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autophagy-related genes, including beclin-1 gene expression, which was
required for realization of the antiapoptotic phenotype. Most importantly,
upon transfer of human rapamycin-resistant and apoptotic-resistant Th1
cells into immune-deficient murine hosts, such Th1 cells stably engrafted
and mediated lethal xenogeneic GVHD. In sum, these data indicate that
autophagy can be harnessed
ex vivo
for the manufacture of T cells with
enhanced function via attainment of an antiapoptotic phenotype
[88]
.
In light of this biology using
ex vivo
-manufactured RR-Th1 or RR-Th2 cells,
we have developed murine models of allograft engineering that seek to
provide a more favorable post-transplant Th1/Th2 balance. In the case of
transplantation therapy of malignancy, we reasoned that such a balance
would include representation of both Th1 effectors (for GVT mediation) and
Th2 effectors (for modulation of GVHD). Because unmanipulated donor T
cells primarily differentiate along a Th1 pathway
in vivo,
such a balance
may be induced through the augmentation of a T-cell-replete allograft with
donor Th2 cells. We have also evaluated whether it is possible to further
dissect GVT effects from GVHD by a sequential Th1 followed by Th2 strat-
egy that first incorporates unmanipulated donor T-cell infusion with sub-
sequent administration of Th2-polarized donor T cells. Along these lines,
using
ex vivo
-generated murine donor RR-Th2 cells, we found that Th2-
cell allograft augmentation or the strategy of delayed Th2-cell infusion can
yield a GVT effect with concomitant or sequential regulation of GVHD
[81]
.
In further studies, we found that the mechanism of manufactured donor
Th2-cell amelioration of established GVHD: (1) required Th2-cell secretion
of IL-4 and IL-10; (2) involved Th2-cell consumption of IL-2 that was oth-
erwise available for expansion and activation of alloreactive Th1/Tc1 cells;
and (3) involved modulation of host APCs
[89]
.
234
We have also found that donor Th2 and Tc2 cells can play an important role
in terms of reduced experimental graft rejection. Although clinical graft
rejection is relatively uncommon, the host-versus-graft reactivity (HVGR)
that forms a biologic basis of rejection represents a major barrier to the
broader and safer clinical application of allogeneic hematopoietic stem cell
transplantation, particularly in settings such as the aging cancer population,
the use of reduced-intensity conditioning regimens, and transplantation
across increased donor/host genetic disparity (see Chapter 5). In practice,
such HVGR is typically mitigated by the inclusion of unmanipulated donor
T cells in the allograft and by utilization of intensive preparative regimens;
however, these strategies to prevent rejection contribute to GVHD initia-
tion and contribute to transplant-related morbidity and mortality. As such,
investigators have attempted to define donor T-cell subsets that abrogate
HVGR with reduced GVHD; such investigations have focused primarily on
donor CD8
+
T cells (including donor Tc2 cells
[90]
) and CD4
+
Treg cells (see
Chapters 5 and 12).
We have recently identified a new pathway whereby donor Th2 cells prevent
marrow graft rejection, which we have characterized as a host anti-donor
Th1-driven response
[91]
. Several points can be derived from this line of
research. First, in this model of fully major histocompatibility complex-
disparate graft rejection, the capacity of
ex vivo
-generated donor T cells
to prevent graft rejection was associated with donor T-cell persistence
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