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male specific H-Y antigens as an independent risk factor for GVHD in the
HLA-matched setting
[61,62]
. Subsequent studies also showed the associa-
tion of sex-mismatched allo-SCT with GVT responses in leukemia and mul-
tiple myeloma patients
[60,63-65]
. In earlier studies, some of the autosomal
mHag-specific CTLs have been used to type the recipient-and-donor pairs
for mHags in retrospective clinical cohorts. One of these studies demon-
strated a statistical association between the mHag HA-1 and GVHD in adults
[66]
. Subsequently, with the development of genetic typing technologies,
the association between HA-1 and GVHD has been (inconsistently) dem-
onstrated in independent clinical cohorts
[67-69]
. The association of mHag
HA-1 with GVHD is now generally attributed to the presence of host APCs
after SCT, since HA-1 is not expressed in GVHD target organs (see below).
A number of cohorts has also evaluated the impact of individual mHags on
GVT but revealed negative results probably due to the fact that the cohorts
were small and biased by the inclusion of different types of hematological
malignancies
[69,70]
. To avoid such problems, a recent study analyzed the
impact of HA-1 in a large cohort of CML patients. This study for the first time
showed the significant association of HA-1 mismatches with GVT but only
in patients who developed GVHD, suggesting a role for GVHD to drive HA-1-
associated GVT effects in HA-1 mismatched allo-SCT settings
[71]
.
43
To match or to mismatch: paradigm shifts in the
mHag field
Since GVHD occurs due to mHag mismatches in the HLA-identical allo-SCT
setting, one may postulate that GVHD can be eliminated by matching patients
and donors for mHags. However, increased knowledge of the role of mHags in
SCT indicates that this may not be an appropriate strategy because of the risk
of abrogation of the therapeutic GVT effect. Moreover, increasing knowledge
on genetic polymorphisms indicates that matching for mHags is not feasible:
it is estimated that there are more than 90 000 nsSNPs (non-synonymous
single nuclear polymorphisms) in the human genome which may potentially
give rise to mHags
[72]
. In a recent analysis, >10 000 nsSNPs were identi-
fied in a single person, of which 15-20% were rare in the human population
[73]
. Consequently, theoretically each HLA-identical donor-recipient pair is
expected to be mismatched for a large number of mHags. Next to the techni-
cal challenges of typing each patient and potential donors for all mHags, it
seems impossible to find a fully mHag-matched donor for each patient, in
the view of the limited number of available HLA-compatible donors. Thus
mismatching for mHags is not only a highly hypothetical option, but also an
incorrect strategy, because research over the past two decades identified a
set of mHags that is specifically associated with GVT responses. As outlined
below, mismatching for such relevant mHags offers unprecedented oppor-
tunities to boost the GVT effect without increasing the risk of GVHD.
Hematopoietic mHags: ideal targets for separating
GVT from GVHD
Since the therapeutic GVT effects caused by mHag disparities are highly
associated with GVHD, mHags were for a long time considered as “double
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