Intracellular sensors of immunity and allogeneic hematopoietic stem cell transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 435

40 and 80% [140-142] . When used in the context of prevention, GVHD rates
from 20 to 70% have been reported [143-146] . Higher rates in GVHD were
observed when used with cyclosporin and busulfan, while excellent activ-
ity was observed when used with Tacrolimus [147,148] . Studies are under
way to determine whether mTOR inhibition-based approaches can be
enhanced in the absence of methotrexate and calcineurin inhibitors. It is
likely that this approach could be optimally utilized by understanding the
role of mTOR as both an immune regulator and an energy sensor.

Intracellular metabolic changes secondary to
immunity

In the above sections, the role of metabolic perturbations that amplify and
modulate immunity and alloreactivity was discussed. It is important to note
that the process of inflammation and alloreactivity itself leads to metabolic
changes, which too have been shown to secondarily further modulate allo-
reactivity. Thus inflammation and metabolic changes mutually modulate
each other (see Figure 18.2 ). In this context, emerging data have demon-
strated a role for inflammation-induced changes in amino acid metabolism
and glucose metabolism in modulating the severity of GVHD.

440

Under certain settings, when suitably stimulated, some DCs and non-
hematopoietic cells from humans and mice express an enzyme, indole-
amine 2,3-dioxygenase (IDO) [149] . IDO is the key enzyme in the pathways
involved in the catabolism of the essential amino acid tryptophan [149] .
The breakdown of tryptophan and the generation of the downstream
kyneurinine end-products have been implicated in the development of an
immunoregulatory environment that has been shown to play a role in regu-
lating pregnancy at the placental interface and in tumor-induced immu-
nosuppression [149] . The immunoregulation has been shown to induce
Tregs, and also T-cell apoptosis and anergy in a pathway involving GCN2
kinase, which is a stress-response kinase that is activated by elevations
in uncharged tRNA [149-151] . Data have demonstrated that IDO expres-
sion is enhanced following allogeneic BMT and that it attenuates GVHD,
particularly in the GI tract [67,152] . The expression of IDO in the GI tract
decreased allogeneic T-cell proliferation and survival and reduced inflam-
mation in the hosts. Furthermore, the expression of IDO in both nonhema-
topoietic cells (colon epithelial cells) and antigen-presenting cells affected
GVHD. Accordingly, enhancing the expression of IDO in the host antigen-
presenting cells through inhibition of histone deacetylases was shown to
mitigate GVHD [153,154] . The requirement of inflammation-induced IDO
in the GI tract was also suggested by a human study that showed upregula-
tion of IDO expression in the epithelial cells from duodenal biopsies [155] .
The study showed that IDO was also expressed by the macrophages, DCs,

FIGURE 18.2
Inflammation and metabolic changes mutually
modulate each other in GVHD.