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a risk factor for chronic GVHD (63% versus 45% at 3 years,
p
= 0.03). The data
were confirmed in multivariate analysis adjusted for confounding variables.
Because acute GVHD is a major risk factor for subsequent chronic GVHD,
acute GVHD was introduced as a time-dependent covariate in the multivar-
iate analysis model. This analysis confirmed that the risk conferred by the
MICA 129 val/val genotype is independent from acute GVHD. In an explor-
atory study of 236 URD transplants of which 73% of pairs were matched
for HLA 10/10 alleles (HLA A, B, C, DRB1, DQB1), MICA polymorphism was
assessed by sequence-based typing methods and MICA mismatching was
observed in 8.4%. A higher rate of grade II-IV acute GVHD was observed in
MICA disparate pairs (80% versus 40%,
p
= 0.003) irrespective of the degree
of HLA matching. Furthermore, the rate of gastrointestinal acute GVHD was
higher in MICA-mismatched patients (35% versus 17%,
p
= 0.5)
[122]
. These
results are reminiscent of the data obtained using the MHC block matching
technique, a DNA-based MHC matching approach that utilizes non-HLA
DNA polymorphisms in the MHC as markers of blocks of ancestral haplo-
types. Matching for the MHC beta block inclusive of MIC genes was found
to be beneficial over the classical HLA-B, C matching for survival in HCT
[89]
. In addition to MICA genetic polymorphism effects, additional MICA-
related phenotypic features could influence the outcome of HCT. An ele-
vated serum level of MICA was found to be associated with the incidence
of chronic GVHD while the presence of MICA antibodies before transplan-
tation was shown to confer protection against chronic GVHD
[121]
. The
inverse relationship between MICA antibodies and sMICA suggests an anti-
body-based neutralization of deleterious effects of sMICA. Therefore both
genotypes and phenotypes of MICA represent important integrated bio-
markers in HCT monitoring. One can speculate that the lower engagement
of NKG2D receptors by the weak binder MICA 129val allele could impair
the NK/cytotoxic T lymphocyte cell activation co-stimulation and possi-
bly skew Th1 towards Th2 and subsequent B-cell activation and antibody
production, two hallmarks of chronic GVHD pathogenesis. This is corrobo-
rated by the recent observation that sMICA-NKG2D engagement upregu-
lates INF-γ expression by CD56 bright NK cells and therefore contributes to
systemic inflammation, a feature of chronic GVHD
[106]
.
32
Conclusions
The assessment of the genetic risks associated with each locus of the
MHC provides critical information for implementing comprehensive pre-
transplant genetic assessment and matching to lower risks for patients, and
for developing algorithms for targeted GVHD prevention strategies in HCT.
A systems biology approach based on data from experimental and mod-
elling outcomes represents a forward-looking strategy in this field. Analy-
sis of the sequence, polymorphism, transcription and protein expression
profiles of MHC and of the three-dimensional structure of the histocom-
patibility antigens has enabled the elucidation of the structure-function
relationship using innovative experimental approaches and computational
tools. Gene expression profiling applied to an
in situ
skin explant model of
GVHD was recently used to identify new candidate genes for controlling the
risk of GVHD
[123]
. Hematopoietic cell transplantation is a unique model
with which to understand the complex and systemic effects of introducing
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