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In-Depth Information
tumors, the close interaction of tumor cells with the cells of the tumor
microenvironment induce several anti-apoptotic mechanisms in the tumor
cells, which leads to cell adhesion-mediated drug resistance
[119]
. It seems
conceivable that such immune resistance mechanisms are also functional
for T-cell or NK-cell-mediated cytotoxicity (
Figure 3.1
).
Controlling naturally existing and mHag-specific CD8
+
regulatory T cells
Murine and human studies have revealed that GVHD can be controlled by
naturally existing CD4
+
foxp3
+
regulatory T cells (Tregs), while these cells
seem to permit GVT responses
[120]
by as yet unknown mechanisms. The
existence and the impact of mHag-specific Tregs in allo-SCT has not yet
been investigated. Nonetheless, a recent analysis of peripheral blood from
three patients who received HA-1-mismatched renal transplants identified
a population of HA-1-specific CD8
+
T cells that displayed dim staining with
HLA-A2/HA-1 tetramers and suppressed the high avidity HA-1-specific
CTLs, which were also isolated from the same patients, in a TGF-α, IL-10 and
CTLA-4 dependent fashion
[121]
. Remarkably, the patients also displayed
HA-1
+
microchimerism, primarily in the T-cell and DC compartment.
These data demonstrated for the first time that mHag mismatches can also
induce mHag-specific Tregs in patients receiving mHag-mismatched trans-
plants. Subsequent analyses indicated that also healthy adults can harbor
mHag-specific, tetramer-dim CD8 Tregs
[115]
. Thus, the evaluation of
mHag-specific Tregs in the allo-SCT settings is more than just an academic
challenge, as proper control of such Tregs may have important implications
toward improvement of mHag-based immunotherapy as well as the suc-
cessful management of GVHD (
Figure 3.1
).
52
Concluding remarks
Over the past decades, the major impact of mHags as targets of GVHD and
GVT became evident. The scientific community is now looking forward
to the results of current and future clinical trials attempting to separate
GVT from GVHD by exploiting hematopoietic mHag as therapeutic tools.
The success of the mHag-specific therapy is probably also dependent on
tackling the important general issues of cellular immunotherapy includ-
ing proper homing and infiltration, long-term persistence and overcoming
immune suppressive and immune resistance mechanisms induced by the
tumor microenvironment.
References
[1] Thomas ED, Lochte Jr HL, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in
patients receiving radiation and chemotherapy. N Engl J Med 1957;257:491-6.
[2] van Bekkum DW, Vos O. Immunological aspects of homo- and heterologous bone
marrow transplantation in irradiated animals. J Cell Physiol Suppl 1957;50:139-56.
[3] Mathe G, Thomas ED, Ferrebee JW. The restoration of marrow function after lethal
irradiation in man: a review. Transplant Bull 1959;6:407-9.
[4] Dicke KA, van Bekkum DW. Allogeneic bone marrow transplantation after elimination
of immunocompetent cells by means of density gradient centrifugation. Transplant
Proc 1971;3:666-8.
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