Cytokines in graft-versushost disease and graft-versusleukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 355

the recognition of viral double-stranded DNA and TLR7/8 are important for
viral single-stranded RNA recognition. LPS signaling occurs via TLR4 and CpG
DNA motifs signal through TLR9. TLRs induce changes in cellular behavior
via their downstream transcription factors MyD88 and Trif (reviewed in [4] ).
Importantly, all TLRs require MyD88, except TLR3, which signals via Trif, and
TLR4, which can utilize either MyD88 or Trif. Of note, paracrine and autocrine
effects of cytokine signaling itself (e.g., IFN-γ) and T-cell costimulation (CD40-
CD40L) also have an impact on cytokine production by myeloid cells.

Conceptually, donor cytokine production can be divided into either T-cell-
compartment derived or myeloid derived (i.e., from the bone marrow (BM)
compartment). Effector function is acquired by donor T cells as a result of
their initial interaction with host antigen-presenting cells, by which they
become activated by disparate major and/or minor histocompatibility anti-
gens. Donor T cells are then responsible for the majority of IFN-γ, IL-2, IL-4,
and IL-17, as well as actively consuming these cytokines in an autocrine
fashion to drive further T-cell development and survival. Donor myeloid
cells emerging from the BM are influenced by the inflammatory environ-
ment during their development, which stimulates further cytokine produc-
tion, particularly of IL-1, TNF, and the classic dendritic cell (DC)/monocyte/
macrophage-derived cytokines IL-6 and IL-12.

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It is important to recognize that donor- and host-derived factors interact,
such that signaling to recipient tissue by donor-derived factors (for exam-
ple) can induce cytokine production from recipient cells. Because of this,
mouse models of disease have been developed in which both donor and
host can be manipulated from both a cytokine production and a cytokine
receptor-expression point of view. The human correlates are the genetic
profiling studies in which mutations in cytokine genes and cytokine recep-
tor genes are analyzed and associated with various transplant outcomes.

Acute versus chronic GVHD

Acute and chronic GVHD are probably separate pathological entities, as
opposed to chronological descriptors of the same pathological process
( Figure 16.1 ). As discussed elsewhere (Chapter 1) the cardinal feature of
acute GVHD (aGVHD) is apoptosis, with T-cell differentiation toward what
was classically thought to be a Th1/Tc1 pattern. A key problem with this
paradigm was experimental data in animal models suggesting that both
IFN-γ and the pathognomonic Th1 transcription factor T-bet were in fact
dispensable for the induction of GVHD pathology [5,6] . (Reference [5] dem-
onstrates the mechanism underlying the previously observed paradoxical
effects of IFN-γ in GVHD. The authors demonstrated that IFN-γ protected
recipient mice from lung GVHD and confirmed that it was a pathogenic
cytokine in the gastrointestinal tract.) The discovery of IL-17 and “Th17”
evidence highlights that the “Th1” paradigm of the disease is too narrow to
describe GVHD, as other pathological patterns (e.g., Th17, Th9, and Th22)
are increasingly appreciated as playing important roles.

Chronic GVHD (cGVHD) is characterized by fibrosis, affecting the skin, lac-
rimal and salivary glands, and liver, and is often gut sparing. cGVHD shares
many features with the autoimmune diseases (e.g., systemic sclerosis,