Cytokines in graft-versushost disease and graft-versusleukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 359

ubiquitously expressed IFNAR, a two-subunit receptor (IFNAR1 and 2)
[21,22] . These cytokines can be produced by almost all cell types in response
to viral infection; however, plasmacytoid dendritic cells (pDCs) are special-
ized for type I IFN production after viral infection, which occurs after TLR7
and 9 ligation on the cell surface of the pDC, resulting in downstream sig-
naling via MyD88/IRF7 molecules and subsequent type I IFN production
[23] . Importantly, type I interferon has been shown to negatively regulate
pDC numbers, with high levels of IFN-α contributing to cell death within
this population [24] .

As is the case for interferon-γ, STAT1 is also the critical transcription fac-
tor for the type I interferons after their binding to the IFNAR [12] . Type I
IFN signaling is important in both the innate and the adaptive immune
responses. Innate responses to viral infections were initially studied, and
IFN was observed to result in antiproliferative effects as well as the upregu-
lation of MHC I expression [25] . In terms of the adaptive immune response,
type I interferons have been demonstrated to be important for the differen-
tiation and subsequent expansion of effector CTL [26] .

Preclinical models have highlighted the importance of type I IFN signal-
ing in GVHD and GVL. Signaling via recipient tissue has been shown in
preclinical models to protect mice from CD4-dependent GVHD [27] . This
protection is conferred via IFN-α/β signaling to hematopoietic recipient
cells, which, in turn, resulted in decreased proliferation and differentiation
in the donor T-cell compartment. Via a different mechanism, type I inter-
ferons have been shown to enhance protective GVL responses via donor
cell production of IFN-α/β, which was thought to directly act on tumor cells
to retard their growth [27] . In this series of experiments, direct signaling
of type I interferons to donor T cells resulted in enhanced GVL responses
against host-type leukemia.

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This preclinical study highlights that it may be valuable to treat individuals
at high risk of relapse after HSCT with recombinant IFN-α to improve both
tumor sensitivity to GVL and the GVL response itself.

Importantly, in the pre-tyrosine kinase inhibitor (e.g., imatinib) era, recom-
binant IFN-α was used successfully as therapy for chronic myeloid leuke-
mia (CML). The success of this treatment was thought to be due to the anti
proliferative effects of the cytokine [28-30] and, while it has been replaced
by imatinib as the standard of care for these patients [31] , the addition of
recombinant IFN-α treatment appears useful in enhancing responses [32] .
It is thought that combination therapy of IFN-α with a tyrosine kinase
inhibitor promotes cell cycling and thereby increases sensitivity to the tyro-
sine kinase inhibiting agent, as quiescent CML cells are resistant to killing
via these agents [33,34] .

Tumor necrosis factor and lymphotoxin- α

Preclinical models have clearly established soluble TNF and, more recently,
the related TNF superfamily cytokine lymphotoxin-α (LTα3) as key inflam-
matory mediators of GVHD [35-38] . TNF is produced by recipient myeloid
cells after pretransplant conditioning [13] and, subsequently, by acti-
vated donor T cells [38-40] . It is originally present as a membrane-bound