Biology Reference
In-Depth Information
The use of G-CSF treatment after BMT has been controversial, with large
clinical studies reporting conflicting results in recent years, with the Euro-
pean Group for Bone Marrow Transplantation (EBMT) reporting a negative
impact on GVHD and overall survival with G-CSF treatment
[211]
and the
American International BMT registry (IBMTR) finding no contribution to
the worsening of outcome with this therapy
[212]
. A mouse study conducted
to further investigate this found that the difference in outcome may have
been due to the predominant use of TBI-based conditioning regimes in the
European centers, compared with the predominance of chemotherapeutic
conditioning regimens in the United States. In the TBI setting, G-CSFR is
induced on APC, and this leads to a cascade of events, including the pro-
duction of proinflammatory IFN-γ by NKT cells
[213]
and enhanced donor
T cell priming.
**
Summary and conclusions
Cytokines are a critical driver of pathology and protection after HSCT, and
an understanding of their biology is important for understanding both the
pathophysiology of disease and the existing as well as future treatment
modalities. The critical cytokines promoting pathology in GVHD are IFN-γ
and TNF, as these have involvement in the GIT, skin, and lung (though para-
doxically IFN-γ signaling provides protection from lung GVHD/IPS).
380
Key Site-Specific Cytokines in GVHD
Gastrointestinal Tract
IFN-
γ
, TNF
Skin
IFN-
γ
, TNF, IL-17, TGF-
β
(late after transplant)
Lung
IL-17, Th2 cytokines (IL-4 and IL-13); IFN-
γ
is pro-
tective
Liver
Fas/cytolytic T-cell mediated
The regulatory cytokines countering these pathogenic cytokines are IL-10
(produced by regulatory T cells) and, early after transplant, TGF-β.
With respect to GVL, it important to consider cytokine influence on T-cell
function, because GVL is largely a cell-mediated phenomenon and many
cytokines (especially IFN-γ, TNF) enhance T-cell cytolytic function and
antigen presentation.
With respect to clinical therapies, TNF blockade is now part of standard
therapy for steroid-refractory aGVHD in many institutions
[214]
. Further-
more, there is emerging evidence for the early use of TNF blockade in GVHD
therapy, in conjunction with steroids
[53]
. While prospective randomized
studies are required to confirm this finding and study the effects on GVL
more closely, mechanistic preclinical studies suggest that combined block-
ade of TNF and LTα3 may hold considerable therapeutic potential for the
treatment of GVHD.
** Reference [213] used preclinical models to clarify an important clinical question regarding
the use of post-transplant G-CSF treatment. This work established that G-CSF can be
pathogenic in the setting of TBI-based conditioning because radiation leads to the
upregulation of the G-CSF receptor on APC, which in turn enhances donor NKT cell
alloreactivity. This served to mechanistically explain the conflict between reported results of
the IBMTR and the EBMT groups with G-CSF administration after transplant.
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