Cytokines in graft-versushost disease and graft-versusleukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 369

“ trans -signaling” and allows IL-6 to induce responses in cells that do not
express the specific IL-6 receptor [130] . Interestingly, the trans -signaling
phenomenon utilized by IL-6 is thought to be important in maintaining
chronic inflammatory states. Intracellular IL-6 signaling is largely STAT3
dependent [131] .

Studies of IL-6 in GVHD and GVL effects clearly suggest that it is a patholog-
ical cytokine, with either the absence of IL-6 in the donor T-cell population
or the blockade of IL-6 with an anti-IL-6R antibody, resulting in decreased
aGVHD with no adverse impact on GVL effects in the models used [132,133] .
These studies demonstrated that blocking IL-6 signaling can increase CD4 +
FOXP3 + Treg conversion from the FOXP3-negative population; however, the
second study [133] could not confirm this effect, finding instead that the
anti-IL-6R treatment resulted in GVHD protection that was independent of
T-cell differentiation and probably due to direct inhibition of cytotoxicity
mediated by IL-6.

Polymorphic expression of the IL-6 gene by transplant donors has been
correlated with higher transplant-related mortality; however, as is often
the case with these studies of genetic polymorphism, it is unclear whether
the genotypes studied lead to a physiological gain or loss of IL-6 function
[134] . Recipient IL-6 polymorphism has also been studied and various geno-
types have been associated with outcome in both acute and chronic GVHD
[135,136] . These correlative studies are at least suggestive that blockade of the
IL-6 signaling pathway is likely to be of pathological relevance. Some anec-
dotal observations that suggest potential efficacy in treating patients with
steroid-refractory aGVHD with Tocilizumab have also emerged [137,138] .

373

IL-10

IL-10 signals through the IL-10 receptor via induction of STAT3 and is
largely an immunosuppressive cytokine, with signaling leading to suppres-
sion of macrophage and DC function and, in turn, reduction of pathogenic
T-cell responses. It can be produced by Treg, B cells, monocytes, and DCs
[120,139] . IL-10 plays a critical role in the regulation of TNF production and
the reduction of other Th1 cytokines (including IFN-γ) and can directly act
as an inhibitor of T-cell proliferation [140-142] . IL-10 has a key role to play
in the Treg/Th17 axis: IL-10 signaling suppresses the Th17 axis, via inhibi-
tion of both generation and proliferation of cells of the Th17 lineage [143] ,
and promotes the FOXP3 + CD25 + CD4 + Treg population. In this particular
study, it was noted that the source of IL-10 was the Treg population, but that
suppressive effects on the Th17 population could also be exerted by exoge-
nously administered IL-10. With respect to Tregs, it is important to note that
IL-10 can both act on naïve CD4 + T cells to promote Treg differentiation and
licensing and subsequently be produced by the Treg population itself [120] .

IL-10 AND REGULATORY T CELLS

FOXP3-expressing Tregs are important for the maintenance of peripheral
tolerance, and perturbations in the development or function of Tregs is
known to be associated with autoimmune disease [144] . Naturally occur-
ring, thymic-derived FOXP3 + CD25 + CD4 + Tregs have a demonstrated role in
suppressing experimental GVHD [145,146] and this is discussed at length