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during GVHD. IFN-γ, which is the only type II interferon, is also produced
by CD4 and CD8 T cells, B cells, NKT, and APC. Its production is promoted
by IL-12 and IL-18 signaling and downregulated by IL-4, IL-10, and TGF-β.
Signaling occurs through the IFN-γ receptor (IFN-γR), which is a widely
expressed heterodimeric protein with subunits IFN-γRα (constitutively
expressed) and IFN-γRβ (inducible), each of which is required for effective
signaling. Ligand binding and subsequent signaling via the transcription
factor STAT1
[12]
induces a multitude of effects, including the promotion
of T-cell activation and differentiation, MHC class II expression, and inhi-
bition of Th2 differentiation. It is important to note that IFN-γ signaling
can induce expression of molecules that are both suppressive (e.g., indole-
amine-2,3-dioxygenase and nitric oxide synthase) and proinflammatory
(e.g., TNF family members). During GVHD development IFN-γ also has a
role in enhancing the sensitivity of macrophages to LPS, hence increas-
ing their production of proinflammatory cytokines
[13]
. It is also respon-
sible for altering other APC functions, including increasing MHC II and Fas
expression. Additionally, IFN-γ signaling in the bone marrow compartment
has been shown in preclinical models to have an impact on post-transplant
dendritic cell function, with improved presentation of exogenous antigen in
the absence of IFN-γR signaling
[14,15]
.
362
The opposing pro- and anti-inflammatory roles of IFN-γ make it problem-
atic to synthesize a coherent hypothesis regarding the actual outcome of
IFN-γ blockade or administration in GVHD, and in fact, preclinical animal
models have now clearly demonstrated that the cytokine plays a com-
plex role in GVHD with organ-specific pathogenic and protective effects
[5]
. Donor-derived IFN-γ was demonstrated to protect animals from lung
GVHD via signaling to host parenchyma and preventing infiltration of
inflammatory cells
[16]
. In contrast to this protective effect with respect to
idiopathic pneumonia syndrome (IPS) IFN-γ is pathogenic in the gastroin-
testinal tract, where it causes crypt hypertrophy and villous atrophy
[17,18]
via direct signaling of the IFN-γR expressed on recipient gut tissue
[5]
.
In terms of clinical correlates, no relationship has been established between
genetic polymorphisms in IFN-γ or IFN-γR in bone marrow transplant
(BMT) donors or recipients that predicts transplant outcome. Given the
complex pathogenic and protective effects that this cytokine has on GVHD,
this is perhaps not surprising.
Donor T-cell-derived IFN-γ overall has been shown to play a role in CD8-
mediated GVL effects
[19]
. Preclinical models have shown that the expres-
sion of the IFN-γR is not required on tumor cells for maintenance of the
GVL effect
[20]
, suggesting that the effects of IFN-γ on the T-cell and APC
compartments are indirectly involved in tumor clearance. In particular
IFN-γ promotes Tc1 differentiation via autocrine pathways and effects on
APC that lead to enhanced T-cell priming.
TYPE I INTERFERONS
The type I interferons are a 16-member family: namely 12 IFN-α subtypes
(each encoded by distinct genes), a unique IFN-β molecule (encoded by a
single gene), IFN-ε, IFN-κ, and IFN-ω, and all of these signal through the
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