Biology Reference
In-Depth Information
There have been several studies which have examined the contribution of
cytokine-producing T cells to GVHD
[27,28]
. Although Th1 cells are thought
to be the primary inducers of GVHD, Th2 cells can also play a role
[29,30]
.
As Th17 cells were found to induce acute GVHD
[31]
, Iclozan et al. gener-
ated either Th1 or Th17 cells from naïve T cells with polarizing cultures for
5 days
[32]
. Through the use of BLI, they were able to clearly demonstrate
that even 2.5 × 10
5
Th17 cells resulted in more proliferation at early and late
time points than 1.0 ×10
6
Th1 cells. Th17 cells thus had a superior ability to
expand, survive and infiltrate tissues
in vivo
and are significant contribu-
tors to GVHD.
BLI has also elucidated an association between the loss of PD-L1 (B7-
H1) in promoting CD8
+
T-cell proliferation and exacerbating GVHD
[33]
.
PD-L1 is constitutively expressed on T cells
[34,35]
, while its ligand, PD-1,
becomes expressed after being induced by a proinflammatory environ-
ment containing cytokines such as TNF-α and INF-γ
[36-39]
. Thus, PD-L1
is upregulated on activated T cells, and through interaction with PD-1,
T cells are induced towards anergy and apoptosis
[35,40]
. If alloreactive
CD8
+
T cells were administered to wild-type recipients, BLI indicated a
single wave of proliferation; however, in PD-L1
−/−
recipients, CD8
+
T-cell
proliferation was more rapid, and included a second wave of proliferation
which resulted in the death of the mice
[33]
. These results suggest that
treatments to preserve or enhance PD-L1 expression by host tissues could
ameliorate GVHD.
64
Monitoring immunosuppressive therapy of GVHD
An approach to controlling GVHD has been to increase or enhance cell
populations capable of regulating immune reactions. One such popula-
tion of regulatory T cells are a CD1d-restricted population of T cells known
as NK1.1
+
T cells or NKT cells. NKT cells become relatively enriched after
a regimen of total lymphoid irradiation (TLI) and anti-thymocyte serum
(ATS), and, through the production of IL-4, can confer a resistance to ani-
mals against GVHD, such that 1000-fold more allogeneic donor cells can be
transferred without causing GVHD
[41]
. The use of NKT cells has also been
explored by adoptive cellular transfer in a mouse model of acute GVHD
[42]
.
In this study,
luc
+
NKT cells were observed to have a similar migration pat-
tern to conventional T cells (Tcon), however, they did not cause any GVHD
by themselves when administered at similar doses. NKT were highly effi-
cient in regulating GVHD even at very low cell numbers so that the NKT to
Tcon ratio was between 1:20 and 1:50. Surprisingly, BLI indicated that NKT
cells, in stark contrast to CD4
+
CD25
+
regulatory T cells (Treg), were not sig-
nificantly affecting the proliferation of Tcon. This indicates that NKT cells
have a different and novel mechanism(s) than those of regulatory T cells.
Analysis of cytokine production of Tcon indicates a significant reduction of
Th1-type cytokine production by Tcon in the presence of NKT cells, indicat-
ing that one possible mechanism of NKT-mediated suppression of GVHD
may be in re-directing Tcon towards a less inflammatory phenotype. NKT
cell treatment also correlated with an improvement in GVHD histopathol-
ogy and the survival improvement was impacted by IL-4 production by the
NKT cells. Importantly, this regulation of GVHD did not interfere with the
GVL function of Tcon.
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