Biology Reference
In-Depth Information
Table 16.1
Important Cytokines in GVHD —cont'd
Mechanism of Action
IL-2
Critical cytokine for T-cell survival
At low dose, has been demonstrated to increase Treg
numbers in GVHD
IL-6
Activates T cells
Promotes Th17 differentiation
Acts in concert with IL-2 to promote naïve T-cell differentia-
tion to CTL
Stimulates hepatic acute-phase response to injury, along
with differentiation/activation of macrophages
IL-12
Produced by activated APC and promotes Th1 differentia-
tion
IL-17
Both proinflammatory and regulatory effects have been
reported in various disease settings and in vitro conditions
Inhibits Th1 differentiation
IL-18
Promotes IL-12 production
“Anti-inflammatory”
cytokine
IL-10
369
Negative regulator of TNF and Th1 cytokine production
Inhibition of T-cell proliferation
Role appears to be dose sensitive: low concentrations are
protective, but very high concentrations are pathogenic
TGF- β
Promotes Th17 and regulatory T-cell differentiation
Inhibition of macrophage activation
Inhibition of Th1 responses and T-cell proliferation
Reduction of alloantigen-specific T-cell responses
Promotes fibrosis in cGVHD
Modified from Reference [215]. [215] .
Cytokines involved in Th1 differentiation
IL-12
IL-12 is a dimeric protein consisting of the p35 and p40 subunits and is clas-
sically produced by APC including macrophages, DC, and Langerhans cells
[93,94] . IL-12 signals through the IL-12R, which, in turn, activates a STAT4-
dependent intracellular pathway. This results in the production of IFN-γ,
but also directly leads to IL-18 synthesis. IL-12 acts to stimulate the prolif-
eration and cytotoxicity of both NK cells and CTL [95] . In the setting of acute
GVHD, IL-12 p40 mRNA has been associated with high IFN-γ concentration
in the target organs during disease [96] .
Paradoxically, despite the described “proinflammatory” properties of IL-12,
animal studies have demonstrated that if administered at an appropri-
ate time in the peritransplant period, IL-12 can attenuate GVHD [97,216] .
Unfortunately these positive effects were highly time dependent, and alter-
ations in timing resulted in rapid GVHD mortality. Because of this, adminis-
tration of IL-12 has not been pursued in the clinical setting.
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