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human mHags in GVHD and GVT could not be addressed in a direct experi-
mental way. Instead, pioneering studies in the mid-1970s demonstrated suc-
cessful isolation and
in vitro
culture of mHag-specific T-cell lines and clones
from the peripheral blood of patients after allo-SCT
[10]
. From then on, these
cellular reagents became the major and highly instrumental tools for revealing
the immunobiology, molecular identity, as well as the clinical impact of mHags.
Murine mHags, challenges for the human system
In mice, mHags were discovered after the observations of slow but definitive
rejection of grafts from MHC-identical mice strains
[11]
. While the explo-
ration of human mHags is mainly restricted to cellular tools isolated from
patients, well-defined mHag-mismatched mice strains are highly instrumen-
tal for the experimental exploration toward the fundamental immunobiology
of mHags and their impact in graft rejection, GVHD and GVT. Similar to the
human system, murine mHags are encoded by Y-chromosome linked genes
or bi-allelic autosomal genes
[12]
. Although the genetic polymorphisms are
expected to result in thousands of mHags, in the murine system the number
of mHags strikingly ranges from as little as two up to ten, depending on the
strain combination, indicating “immunodominance”. The mechanisms of
immunodominance can be different. For instance, the mHag H60, which is
derived from a ligand for the NKG2D receptor, is dominant over several other
mHags such as H4, H7, H13, H28 and HY due to a high naïve precursor cyto-
toxic T cell (CTL) frequency in the blood
[13]
. The high levels of naïve H60 T
cells are presumably due to the absence of a self-analog, because the H60
actually arises due to the deletion of the whole gene. On the other hand, the
mHag B6dom1 appears to dominate above other mHags by its strong affinity
for MHC which results in a competition for the APC surface
[14]
.
40
Although it is known that some human mHags, such as HA-1 and HA-2,
are very immunogenic, a genuine immunodominance of a human mHag
over others has not yet been demonstrated. The co-existence of CTLs
directed at more than 20 different mHags in an SCT recipient
[15]
suggests
that immunodominance, if it exists, is more difficult to demonstrate in the
human setting. Nonetheless, addressing immunodominance remains an
important issue in the human setting, since immunodominant mHags may
importantly determine the clinical outcome of transplantation.
In mice, both H60 and b6dom1 have been utilized to explore several impor-
tant aspects of immunotherapy. One of the most remarkable findings of the
last decade was the observation of strong GVT but absence of GVHD after
immunotherapy with CTLs specific for B6dom1, even though this antigen
is broadly expressed
[16]
. Recently, similar results were also observed using
H60-specific memory T cells (Tm) isolated from H60-vaccinated animals
[17]
. Upon adoptive transfer the H60-specific Tm cells underwent dramatic
in vivo
expansion that mediated an effective GVT but caused only a little
liver GVHD even when the H60 was ubiquitously expressed. In both models,
however, the broad expression of the mHag seems to reduce the GVT effect.
These remarkable results suggest that immunotherapy with a single broadly
expressed mHag may be sufficient to achieve an effective antitumor effect
but will not initiate GVHD. Furthermore both studies indicate the possibility
of overcoming technical problems of adoptive immunotherapy by isolating
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