVHD
prophylaxis (
n
= 144) was re-analyzed. No change was found in the above-
mentioned association, which was strengthened despite a reduction in the
sample size. These findings are in line with the data published in different
clinical settings including gestational complications, auto-immunity, infec-
tions, cancers, as well as solid organ transplantation
[107]
. The ins/del poly-
morphic variation in HLA-G seems to influence the RNA splicing stability
by mechanisms that are yet to be understood. The presence of the 14-bp
insertion introduces an additional splice site which results in the removal
of the first 92 bp of exon 8 thereby generating more stable HLA-G mRNAs
species than the complete mRNA
[108-110]
. In fact, the 3′ UTR 14-bp inser-
tion has been consistently associated with low expression of HLA-G mRNA
and low serum sHLA-G
[19,20]
. Such a discrepancy between stability and
output, termed “the 14-bp polymorphism paradox”, predicts complex
mechanisms of regulation of HLA-G expression. Recent studies implicate
the potential role of microRNAs which, by interacting with the HLA-G 3′
mRNA region, may regulate its phenotypic expression
[111,112]
. Indeed,
the observed effect of the insertion allele on acute GVHD could be either
due to a haplotypic effect or due to another yet to be identified linked func-
tional variant. A recent study associated the 14-bp ins/+3142G/+3187A hap-
lotype with the risk to develop pre-eclampsia
[107]
. Data on the effect of
the insertion allele in the incidence of acute GVHD is internally consistent
with the concept that downregulated expression of HLA-G molecules could
decrease immunosuppressive/tolerogenic properties that consequently
result in the development of acute GVHD. The data are also in concordance
with those showing that high pre- and post-transplantation levels of sHLA-
G molecules correlate not only with a decreased incidence of acute GVHD
but also with a high frequency of circulating Tregs. Similar correlation
between sHLA-G and Treg cells was also observed in
in vitro
mixed leuko-
cyte reaction assay
[113]
, in the context of liver transplantation
[114]
and in
the transgenic murine model system
[115]
. These findings are also in agree-
ment with the majority of expression studies of HLA-G in solid organ trans-
plantation that show beneficial effects of HLA-G molecules and lowered
acute rejection/chronic dysfunction of the transplanted heart and kidney
[116,117]
and also with those establishing correlations between the pres-
ence of the HLA-G 14-bp ins allele and organ rejection
[118-120]
. HCT is a
sensitive
in vivo
setting capable of revealing fine immune response traits,
undetectable in physiological situations. This may be a plausible reason
why the effect of the ins/ins HLA-G genotype on conferring low immune
tolerance has been uncovered.
31
MIC genes in HCT-GVH
The functional implications of the MICA 129 dimorphism have been inves-
tigated in many clinical settings including transplantation. In a cohort of
211 consecutive patients who underwent non-T-cell-depleted allogenic
HCT in a single institution from HLA identical siblings
[121]
, MICA 129
genotyping (val/met) revealed that a recipient MICA 129 val/val genotype is
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