Biology Reference
In-Depth Information
edged swords”. However, this general opinion has undergone a revolution-
ary revision after the discovery that some mHags show tissue-restricted
expression: employing
in vitro
assays, de Bueger et al. demonstrated that
several mHag-specific CTLs display cytotoxic activity toward a wide range
of target cells including hematopoietic cells and non-hematopoietic cells
such as skin fibroblasts, keratinocytes and vascular epithelial cells. In con-
trast, CTLs directed against mHag HA-1 and HA-2 exclusively lysed hema-
topoietic cells
[74]
. This illustrated for the first time that the expression of
these antigens was restricted to the hematopoietic cell lineage. These obser-
vations raised the possibility that such hematopoietic mHags are exclu-
sively involved in the development of GVT effect but not GVHD. Consistent
with this idea, HA-1 (and HA-2) specific CTLs were subsequently shown to
lyse malignant hematopoietic cells and inhibited the outgrowth of malig-
nant precursors but failed to induce GVH reactions in an
in situ
skin explant
assay system
[75,76]
. After the molecular identification of HA-1 and HA-2
[31,32]
, their strictly hematopoietic-specific expression was also confirmed
at gene expression level
[55,77]
.
The discovery of hematopoietic mHags and their involvement in the effec-
tive lysis of malignant cells caused a fundamental shift in the general think-
ing about mHags and laid the basis of a novel immunotherapy concept,
which proposes exploiting (deliberate) mHag mismatches to separate GVT
from GVHD
[78]
. According to this concept, targeting the T cells of the
mHag-negative donor toward the recipient's hematopoietic mHags will
evoke a specific GVT effect without causing detrimental immunity to the
non-hematopoietic target organs of GVHD. This therapy will also spare the
normal hematopoiesis as the hematopoietic cells are derived from the stem
cells of the donor after transplantation. This original mHag-based immu-
notherapy concept is developed for hematological malignancies. There is
however a possibility of also extending this concept to some solid tumors,
because a number of hematopoietic-mHags, such as the HA-1, ACC-1,
ACC-2 and LRH-1, are aberrantly expressed on solid epithelial tumors of
various origin
[79-81]
.
44
The possibility of exploiting hematopoietic mHags for immunotherapy
gave a boost for the identification of new hematopoietic mHags. Over the
past 15 years, eight more mHags, namely the HB-1, PANE-1, ACC-1, ACC-2,
ACC-6, LRH-1, HEATR1 and most recently the UTA2-1 have been described
as strictly hematopoietic mHags recognized by CD8
+
HLA class I-restricted
CTLs (
Table 3.1
)
[35,39,43,44,50,54,82]
. The polymorphic HA-1 peptide has
been shown to be presented by three different HLA molecules - HLA-A*0201
[32]
, HLA-A*0206
[83]
and HLA-B*60 - though the peptide presented by the
HLA-B60 molecule is a shifted form of the peptide presented by HLA-A*02
[36]
. Further, HB-1 and ACC-1 are bilaterally immunogenic. Tissue distribu-
tion of these hematopoietic mHags is somewhat heterogenic: while HA-1,
HA-2, LRH-1, ACC-1, ACC2 and UTA2-1 are expressed in all myeloid and lym-
phoid malignancies
[39,43,55,79]
, ACC-6 is abundantly expressed in acute
myeloid leukemia and multiple myeloma cells
[54]
. HEATR1 was shown
in AML cells and their precursors
[50]
; PANE-1 is preferentially expressed
in the B-cell lineage
[44]
and the HB-1 was described as an acute B-lym-
phoblastoid-leukemia specific mHag
[82]
. In addition, SP110 was shown to
have a specific expression in hematopoietic cells under non-inflammatory
Search WWH ::
Custom Search