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Perhaps the best characterized and most popular regulatory T cells are a
subset of CD4
+
T cells expressing the IL-2 receptor α-chain (CD25) and the
transcription factor forkhead box P3 (FoxP3)
[43]
. It has been demonstrated
by several groups that the adoptive transfer of Treg with conventional T cells
(Tcon) at equal numbers can control GVHD, while allowing GVL reactions
[44-47]
. Bioluminescence revealed both suppression of
luc
+
Tcon prolifera-
tion and clearance of
luc
+
tumors
[44]
. The mechanism responsible for how
GVHD can be suppressed without impacting GVL appears to be due to the
suppression of proliferation by the Treg without impacting activation of the
Tcon which lysed tumor cells through a perforin/granzyme mediated mech-
nanism. Therefore, under conditions where the tumor load is relatively low
and the T-cell precursor frequency for tumor reactive T cells is high, GVT
can be preserved. These conditions exist following allogeneic HCT.
BLI analysis of the
in vivo
dynamics of
luc
+
Tregs following allogeneic
transplantation has revealed many interesting findings about this regula-
tory cell and its ability to control graft-versus-host reactions
[48]
. A robust
expansion of
luc
+
CD4
+
CD25
+
Tregs in lymphoid organs was observed fol-
lowed by a migration to GVHD target tissues in parallel to CD4
+
CD25
-
T
cells. However, in contrast to CD4
+
CD25
−
T cells, Treg signals did not reach
levels as high as CD4
+
CD25
−
T cells, nor did they persist for as long. Expan-
sion of Tregs was enhanced by both an allogeneic environment and con-
ditioning irradiation. In this allogeneic, conditioned model, Tcon did not
affect the proliferation of the Treg, indicating that host APCs and the pro-
inflammatory environment following irradiation were sufficient to provide
the required signals and costimulatory molecules to Treg including CD30L
[49]
and IL-2. However, when irradiation was not provided, and Tregs were
transferred into Rag2
−/−
gamma chain(γC)
−/−
mice, either exogenous IL-2
or a co-transfer of conventional T cells (Tcon) was required for Treg expan-
sion (Vu H Nguyen, unpublished data); this suggests that Tcon can pro-
vide the requisite simulation for Treg expansion. Treg caused a pronounced
reduction in early Tcon expansion, indicating that Tregs can exert their
suppressive function in secondary lymphoid organs. Tregs also co-local-
ized with Tcon in both lymphoid and non-lymphoid tissues which suggests
that their mechanism may involve dendritic cells (DCs) in priming sites,
as previously reported
[50,51]
and/or inhibiting the ongoing expansion of
Tcon in other tissues by other mechanisms, possibly involving molecules
such as TGF-β
[52-54]
. Finally, this study indicates that an effective strategy
to deal with the relative paucity of Tregs is to infuse Treg earlier than Tcon.
Early administration provided the greatest protection against GVHD as
Tregs were able to localize and proliferate before Tcon infusion. By inject-
ing Treg 2 days prior to Tcon, a nearly physiologic ratio of Treg to Tcon of
1:10 protected allogeneic recipients from GVHD without limiting the GVL
capabilities of the Tcon. This approach has been explored clinically with
encouraging early results in patients undergoing haploidentical transplan-
tation. Here, the dose of Tcon that was infused (up to 2 × 10
6
/kg) in the
absence of immunosuppressive mediations is much more than can be tol-
erated, but did not result in a high risk of GVHD when Treg was infused 2
days prior to the Tcon
[55]
.
65
An alternative approach is to expand Treg
ex vivo
. A number of groups have
explored how best to expand Treg. Taylor et al. evaluated several different
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