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of GVL/GVT effect and decreasing rates of graft failure. Strategies to do
this based on CD25 and/or CD69 positivity or with an agonistic antibody
to CD95 resulting in the selective activation-induced cell death of acti-
vated T cells have been developed and appear to prevent GVHD in mouse
models
[146,147]
. The use of post-transplantation high-dose cyclophos-
phamide to target proliferating alloreactive T cells
in vivo
has been inves-
tigated both in haploidentical and in HLA-matched transplants and as the
sole GVHD prophylaxis following myeloablative conditioning
[148,149]
.
In the latter setting, cyclophosphamide, 50 mg/kg/day on days 3 and 4
post-transplantation, resulted in rates of grade III-IV aGVHD and cGVHD
as low as 10%
[149]
. Memory T cells, on the other hand, have been shown
to cause less GVHD while exhibiting anti-tumor effects in mouse models.
This population of T cells could be targeted for positive selection within
a stem cell graft but this has not been explored in humans
[150,151]
. A
similar approach can potentially be explored to select for Tregs in the graft
to prevent GVHD, or for infusion to treat GVHD, but this has been dif-
ficult to accomplish in humans because of the inability to yield adequate
Treg numbers. Mechanisms for the
ex vivo
expansion of both alloantigen-
specific and nonspecific Treg cells have been developed, now making this
approach possible
[134,135]
.
317
The appreciation that the efficacy of ASCT lies largely in its immunologic
GVL/GVT effects allowed for the development of nonmyeloablative and
reduced-intensity conditioning approaches to transplant in which the con-
ditioning regimen serves as immunosuppression to prevent graft rejection
rather than to exert antineoplastic effects. The clinical result is often the
persistence of mixed chimerism of host and donor immune systems. With
time, the donor immune system achieves dominance, at which point the
desired GVL/GVT effect of this type of transplantation can be attained. This
type of transplantation and the ability to achieve mixed chimerism have
the potential to be effective in separating GVL/GVT from GVHD. The estab-
lishment of mixed chimerism indicates immunologic tolerance of the stem
cell donor; delayed administration of nontolerant donor lymphocytes is
successful because of a lack of a host-versus-graft effect. The result is the
achievement of full donor chimerism with a potent GVL/GVT response
facilitated by donor T-cell activation by host antigen-presenting cells that
remain at the time of DLI owing to a mixed chimeric state
[152,153]
. In
mouse models, this is not associated with GVHD, even across HLA barriers,
and this is thought to be a result of the resolution of inflammation in target
organs that occurs as a result of conditioning at the time of original trans-
plantation
[154,155]
. In these models, activated T cells do not migrate to
these target organs following delayed DLI after reduced-intensity transplan-
tation because of the absence of inflammatory signals in these tissues
[156]
.
Using T-cell-depleted grafts further minimizes GVHD in this model
[157]
.
In humans the protection against GVHD following reduced-intensity ASCT
and delayed DLI is not as complete as has been observed in mouse models,
perhaps owing to the deficiency in lymphoid recovery and increased rate of
infections with associated tissue inflammation and immune activation that
occurs in humans post-transplantation
[156]
.
Lastly, therapies targeting cytokines define an alternate approach to
achieving a separation of GVL/GVT and GVHD. Strategies include the
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