Cytokines in graft-versushost disease and graft-versusleukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 373

blocking antibodies. Prevention of IL-21 signaling using IL-21R-deficient
animals leads to a decrease in GIT GVHD, with maintenance of periph-
eral T-cell function and GVL [177,178] . This cytokine is also critical in the
development of scleroderma [162] . The use of IL-21-blocking monoclonal
antibodies in a xenogeneic mouse model (with NOD/SCID/γ c −/− recipients)
has demonstrated a decrease in CD8 + T cells and an increased proportion
of Tregs. This group also demonstrated local protein expression of IL-21
in the GIT and skin, but not serum [179] . These data were consistent with
a previous report showing an increase in FOXP3 Tregs in association with
IL-21 blockade [180] . From a preclinical point of view, neutralization of
IL-21 represents a promising clinical therapeutic target that requires fur-
ther investigation.

Cytokines influencing myeloid development and
function
Flt3L, GM-CSF, and CSF-1

In the steady state, Flt-3L [181] and GM-CSF (and to a lesser extent, mac-
rophage colony-stimulating factor) are required for DCs development and
homeostasis [182] . There is some redundancy in these signaling pathways,
however, as DC development in mice lacking either the GM-CSF receptor or
the CSF-1 receptor is only partially impaired [183] . Absence of the Flt3 path-
way in genetically modified mice results in a 10-fold decrease in lymphoid
organ pDC and conventional DC (cDC), highlighting the predominant role
of Flt3 signaling in these populations [184,185] . Of note, Langerhans cells
are largely unaffected by an absence of Flt3 signaling [186] .

377

The role of donor DCs in GVHD is discussed in depth elsewhere; however,
there is emerging preclinical evidence that these cells have limited capacity
to invoke GVHD, particularly in the acute setting [15,187] . This is in con-
trast to previous paradigms suggesting that donor DCs were critical for
driving GVHD pathogenesis and that depleting them as a population would
be beneficial for disease outcome. It is therefore possible that providing
DC-specific growth factors could enhance adaptive immune response to
pathogens without affecting alloreactivity (and resultant GVHD) to any real
extent. Whether the administration of myeloid growth factors that promote
DC reconstitution and function (e.g., Flt3L and GM-CSF) has a role after
HSCT remains an area for future exploration.

FLT3L

Flt3 ligand signaling is critically important for DC development. Signaling
occurs through the Flt3 molecule, its receptor, which is expressed on DC
progenitors, as well as mature pDC and cDC [188] . Outside the HSCT set-
ting, Flt3L is used extensively in the generation of bone marrow-derived
DC during in vitro cultures [189] , and it has been demonstrated to prefer-
entially drive CD8 + DC development in mice when administered in vivo
[190] . Administration of Flt3L after transplantation in preclinical models
results in marked expansion of CD8-expressing DCs and a small increase
in the presentation of exogenous alloantigen within MHC class II during
GVHD [15] .