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intracellular enzyme indoleamine 2,3-dioxygenase
[67]
. The experimental
observations collectively suggest that stimulation of intracellular sensors
such as TLR7/8 can lead to either localized or systemic inhibition of inflam-
mation and thus either aggravate or reduce GVHD following allo-BMT.
These studies, however, do not reveal the specific TLR7/8-expressing cel-
lular subsets that may be critical for mediating the above effects. They also
suggest that untimely infections with the various viruses that can stimulate
TLR7/8 might lead to aggravation of GVHD.
TLR9
The role of TLR9 was explored in the context of MHC-disparate experi-
mental BMT
[66,68]
. TLR9
−/−
deficient recipients demonstrated reduced
activation status in splenic APCs following radiation and a reduced capacity
to stimulate alloreactive T cells
ex vivo.
These observations were correlated
with reduced GVHD severity
in vivo
[68]
. However, in the same study BM
chimera experiments suggested that TLR9 expression in the nonhemato-
poietic and not the host hematopoietic cells was critical for the impact on
GVHD. In another study, ligation of TLR9 with CpG ODNs at the time of
allogeneic BMT enhanced alloreactive T-cell responses and the increase in
GVHD
[66]
and was dependent on TLR9 signaling in host APCs. Another
study also demonstrated reduced intestinal GVHD with alteration in micro-
bial flora in TLR9-deficient recipients after allogeneic BMT
[69,70]
.Thus
TLR9 stimulation appears to enhance GVHD, although the specific cells
that are crucial for the effect remain controversial.
432
A clinical study analyzed the impact of host TLR9 polymorphisms (T1486C
and T1237C), which are associated with a lower TLR9 expression, on the
clinical outcomes after allogeneic HSCT
[70]
. The TLR9 polymorphisms
were not associated with GVHD severity but had a significant impact on
reducing treatment-related mortality and relapse rate. This suggests that
in contrast to the impact on specific-pathogen-free-housed mice, in the
case of outbred humans, TLR9 might not have a direct effect on GVHD.
Instead the better outcomes could be attributable to less severe inflamma-
tory response to TLR9 stimulation by microbial or other damage-associated
stimuli in the patients with hypomorphic TLR9 polymorphisms.
TLR3
In most patients who undergo allo-HSCT the primary antigenic targets of
donor T cells responsible for GVHD are the host mHAs
[71-73]
. These anti-
gens are also critical for graft-versus-leukemia (GVL) responses
[71]
. In addi-
tion to the mHAs, donor T cells respond to leukemia-specific antigens (LSAs)
that are either virally encoded or mutated tumor antigens and represent addi-
tional important targets for GVL without causing concomitant GVHD
[71,72]
.
Mice that were deficient in TLR3 did not show any effect on GVHD, but were
less capable of generating a (virus-driven) leukemia-specific antigen response
and showed poor GVL responses (our unpublished observations). Absence of
TLR3 led to poor cross-presentation of the LSA but had no impact on alloanti-
gen presentation, while TLR3 stimulation with poly(I:C) enhanced GVL. These
observations suggest that modulating intracellular sensors may be exploited
under certain conditions to enhance outcomes after allogeneic BMT.
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