Biology Reference
In-Depth Information
GM-CSF
Signaling occurs through the dimeric GM-CSF receptor, which comprises
the GM-CSF-specific GM-CSFRα and a common β chain (β
c
) that is shared
with the IL-3 and IL-5 receptors
[191,192]
. Like Flt3, it is expressed on DC
progenitors, but with respect to mature cells, it is largely present on mono-
cytes, cDC, and dermal DC
[188]
. GM-CSF signaling results in the activa-
tion of NF-κB (activating) and STAT5 (suppressive) signaling pathways. Of
note, secretion of this cytokine is known to be increased during infection
and inflammation.
GM-CSF has been administered after transplant with the aim of stimulating
granulopoiesis and hastening neutrophil recovery (as has G-CSF), though
this is of unclear overall benefit, with meta-analyses suggesting a small
reduction in infection rate but no alteration in overall infection-related
mortality with GM-CSF as prophylactic therapy
[193,194]
. As such, this
cytokine has not found a routine clinical use in HSCT.
MACROPHAGE COLONY-STIMULATING FACTOR (CSF-1)
CSF-1 signals through the CSF-1R (encoded by the
c-fms
gene), which is
present on myeloid progenitor cells, macrophages, and DCs
[195]
. CSF-1R
expression is restricted to cells of the myeloid lineage and can be used as
a marker of macrophage differentiation
[196]
. Signaling promotes the dif-
ferentiation of myeloid progenitor cells into multiple cell types, including
monocytes, macrophages, DCs, and bone-resorbing osteoclasts (reviewed
in
[197]
), as well as providing a critical survival signal for these cell types.
Mice deficient in the CSF-1R are deficient in tissue macrophages
[198]
, but
importantly, DC populations remain largely intact, with only some DC pop-
ulations disrupted (e.g., the CD11b
high
population in mouse nonlymphoid
tissue
[199]
).
378
CSF-1 has been found to be significantly elevated in the circulation during
murine aGVHD
[200]
, but the significance of this with respect to disease
outcome and pathogenesis is unclear. CSF-1 treatment has been assessed
in BMT models with inconsistent results. It has been reported that CSF-1
can inhibit donor cell engraftment, via an unclear mechanism, prefer-
entially sensitizing grafts to NK-mediated rejection
[201]
. The effect of
pretreating recipient mice with CSF-1 to expand recipient myeloid cells
was recently explored, and the authors demonstrated that the pretreat-
ment regimen reduced the severity of disease without having an impact
on engraftment
[199]
. Of note, results of pretreatment appear to vary
between groups and treatment regimens, with additional reports in the
literature that there was no protective effect seen with administration of
CSF-1 pretransplant (reviewed in
[197]
). It has also been demonstrated
that depletion of CSF-1R-expressing cells using antibodies directed
against the receptor results in elimination of recipient-type tissue mac-
rophages, which caused accelerated GVHD after HSCT, with amplified
activation of donor T cells
[202]
. These studies serve to highlight the pro-
tective role of CSF-1R-expressing myeloid cells in GVHD. With respect to
clinical evidence, pretreatment of HSCT recipients with CSF-1 has not yet
been reported, and the outcome is difficult to predict from the preclini-
cal data thus far. Post-transplant treatment has been studied and results
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