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processing for presentation via MHC II but not MHC I. These data imply
that manipulation of these processes might represent a strategy for enhanc-
ing or reducing immune responsiveness. Indeed, induction of autophagy
by rapamycin treatment enhanced killing of intracellular mycobacteria and
subsequent antigen presentation to T cells by both macrophages and DCs
[130,131]
. Furthermore, mice that were transfused with rapamycin-treated
DCs were more resistant to challenge with virulent strains of
M. tuberculosis
than were mice that received control DCs
[130,131]
.
HDAC ENZYMES
There are four classes of HDAC enzymes. Classes I, II, and IV are the con-
ventional Zn-containing histone deacetylase enzymes
[132]
. Class III
HDACs are the sirtuins that were first discovered in yeast as silent infor-
mation regulator 2 (Sir2). Sir2 was found to be a NAD-dependent HDAC,
and sirtuins serve both as energy sensors and as transcriptional effectors
by controlling the acetylation state of histones
[16,132]
. In mammals the
sirtuin family comprises seven proteins (SIRT1-SIRT7), which vary in tis-
sue specificity, subcellular localization, enzymatic activity, and targets
[117]
. SIRT1 is the best described sirtuin, with a critical role in metabolic
homeostasis and an emerging role in immune tolerance
[133]
. In addition
to histones H3 and H4, the first described nonhistone target for SIRT1 was
p53, which is deacetylated and repressed upon DNA damage or oxidative
stress, resulting in impaired apoptosis
[117]
. It is now known that other pro-
teins such as peroxisome proliferator-activated receptor-γ coactivator 1α
and forkhead box O transcription factors, which are important regulators
of lipid and glucose metabolism, are also targets of SIRT1
[117]
. SIRT1 has
been shown to negatively regulate T-cell activation and play a major role in
T-cell anergy in a cell-intrinsic manner
[133]
. Mice carrying null alleles for
Sirt1
are viable only with outbred genetic backgrounds and they show evi-
dence of autoimmunity. Targeting of Sirt1 decreased Foxp3 polyubiquitina-
tion and promoted its acetylation and protein levels and promoted allograft
survival
[134,135]
.
439
Metabolic sensors that regulate allogeneic HSCT
The specific roles of individual inflammasomes and, specifically, NLRP3
in the induction of GVHD and post-BMT outcome have not been specifi-
cally evaluated. However, an mTOR inhibitor, Sirolimus (rapamycin), has
been shown to enhance Tregs and reduce conventional T cell responses
after experimental BMT
[136-138]
.
Ex vivo
culturing of donor T cells with
rapamycin mitigated GVHD severity and enhanced polarization to Th2 and
increased secretion of IL-10
[138,139]
. However, the metabolic impact of
rapamycin and conversely the role of mTOR as the metabolic and energy
sensor in causing these effects on GVHD and T-cell responses are unknown.
Nevertheless, the mTOR inhibitor Sirolimus has emerged as one of the most
promising immunosuppressive agents for use in allogeneic HSCT. Several
recent trials have demonstrated the utility of this agent in the prevention or
treatment of acute and chronic GVHD. The response rate for Sirolimus in
the treatment of acute GVHD has been reported to be anywhere between
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