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of mHags, HB-1 and ACC-1 for instance, both allelic peptides are bilaterally
expressed on the cell surface and can be differentially recognized by the
T cells of mHag-negative individuals
[35,39]
. For a majority of HLA class
I restricted mHags, however, the aa substitution hinders the cell surface
expression of the allelic peptide by either negatively influencing the intra-
cellular cleavage of the peptide from the whole protein
[40]
, or by disturbing
the translocation of the cleaved peptide into the ER
[52]
or by abrogating the
(stable) binding of the peptide to the HLA molecule
[53]
. Beyond aa subs-
titutions, the mHag difference between the donor and recipient can also be
generated by non-coding SNPs causing a frame-shift
[43]
, stop codon
[44]
,
or even an alternative RNA splicing
[54]
. Occasionally, mHags are also gen-
erated by the deletion of a whole gene in some individuals
[38]
or by splicing
of non-contiguous peptides in the reverse order
[45]
. Thus, for many HLA
class-I restricted mHags identified to date, their disparities appear to be the
result of a “functional null allele”, whereby only the immunogenic peptide
is presented on the cell surface in the context of MHC molecules. Currently
it is not known whether this also applies for HLA class II restricted mHags.
Since not all mHag-specific T cell receptors (TCR) are able to discriminate
single aa differences
[55]
, it may be possible that differential surface expres-
sion of allelic peptides is a frequent requirement, rather than a coincidence,
for the generation of mHags. Systematic investigation of this intriguing pos-
sibility is relevant since a requirement for a “null allelism” will significantly
reduce the number of SNPs that can become immunogenic mHags.
42
The impact of individual mHags on GVHD and GVT
The relative ease of isolating mHag-specific T cells at the time of GVHD and
effective clinical responses represent the first indirect experimental observa-
tion suggesting a role for mHags in GVHD and GVT. Functional analyses of
these T cells provided further support for the involvement of mHags in GVT:
virtually all mHag-specific CD4
+
and CD8
+
CTLs evaluated so far are able to
lyse the malignant cells from mHag
+
patients with leukemia, lymphoma and
myeloma. In addition, a number of mHag-specific CTLs were also shown
to inhibit the outgrowth of clonogeneic malignant precursor cells
in vitro
.
Furthermore, so far all
in vivo
evaluations of mHag-specific CD4
+
and CD8
+
CTLs for anti-tumor activities revealed strong
in vivo
GVT effects against
lymphoblastoid leukemic cell lines, myeloma cells and even against mHag-
positive solid tumor cell lines in appropriate
in vitro
and
in vivo
GVT models.
Starting from the mid-1990s, the novel technical tool, dimeric or tetrameric
HLA/peptide molecules, have been increasingly used to detect mHag-spe-
cific T cells directly in longitudinally collected blood samples of patients
after allo-SCT or donor lymphocyte infusions (DLIs)
[43,51,56-60]
. These
analyses substantiated the possible involvement of mHags such as H-Y and
HA-1 in GVHD and HA-1, HA-2, ACC-1, LRH-1, UTA2-1 in GVT by demon-
strating the time-dependent correlation between the clinical manifestation
of GVHD and/or GVT and the expansion of mHag-specific CTLs in the cir-
culation after allo-SCT or DLIs.
Apart from
in vitro
studies, the correlation between individual mHags, GVHD
and GVT has also been evaluated in clinical cohorts. Studies in the mid-1980s
identified female-to-male SCT, which is related to allo-immunity toward
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