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female donors. Murine and human studies have shown that pregnancy is a
natural event to mutually immunize the mother and the fetus for mHags. In
mice this has been best illustrated by the priming of the mother against H-Y
antigens during carriage of a male offspring
[112]
. Also, in humans, CTLs
directed to the infant's paternal HY and autosomal mHags can be detected in
the blood of healthy mothers up to several decades after the last delivery
[113]
.
Interestingly, in such cases mothers also display detectable levels of microchi-
merism of child-derived cells. Likewise microchimerism from mother to child
also exists, and the evidence for immunization of the fetus by the mismatched
mHags of the mother has also been provided by the detection and isolation of
HA-1-specific CTLs from the cord blood of neonates who were mismatched for
HA-1 with their mothers
[114]
. Interestingly, the latter cells remain life-long in
the child's circulation
[115]
. Hence, in contrast to many inbred murine models
of allogeneic transplantation, allogeneic stem cell grafts from both adults as
well as cord blood may contain antigen experienced memory T cells specific
for mHags. Although the clinical consequences of this natural donor immuni-
zation against mHags is not well understood, it is conceivable that the chance
and the robustness of the mHag-specific T-cell response after allo-SCT may
depend on the mHag-immunization status of both the female and the male
donor, which may be an important issue from the viewpoint of immunother-
apy. For instance, it seems conceivable that natural immunization of the donor
against mHags may facilitate the
ex vivo
generation of mHag-specific CTLs for
therapeutic purposes. Furthermore, the natural immunization against mHags
in fully healthy individuals indicates that immunization against mHags is safe
and may provide an objective rationale for earlier proposed intended vaccina-
tion of donors with hematopoietic mHags prior to DLI
[116]
to increase the fre-
quency of CTLs specific for therapeutic mHags in the leukapheresis products.
Supporting this notion, in murine models bone marrow transplantation (BMT)
combined with immunotherapy using WT1 peptide vaccination of donors
induces more potent anti-tumor activity than either therapy alone
[117]
.
51
Reducing the tumor load
In addition to effector T-cell-related issues, the success of mHag-based
immunotherapy may be dependent on the condition of the patient. Clinical
studies indicate that DLI is most effective in a minimal residual disease situ-
ation
[118]
because a high tumor load is probably difficult to combat with
cellular immune therapy
[92-94]
. This is probably not only due to outnum-
bering of mHag-specific CTLs by tumor mass but also due to the cancer-
induced immunosuppressive environment, neovascularization-supported
tumor growth, and the reduced ability of CTLs to infiltrate the tumor-infil-
trative capacity of mHag CTLs
[92-94]
.
Overcoming immune escape and immune resistance
Similar to cellular immunotherapy with TAAs, the success of mHag-specific
therapies is largely dependent on the capability of mHag-specific CTLs in
infiltrating and killing the malignant cells and their precursors in the tumor
microenvironment, which it is becoming increasingly clear that it is immu-
nosuppressive
[90,91]
. Therefore, future strategies need to overcome the
tumor escape due to immunosuppressive factors generated by the microen-
vironment. Furthermore, in several hematological and non-hematological
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