IDO activates Tregs, blocks Th17 cells; should the autoimmune eat turkey/take tryptophan?

Tryptophan inhibits IDO and turkey is rich in IDO.  This indicates that
consuming a lot of tryptophan would stoke Th17 cells and an autoimmune
process.  It also hints at why intermittent fasting might be helpful -
it's increasing the amino acid starvation response.

Given the role tryptophan plays in serotonin synthesis, this kind of
ties up the whole serotonin pathway in autoimmunity.  Compare this to
the recent work on 5-HT4 and neurogenesis [PMID 19657021].

Blood. 2009 Jun 11;113(24):6102-11. Epub 2009 Apr 14
 
Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to
TH17-like cells in tumor-draining lymph nodes.
Sharma MD, Hou DY, Liu Y, Koni PA, Metz R, Chandler P, Mellor AL, He Y,
Munn DH.
Department of Pediatrics, Medical College of Georgia, Augusta, GA 30912,
USA.

The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) is
expressed by a subset of murine plasmacytoid DCs (pDCs) in
tumor-draining lymph nodes (TDLNs), where it can potently activate
Foxp3+ regulatory T cells (Tregs). We now show that IDO functions as a
molecular switch in TDLNs, maintaining Tregs in their normal suppressive
phenotype when IDO was active, but allowing inflammation-induced
conversion of Tregs to a polyfunctional T-helper phenotype similar to
proinflammatory T-helper-17 (TH17) cells when IDO was blocked. In vitro,
conversion of Tregs to the TH17-like phenotype was driven by
antigen-activated effector T cells and required interleukin-6 (IL-6)
produced by activated pDCs. IDO regulated this conversion by dominantly
suppressing production of IL-6 in pDCs, in a GCN2-kinase dependent
fashion. In vivo, using a model of established B16 melanoma, the
combination of an IDO-inhibitor drug plus antitumor vaccine caused
up-regulation of IL-6 in pDCs and in situ conversion of a majority of
Tregs to the TH17 phenotype, with marked enhancement of CD8+ T-cell
activation and antitumor efficacy. Thus, Tregs in TDLNs can be actively
reprogrammed in situ into T-helper cells, without the need for physical
depletion, and IDO serves as a key regulator of this critical conversion.

Publication Types:
*  Research Support, N.I.H., Extramural

PMID: 19366986

in mice, HDAC inhibitors (in this case, Vorinostat) seem to reduce the
graft-versus-host disease that accompanies the bone marrow transplants
used to reduce organ rejection in organ transplants; HDAC inhibitors
depress the inflammatory impulses of transplanted dendritic cells; this
approach may also be useful in preventing autoimmune diseases in bone
marrow transplants when treating leukemias and lymphomas; HDAC
inhibitors increase IDO (indoleamine 2,3-dioxygenase; IDO degrades
tryptophan which is essential to T-cell survival), which depresses
dendritic cell (DC) responses; pretreatment of DCs with HDAC inhibitors
significantly reduced TLR-induced secretion of proinflammatory
cytokines, suppressed the expression of CD40 and CD80 and reduced in
vitro and in vivo allostimulatory responses induced by the DCs; blocking
IDO abrogated most effects of the HDAC inhibitors
<http://www.sciencedaily.com/releases/2008/07/080710170545.htm> [PMID
18568076]

a gene (GCN2) that tells mice to eat a well-balanced diet and yeast to
make bread rise also selectively silences the immune system; GCN2
responds to low amino acid levels; GCN2 is a nutrition sensor in yeast
telling it it has enough nutrients to grow; indoleamine 2,3-dioxygenase
(IDO) is expressed in the GI tract and tonsils where the immune system
regularly meets foreign substances it might need to ignore; IDO protects
the fetus from rejection during pregnancy; tumors and persistent viruses
can hijack the IDO mechanism to hide from attack; IDO degrades
tryptophan which is essential to T-cell survival; this doesn¹t kill the
T-cell but does render it selectively non-responsive; the T-cells in
GCN2 knockout mice ignore IDO so GCN2 is necessary for immune tolerance
<http://www.sciencedaily.com/releases/2005/05/050518103418.htm>;

pneumonia can be caused by bacterial, viral and parasitic pathogens;
staphylococcus aureus is a common cause of lung abscesses in humans and,
in immunocompromised patients, herpes simplex virus type I and
Toxoplasma gondii can cause severe life-threatening pneumonia;
IFN-gamma-stimulated lung cells can inhibit T cell proliferation and
restrict the replication of T. gondii, S. aureus and herpes simplex
virus; this effect was enhanced in the presence of IL-1 or tumor
necrosis factor-alpha (TNF-alpha); the IFN-gamma-dependent antimicrobial
effects of HBE4-E6/E7 (human lung bronchus epithelial cells) and A549
(human type II alveolar cells) was correlated with the activation of the
tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO); both the
abrogation of IDO activity by the specific IDO-inhibitor
1-L-methyltryptophan and the supplementation of cultures with tryptophan
result in an inhibition of IFN-gamma-induced antimicrobial effects
mediated by lung cells; tryptophan depletion via IFN-gamma-mediated IDO
induction is a major antibacterial, antiparasitic, antiviral and
immunoregulatory mechanism in human lung cells [PMID 18205804]

chronic active Epstein Barr virus (EBV)-infection is characterized by
mononucleosis like symptoms including fatigue, lymphadenopathy and/or
hepatosplenomegaly and serologic evidence for ongoing EBV replication;
interferon-gamma (IFN-gamma) triggers several antiviral mechanisms
including the induction of indoleamine-2,3-dioxygenase (IDO), which
degrades the essential amino acid tryptophan to kynurenine; since
tryptophan is a precursor of the serotonin (5-hydroxytryptamine),
tryptophan depletion by IDO can cause mood disturbances in patients with
chronic immune activation; in 20 patients with chronic active
EBV-infection followed up for 4 to 8 months vs. 10 healthy age-matched
controls, patients with detectable EBV-DNA had higher serum neopterin
(p<0.01) and lower tryptophan concentrations than EBV-DNA negative
patients; serum concentrations of neopterin, indicating Th-1 mediated
immune activation via IFN-gamma, were positively correlated to enhanced
tryptophan degradation in patients, but not in healthy individuals;
patients with more severe symptoms tended to have aggravated tryptophan
degradation [PMID 17945348]

tryptophan metabolism occurs via the protohemoprotein enzymes tryptophan
2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) - which
regulates the immune system and defends against microorganisms; the
antimicrobial action of IDO is due largely to depletion of the essential
amino acid tryptophan but its immune regulatory function is still
unclear; pathogens sensitive to IDO-mediated tryptophan degradation
range from intra-cellular parasites like toxoplasma and possibly
plasmodia to viruses (herpes viruses) to intra-cellular bacteria
(chlamydia and rickettsia) and extra-cellular bacteria such as
streptococci, enterococci and staphylococci [PMID 17430112]

indoleamine (2,3)-dioxygenase (IDO) catalyses the initial, rate-limiting
step in the degradation of the essential amino acid tryptophan; via
tryptophan deprivation, IDO activity suppresses T cell proliferation and
differentiation and is a fundamental immune escape mechanism for tumor
cells; serum tryptophan and kynurenine concentrations and the
kynurenine-to-tryptophan ratio (kyn/trp) in 87 patients with malignant
melanoma were compared to the course of the disease and to
concentrations of the immune activation marker neopterin; melanoma
patients had lower tryptophan levels due to accelerated degradation,
especially for the subgroups of patients with distant metastases (p
0.01), though not in patients with lymph node metastases or in patients
who had not yet progressed; there was positive correlation between
kyn/trp and neopterin concentrations; in patients who died from
dissemination of the tumor, median tryptophan concentrations were
significantly decreased and kyn/trp and neopterin concentrations were
higher compared to survivors; lower tryptophan as well as higher kyn/trp
and neopterin predicted a shorter survival [PMID 17191041]

IDO is activated by interferon-gamma (IFN-gamma) and via tryptophan
depletion, suppresses adaptive T cell-mediated immunity in inflammation,
host immune defense, and maternal tolerance (IDO is also an
antiproliferative strategy which may backfire and dampen immune reaction
to cancers); kynurenine/tryptophan ratios (an estimator of IDO activity)
and neopterin were detectable at low levels in serum of healthy
volunteers and were increased in non-rejecting kidney allograft
recipients; serum levels of kyn/trp were higher in recipients with
rejection compared to non-rejectors as early as by day 1 post-surgery;
rejection episodes occurring within weeks of transplantation were
accompanied by elevated kyn/trp in serum/urine compared to levels during
stable graft function; kyn/trp correlated significantly with neopterin
suggesting an IFN-gamma-induced increase in IDO activity; in biopsies of
rejected grafts, IDO was upregulated, localized in tubular-epithelial
cells; non-rejected grafts had no IDO expression; acute rejection is
associated with simultaneously increased serum and urinary kyn/trp in
patients after kidney transplantation; IDO might offer a novel
non-invasive means of immunomonitoring of renal allografts [PMID
17136028]
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