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to expand, develop effector function, and cause lethal GVHD in the
MHCII-mismatched, miHA-matched B6
bm12
→ B6 model. As predicted
B6
bm12
CD4 cells were unable to induce GVHD in B6 MHCII
−/−
hosts. How-
ever, the infusion of WT B6 splenic CD11c
+
cells restored GVHD. A parallel
approach was taken in the B6
bm1
→ B6 MHCI-mismatched, miHA-matched
model to show that host DCs were sufficient for alloreactive CD8
+
T-cell
generation
[91]
. Of note, transferred wild-type B cells were unable to
restore GVHD.
While the Duffner study established that host DCs were sufficient for
GVHD induction in MHC-mismatched models, it did not address whether
DCs are required. This is a key point as the translational question would
be whether the selective depletion of host DCs would diminish GVHD.
To address this, Geoff Hill's group and our own group have explored the
selective depletion of host DCs in multiple models wherein host APCs
are required
[51, 105]
. Both Hill and colleagues and our group exploited
transgenic mice that express the simian DTR, controlled transcriptionally
by a CD11c promoter (CD11c-DTR mice)
[106, 107]
. Treatment of these
mice with DT induces rapid killing of CD11c
+
conventional DCs, but not
plasmacytoid DCs. Mouse cells that do not express the transgene are unaf-
fected as the murine DTR homolog does not bind DT with high affinity.
Our group also used hosts that had a constitutive absence of conventional
DCs by virtue of the direct expression of diphtheria toxin A chain in CD11c
+
cells. Both groups found no diminution of GVHD with DC depletion in all
models tested.
184
One interpretation of these results is that conventional host DCs are
required, but that a very small number survived ablation and were sufficient
to initiate GVHD, as is suggested by add-back experiments
[70,91]
. Alter-
natively, other subsets of APCs may be sufficient. In the models employed
by our group, host hematopoietic APCs were absolutely required, whereas
data from Hill and colleagues support the notion that GVHD could also
have been initiated by nonhematopoietic cells. Regardless of which of these
interpretations is correct, it seems unlikely that selective host DC depletion
in the clinic will meaningfully diminish GVHD.
In contrast to the situation in transplantation with ablative conditioning,
in an MHC-mismatched model wherein mixed donor:host BM chimeras
receive DLI, T-cell cytolytic activity against host hematopoietic cells was
found to depend at least in part on recipient CD11c
+
cells
[108]
.
Hill and colleagues consistently observed more severe GVHD in host
DC-depleted recipients and we observed the same in some experiments,
suggesting a regulatory role for DCs. Prior studies have suggested regulatory
properties of DCs in GVHD. Sato et al. reported that the infusion of
ex vivo
-
generated regulatory DCs suppressed GVHD
[109]
.
Fms
-like tyrosine kinase
3 (Flt3)-ligand treatment of transplant recipients prior to allo-BMT resulted
in expansion of CD8α
+
DCs, which correlated with protection from GVHD
[110]
. The timing of Flt3-ligand treatment appears to be crucial in induc-
ing GVHD resistance, as treatment of transplant recipients with Flt3-ligand
after BMT exacerbated GVHD
[111]
. A subsequent study has shown expan-
sion of natural T regulatory cells (Tregs) occurring in association with DC
expansion in Flt3-ligand-treated mice
[112]
, and perhaps this explains the
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