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effect on survival
[100]
, while in another study of 116 HLA-matched unre-
lated donor transplants, HLA-E polymorphism did not influence acute
GVHD, TRM or disease-free survival (DFS)
[101]
. The number of confound-
ing factors are likely to be higher in unrelated donor than in sibling HCT
and may very well explain the heterogeneous results in the two most recent
studies. Interestingly, combined data from siblings and unrelated donor
marrow transplants suggest a potential paradigm of an HLA-E*01:03 mol-
ecule that may present minor histocompatibility antigen (MiHA) peptides
inefficiently without inducing T-cell recognition, while HLA-E*01:01 dis-
plays a lower capacity to present nominal antigen from pathogens
[102]
.
More functionally integrated data is needed to elucidate and quantify the
impact of HLA-E on GVH and overall in HCT outcomes. In addition, identi-
fication in renal transplantation of anti-HLA-E antibodies that account for
non-donor-speciic antibodies (DSA) and correlate with lower graft survival
may well have to be taken into account in the near future in HCT
[103]
.
HLA-G in HCT-GVH
The pleiomorphic role in modulating immune responses justifies the inter-
est of studying the HLA-G system in HCT both at genetic and functional
pathophysiological levels. The first study of HLA-G in transplantation was
performed in 53 HLA-matched unrelated donor transplants for β thalas-
semia and found that the HLA-G 14-bp deletion polymorphism correlated
with acute GVHD. While the acute GVHD risk associated with the HLA-G
14-bp del/del genotype
[104]
appears to be in contradiction with the estab-
lished fact that the 14-bp del allele is associated with higher levels of sHLA-
G than the 14-bp ins allele, the mechanism leading to clinical acute GVHD
could however be different in the unrelated donor transplant situation.
Since the HLA-matched unrelated donor-recipient pairs are not identical
by descent, it could be possible that the HLA-G 14-bp del/del genotype may
reflect the MHC non-HLA haplotype disparity. More recently, an analysis of
47 transplant patients with a variety of hematological malignancies failed
to observe any significant association between the HLA-G 14-bp ins/del
polymorphism and acute GVHD
[105]
, but found that patients homozy-
gous for the 14-bp ins allele were characterized by lower survival rate and
disease-free survival. The authors related their findings to the possible rela-
tionship between HLA-G 14-bp dimorphism, methotrexate (MTX)-based
acute GVHD prophylaxis and HLA-G expression. In contrast, in a recent
series of 157 sibling pairs from a single institution, the HLA-G low expres-
sion genotype (ins/ins) was associated with severe acute GVHD
[106]
. In
this study, the donor-recipient sibling pairs were fully matched for HLA-G
genotypes with frequencies comparable to those previously reported. Uni-
variate analysis using competing risk showed that the homozygous state of
the HLA-G 14-bp ins/ins genotype was more prevalent among patients who
experienced acute GVHD (grade 0, versus II, III, IV), but failed to reach sta-
tistical significance (
p
= 0.06). Nevertheless, additional univariate analyses
after patient stratification based on acute GVHD severity (grade 0, I, II, ver-
sus III, IV) revealed a significant association between the HLA-G 14-bp ins/
ins genotype and severe acute GVHD (22% in HLA-G 14-bp ins/ins versus
6% in other;
p
= 0.008). These data were further confirmed using two differ-
ent multivariate analyses adjusted for confounding variables (gender, CMV
30
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