Biology Reference
In-Depth Information
receptors may hinder clinical efficacy in the context of GVHD prevention
or therapy. As such, targeting lymphocyte/integrin interaction may be a
more promising way to explore this issue. Indeed the research of targeting
lymphocyte trafficking has been taken into the clinic in diseases related to
GVHD, such as rheumatoid arthritis and colitis.
Effector stage; T cells and others
After migration of alloreactive effector T cells to the target tissues of GVHD,
these cells can mediate tissue destruction through both direct cytotoxic
activity and the recruitment of other leukocytes. Targeting these effector
pathways has been studied as a strategy to prevent or reduce GVHD sever-
ity. Researchers have considered acute GVHD to be a Th1/T cytotoxic-type
(IL-12, IL-2 and IFN-γ) disease on the basis of the predominance of cyto-
toxic T-cell-mediated pathology and of increased production of Th1-type
cytokines. However, several recent studies have suggested that the influ-
ence of Th1 and Th2 cytokines in acute and chronic GVHD is not so simply
explained (reviewed in chapter 11).
The concentration and timing of cytokine release into the circulation and
relevant target organs appear to be critical for GVHD (reviewed in chapter
16). For example, IL-10 promotes Th2 and type 1 regulatory T-cell responses,
which can be important in the induction of tolerance to allografts (reviewed
in reference
[6]
). Higher production of IL-10, as demonstrated in human
recipients with an IL-10 polymorphism, is associated with reduced occur-
rence and severity of GVHD
[90]
. Paradoxically, high dose of IL-10 admin-
istration can accelerate GVHD in a murine model, and high-serum IL-10
levels in patients after HSCT are associated with a fatal outcome. However,
conversely, low-dose IL-10 administration can inhibit acute GVHD in mice
(reviewed in reference
[6]
). These findings highlight the pleiotropic, some-
times opposing, nature of cytokines during the different phases of GVHD
pathogenesis and on various effector and regulatory cell populations.
10
T cells mediate the final effector pathway in GVHD by multiple pathways
[30,91,92]
. The expression of both Fas and FasL is increased on CD8
+
and
CD4
+
donor T cells during acute GVHD in patients and mice, and serum
levels of soluble FasL and Fas were found to correlate with GVHD severity
or the response to GVHD therapy. Several studies in experimental mouse
models have analyzed the role of the Fas-FasL and perforin-granzymes
pathways in the development of GVHD by using mice that are deficient for
FasL (gld mice), perforin or granzyme B as donors, or by the
in vivo
admin-
istration of neutralizing anti-FasL antibodies. Although these differences in
experimental design affect the opportunity to draw a uniform conclusion,
most studies have shown a role for the Fas-FasL pathway in GVHD mor-
tality. With respect to the perforin-granzyme pathway, approximately two-
thirds of studies demonstrated the importance of this pathway in GVHD
pathogenesis (reviewed in reference
[5]
).
In studies of transplant patients, polymorphisms in the TNF-α gene of
HSCT recipients are associated with higher levels of production of the cyto-
kine and are correlated with a higher incidence of severe acute GVHD [93]
(and reviewed in reference
[48]
), which suggests that, in humans, induc-
tion of TNF-α from recipient cells may make an important contribution
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