Biology Reference
In-Depth Information
in Chapter 12. Of note, regulatory T cells are diminished in the presence of
both acute and chronic GVHD
[147-149]
; however, the mechanism under-
lying this relative absence is not clear. Importantly, nor is it clear if this is a
cause or effect of GVHD.
IL-10 is known to have an important role in Treg-mediated suppressive
effects, though it represents just one of the mechanisms by which regula-
tory T cells can exert their suppressive activity. Of note, one of the classi-
cal methods for assessing suppressive capacity of regulatory T cells—the
in vitro
suppression assay—has been shown to be IL-10-independent
[150]
.
PRECLINICAL EVIDENCE FOR IL-10 IN GVHD
Preclinical studies have demonstrated that B-cell- and IL-10-deficient recip-
ient mice develop more severe aGVHD than wild-type controls
[151,152]
,
confirming the regulatory role of recipient-derived IL-10. More recently,
donor-derived IL-10, from either mature Tregs or the myeloid/bone marrow
compartment, has also been shown to be important, with an acceleration of
GVHD seen when this cytokine could not be produced
[153]
.
374
CLINICAL EVIDENCE FOR IL-10
IL-10 polymorphisms were among the first to be correlated with disease
outcome in GVHD
[154]
. This seminal paper by Lin and colleagues
[154]
demonstrated a clear and dramatic association of recipient IL-10 genotype
with GVHD outcome. Donor IL-10 genotype has also been associated with
significantly lower risk of grade III-IV aGVHD
[155]
. The phenotypic cor-
relation of these polymorphisms does remain uncertain, however; i.e., it is
not clear whether they lead to gain or loss of IL-10 function. It has been
hypothesized that the protection from aGVHD is due to enhanced IL-10
production from APC
[151]
.
IL-17 and IL-23
There is increasing evidence that IL-17 has an important role to play in both
acute and chronic GVHD, and it is likely to be most relevant in skin and lung
disease. It is produced by “Th17” CD4 T cells, but can also be produced by
CD8 T cells and can be coproduced by interferon-γ-producing CD4 T cells
that may have formerly been considered classical Th1 cells.
The cytokine itself has six isoforms—IL-17A through F, with A and F being
the two most commonly studied at present. IL-17A is the most potent
form, and this molecule, as well as the A/F heterodimer, constitutes
the majority of available, active cytokine. In addition to the IL-17A and
F molecules, Th17 cells generate other important cytokines, including
IL-21, IL-22, TNF, and GM-CSF, in addition to the chemokines CXCL1,
CXCL2, and CXCL8. Th17 cells express CCR6 and CCL20 and are spe-
cifically recruited to sites of inflammation via this chemokine receptor.
Signaling of IL-17A itself occurs via surface binding of the ubiquitously
expressed IL-17R (and this has two subunits, the RA and RC components)
and is propagated intracellularly via Act1/STAT6 and eventually NF-κB
[156]
. Importantly, generation of Th17 cells requires signal transduction
activity from ROR-γτ, ROR-α, and IRF4.
Search WWH ::
Custom Search