Biology Reference
In-Depth Information
remain unclear, as reports of both detrimental effects of CSF-1 treatment
on extensive cGVHD
[203,204]
and an attenuation of disease have been
made
[217]
.
G-CSF
Granulocyte-colony stimulating factor is a physiological regulator of gran-
ulopoiesis and neutrophil egress from the BM in nondisease states and has
multiple utilities in HSCT. Donor treatment with G-CSF is used as a means
to mobilize BM stem cells into the peripheral blood for stem cell har-
vest via apharesis, and the cytokine is also commonly administered after
transplantation in an attempt to shorten the period of post-transplant
neutropenia.
Administration of G-CSF to donors results in a complex cascade of events,
which are initiated by signaling to the G-CSFR, which is expressed on hema-
topoietic cells including pluripotent and myeloid progenitors, neutrophils,
monocytes, some lymphocyte subsets, and endothelial cells
[205,206]
. One
of the end results of this signaling cascade is the expansion of neutrophils
within the BM. This granulocyte expansion leads to the secretion of prote-
ases, which in turn, disrupt adhesion molecules and chemokine receptors
(e.g., VCAM-1, CXCL12) that are key for the maintenance of stem/progeni-
tor cells within the BM compartment—hence, disrupting these molecules
facilitates their egress into the periphery where they can be harvested by
apharesis
[207]
.
379
The era of G-CSF-mobilized donor grafts (compared with bone marrow as
a stem cell source) has ushered in changes to GVHD kinetics and pathol-
ogy, with significant increases in cGVHD. While much remains to be learned
regarding cGVHD pathophysiology, it is now established that the effector
pathways involve cells of the myeloid lineage and fibrogenic cytokines such
as TGF-β, all of which are amplified by G-CSF
[126,208]
. Leukemia relapse
rates are reduced in patients developing cGVHD
[209]
, reflecting ongoing
effective CTL responses, and lead to an overall improvement in long-term
survival, despite the presence of cGVHD, in recipients of G-CSF mobilized
grafts.
G-CSF mobilization leads to several immunomodulatory effects, which
have long-term consequences for donor graft function:
•
The aforementioned disruption of adhesion molecules by proteases re-
leased from myeloid precursors may influence the ability of T cells to
traffic to lymphoid tissue and induce GVHD. CD62L, for example is pro-
foundly reduced on donor T cells following G-CSF administration
[210]
.
•
The disrupted lymphoid environment may change the ability of T cells
to interact with APC.
•
Hematopoietic tissue expanded by G-CSF and stromal tissue stimulated
by G-CSF may induce cytokines such as IL-10, TGF-β, and IFN-α.
•
G-CSF mobilization induces the development of a Th/Tc17 phenotype
after transplant, which promotes cGVHD, particularly of the skin
[162]
.
These immunomodulatory effects are initiated during the brief period
of donor graft exposure to G-CSF prior to harvesting, but clearly have
long-term effects on graft function and disease outcome in the recipient.
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