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active, cytokine-focused therapies (e.g., TNF receptor (TNFR):Fc treatment is
now standard for steroid refractory GVHD in many institutions).
Both donor and host tissues contribute to the generation of inflammatory
cytokines after transplant, including TNF, interferon-γ (IFN-γ), and inter-
leukins 1, 6, 12, and 17 (IL-1, IL-6, IL-12, IL-17). This process is concurrently
regulated by the generation of “anti-inflammatory” cytokines (such as IL-10
and tumor growth factor-β (TGF-β)) and regulatory cellular components
(regulatory T cells, NKT cells, and myeloid suppressor cells), which are dis-
cussed elsewhere.
This chapter aims to clarify the basic preclinical studies that have identified
important cytokines in GVHD and graft-versus-leukemia (GVL) effects and
to discuss the clinical relevance of these elements of GVHD pathophysiol-
ogy, particularly with regard to current therapies.
Cytokine signaling is capable of inducing a vast array of biological responses.
This occurs because binding to specific cell-surface receptors results in the
activation of intracellular signaling cascades (e.g., by phosphorylation of
proteins). These intracellular cascades result in nuclear translocation of
various transcription factors (e.g., nuclear factor-κB (NF-κB) or the signal
transducer and activator of transcription (STAT) family of molecules), which
then influence cell transcription, translation, protein production, and ulti-
mately cellular behavior within the overall biological microenvironment.
358
Stimuli for cytokine production after hematopoietic
stem cell transplantation
Current paradigms suggest two major stimuli for inducing cytokine genera-
tion, from either donor or recipient tissue:
1.
Toll-like receptor (TLR) signaling by various “danger signals” and
2.
T-cell interaction with antigen-presenting cells (APCs).
Pretransplant conditioning (with chemotherapy and radiation) results in pro-
found immunosuppression, which prevents graft rejection and has the side
effect of invoking tissue damage, which compromises gastrointestinal tract
(GIT) integrity. This allows translocation of bacterial products (including lipo-
polysaccharide (LPS) and CpG DNA) into the systemic circulation and pro-
motes inflammation within recipient tissue, characteristically inducing TNF,
IL-1, and IL-6 release
[1-3]
. (Reference
[2]
represents a critical development in
the field of GVHD biology, demonstrating the importance of conditioning in
GVHD pathophysiology and shows that the TNF produced by recipient cells
in response to GIT damage is a precipitant for subsequent severe acute GVHD.
This paper defines early events in disease pathogenesis and is the basis for cur-
rent paradigms. Reference
[3]
is an important preclinical study that confirmed
the critical importance of IL-1 and TNF in GVHD and established that disease
could be prevented by neutralization of these cytokines.) These signals lead to
proinflammatory cytokine production by both innate and adaptive elements
of the immune system, as well as recipient stromal cells, which are collectively
known as PAMPS or DAMPS (pathogen or damage-associated molecular pat-
terns). Innate sensing of these patterns occurs via TLR, a large family of mol-
ecules that is highly conserved across species. TLR3 has been implicated in
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