While it shouldn't come as any surprise that butyrate and other HDAC
inhibitors have potential against autoimmunity since they boost FoxP3
expression and regulatory T-cell numbers, this recent link to IDO is an
interesting twist. IDO is indoleamine 2,3-dioxygenase. It degrades
tryptophan which is essential to T-cell survival.
Of particular interest is butyrate, the bacterial byproduct of fiber
digestion in the GI tract. Itıs an HDAC inhibitor. Many of these
autoimmune problems may be the result of a combining a sugary, low-fiber
American diet with antibiotics - something thatıs probably
all-too-common in hospitals these days.
There is also evidence from lung cells that IDO is part of the innate
immune system.
Certain viruses also hijack the IDO system to avoid attack. There's
evidence Epstein Barr, responsible for chronic fatigue, HIV/AIDS and
hepatatis upregulate IDO - perhaps to escape from certain T-cell
attacks. Other viruses like the measles can be damaged by IDO. This
rang some bells for me since certain autistics have the
autoimmune/allergic response you'd expect from regulatory T-cell
depletion
<http://www.sciencedaily.com/releases/2008/07/080714155301.htm>
and they
have cryptic measles infections of the gut they can't clear out.
S*****onin is formed from tryptophan and not so coincidentally, SSRIs
have antifungal properties (perhaps via progesterone's effects on innate
immunity [PMID 12957330]), as does butyrate. Perhaps there's a deeper
connection here.
<http://www.sciencedaily.com/releases/2008/07/080710170545.htm>
Bone Marrow Transplants: Cancer Drug Shows Promise Against Graft Vs.
Host Disease
ScienceDaily (July 16, 2008) A new University of Michigan study in
mice suggests that a drug recently approved to fight cancer tumors is
also able to reduce the effects of graft-versus-host disease, a common
and sometimes fatal complication for people who have had bone marrow
transplants.
Plans are under way at U-M for an initial trial of the drug in people as
a new way to prevent graft-versus-host disease. Researchers expect to
begin a trial within a year.
The U-M scientists tested the effects of the drug SAHA, as well as
another member of a group of drugs known as HDAC inhibitors, on key
immune system cells called dendritic cells. In mice, both drugs were
able to significantly diminish the destructive inflammatory effects that
these cells cause in graft-versus-host disease.
Graft-versus-host disease occurs when immune cells in the transplanted
bone marrow mount a misguided attack on body tissues. If HDAC inhibitors
turn out to be safe and effective in people, they might offer a
treatment option preferable to the immunosuppressant drugs used now to
treat the disease. These leave people vulnerable to infection and have
other significant side effects.
"To make bone marrow transplants more effective, we need better control
of the very powerful reactions between the immune systems of the donor
and recipient. This study shows how drugs like SAHA regulate those
reactions, and takes us a major step closer to bringing this new
approach to patients who need transplants," says James L.M. Ferrara,
M.D., director of the U-M Combined Bone Marrow Transplant Program and a
senior author on the study. Ferrara is also professor of internal
medicine and pediatric and communicable diseases at U-M.
"These HDAC inhibitors were thought to just kill cancer cells, but at
lower doses, it's possible they can modulate a number of immune
diseases," says Pavan Reddy, M.D., the study's lead and corresponding
author, and an assistant professor of internal medicine at the U-M
Medical School. "The mechanism we have identified in graft-versus-host
disease may be involved in autoimmune diseases as well."
Context
Bone marrow stem cell transplants are most commonly used to treat
leukemia and lymphoma. By repleni****ng depleted blood cells, the
transplants allow higher doses of chemotherapy to more effectively get
rid of cancer cells.
But as many as half of bone marrow transplant recipients develop acute
or chronic symptoms of graft-versus-host disease, which can affect the
skin, liver and gastrointestinal tract. Reddy calls the disease "the
single biggest barrier to bone marrow transplant."
The study suggests a novel way to treat graft-versus-host disease with
an already available drug that is stirring considerable interest as an
anti-cancer agent. The FDA approved SAHA, marketed under the name
Vorinostat, as a treatment for one kind of lymphoma in 2006 and for
leukemia in 2007. SAHA is being used off label for other cancers,
including lung, brain and colon cancer.
The U-M study adds to a growing body of research suggesting HDAC
inhibitors also may be useful tools to reign in misguided immune
responses. Researchers elsewhere have recently shown that HDAC
inhibitors have been beneficial in animal studies of lupus and
inflammatory bowel disease. Other studies suggest the drugs could be
useful in regulating the immune response in heart and islet cell
transplants.
Research details
The U-M researchers studied the responses of immune system dendritic
cells in mice given SAHA and ITF 2357, another new HDAC inhibitor.
Dendritic cells are im****tant immune system cells whose varied roles are
beginning to be fully understood.
The scientists looked at the two HDAC inhibitors' effects on mouse and
human dendritic cells in culture. They found that as they suspected, the
drugs acted to diminish the dendritic cells' key role in promoting
pro-inflammatory proteins called cytokines. Specifically, the
researchers found that the HDAC inhibitors increase the expression of
IDO, an enzyme which represses dendritic cell activity.
They tested the HDAC inhibitors in mice bred to display the effects of
graft -versus-host disease. When they injected the mice with dendritic
cells treated with the drugs, they found the drugs were able to reduce
the disease's effects.
The clinical trial: The trial is not yet recruiting patients. For
questions and information on the U-M bone marrow transplant program,
contact the U-M Cancer AnswerLine, 800-865-1125, .edu
Journal citation: Journal of Clinical Investigation, Vol. 118, no. 7,
July 2008.
Funding: National Institutes of Health, Doris Duke Clinical Scientist
Development Award, Amy Strelzer Manasevit-National Marrow Donor Program
Additional authors: Yaping Sun, M.D., Ph.D., Elizabeth Weisiger, B.S.,
Yo****nobu Maeda, M.D., Ph.D., Oleg Krijanovski, M.D., Ph.D., Chelsea
Malter, B.S. and Tomorni Toubai, M.D., Ph.D., U-M Department of Internal
Medicine; Raimon Duran Struuck, D.V.M., Shawn G. Clouthier, M.S., Isao
Tawara, M.D., Ph.D. and Erin Gatza, Ph.D., Department of Pediatrics, U-M
Comprehensive Cancer Center; Cen Liu, M.D., Ph.D., University of
Florida; Paolo Mascagni, Ph.D., ItalFarmaco S.p.A., Milan, Italy; and
Charles A. Dinarello, M.D., University of Colorado Health Sciences
Center.
------------------------------------------------------------------------
Adapted from materials provided by University of Michigan Health System,
via EurekAlert!, a service of AAAS.
Need to cite this story in your essay, paper, or re****t? Use one of the
following formats:
APA
MLA
J Clin Invest. 2008 Jul 1;118(7):2562-2573.
Histone deacetylase inhibition modulates indoleamine
2,3-dioxygenase-dependent DC functions and regulates experimental
graft-versus-host disease in mice.
* Reddy P,
* Sun Y,
* Toubai T,
* Duran-Struuck R,
* Clouthier SG,
* Weisiger E,
* Maeda Y,
* Tawara I,
* Krijanovski O,
* Gatza E,
* Liu C,
* Malter C,
* Mascagni P,
* Dinarello CA,
* Ferrara JL.
Department of Internal Medicine and Department of Pediatrics, University
of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA.
Department of Pathology, University of Florida, Gainesville, Florida,
USA. ItalFarmaco S.p.A, Milan, Italy. Department of Medicine, University
of Colorado Health Sciences Center, Denver, Colorado, USA.
Histone deacetylase (HDAC) inhibitors are antitumor agents that also
have antiinflammatory properties. However, the mechanisms of their
immunomodulatory functions are not known. We investigated the mechanisms
of action of 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA)
and ITF 2357, on mouse 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 the in vitro and in vivo allostimulatory responses induced
by the DCs. In addition, injection of DCs treated ex vivo with HDAC
inhibitors reduced experimental graft-versus-host disease (GVHD) in a
murine allogeneic BM transplantation model. Exposure of DCs to HDAC
inhibitors increased expression of indoleamine 2,3-dioxygenase (IDO), a
suppressor of DC function. Blockade of IDO in WT DCs with siRNA and with
DCs from IDO-deficient animals caused substantial reversal of HDAC
inhibition-induced in vitro suppression of DC-stimulated responses.
Direct injection of HDAC inhibitors early after allogeneic BM
transplantation to chimeric animals whose BM-derived cells lacked IDO
failed to protect from GVHD, demonstrating an in vivo functional role
for IDO. Together, these data show that HDAC inhibitors regulate
multiple DC functions through the induction of IDO and suggest that they
may represent a novel class of agents to treat immune-mediated diseases.
PMID: 18568076
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]
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 doesnıt 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>
IDO represses the immune system by degrading tryptophan (the precursor
to s*****onin; tryptophan promotes ovulation and may improve performance
under stress) which is im****tant to the function of T-cells; tumors can
recruit IDO secreting dendritic cells to protect themselves from the
immune system
<http://www.sciencedaily.com/releases/2004/07/040716081345.htm>
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]
in a mouse model of hepatitis B, IDO is upregulated in liver cells [PMID
18397228]; hepatatis C in people also upregulates IDO [PMID 17229698];
HIV/AIDS upregulates IDO [PMID 17430110]
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 s*****onin (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]
IFN-gamma is higher in patients with acute measles and after
vaccination; it exhibits protective functions in brains of patients with
subacute sclerosing panencephalitis, and IFN-gamma mediates a
noncytolytic clearance of measles virus (MV) from rodent brains; while
attenuated measles (MV) strains are more sensitive to IFN-alpha/beta
than are wild-type strains, IFN-gamma inhibits the replication of all MV
strains in epithelial, endothelial, and astroglial cells, but not in
lymphoid and neuronal cell lines; the antiviral activity induced by
IFN-gamma correlates with the induction of indoleamine 2,3-dioxygenase
(IDO), an enzyme of the tryptophan degradation pathway known to mediate
antiviral as well as antibacterial and antiparasitic effects; IFN-gamma
antiviral activity can be blocked by excess amounts of l-tryptophan,
indicating a specific role of IDO in the anti-MV activity [PMID 15919929]
mammalian chitinases digest chitin; chitin is an abundant polysaccharide
found in fungi, insects, and parasitic nematodes; innate immune host
defense against chitin-containing pathogens include production of
chitinases; in human lower airways, acidic mammalian chitinase (AMCase)
is produced in epithelial cells via a Th2-specific, IL-13-dependent
pathway and may act as an inflammatory mediator in asthma; in eleven
controls vs. twenty-two subjects with chronic rhinosinusitis (CRS), RNA
from ethmoid mucosa was collected and patients were observed over six
monthes after sinus surgery to *****s for polyp recurrence; patients
were classified as either recalcitrant or responsive to therapy based on
the presence or absence of polyps; AMCase mRNA was detected in the sinus
mucosa of 72% of control subjects and 72% of patients with eosinophilic
CRS with nasal polyps (CRSwNP); expression of AMCase was significantly
greater in recalcitrant CRSwNP than in treatment-responsive CRSwNP;
there was no significant difference in IL-13 expression between these
two groups; AMCase may be an im****tant mediator in the pathogenesis of
Th2 inflammatory diseases of the respiratory tract; failure of medical
and surgical therapy in CRSwNP is associated with significantly
increased expression of AMCase but not Th2 cytokines IL-13 and eotaxin
[PMID 16871939]; cerulenin and sodium butyrate inhibit chitin synthesis
in Candida albicans; in vitro studies with isolated membrane-bound
chitin synthase from C. albicans showed neither agent affected the level
of either unactivated or trypsin-activated enzyme activity; more studies
utilizing protoplasts revealed that early in the cell wall regeneration
process, cells treated with cerulenin or butyrate synthesized chitin at
a rate equal to untreated controls as measured by uptake of [3H]GlcNAc
but after 40 min of incubation, the incor****ation of [3H]GlcNAc into
chitin is reduced in cells treated with either agent; on the other hand,
samples taken during the same time intervals suggested that the amount
of chitin synthesis in treated and untreated cells was identical; a
marked drop in fluorescence was observed in similar experiments using
polyoxin D, a direct inhibitor of chitin synthase activity; experiments
that measured uptake of [3H]GlcNAc into both whole cells and protoplasts
demonstrated that cerulenin and butyrate had no effect on the trans****t
of the chitin precursor [PMID 2957042]; Candida albicans germination in
liquid medium was inhibited by the antilipogenic agent cerulenin and
sodium butyrate; these inhibitors prevented germ tube emergence at
concentrations of 1 microgram/ml and 20 mM, respectively but neither
significantly affected cell viability; cerulenin treatment resulted in
inhibition of lipid biosynthesis but lipid biosynthetic capabilities
remained unaltered in sodium butyrate-supplemented cultures; because
each inhibitor blocks germination by different mechanisms, their utility
in distingui****ng events directly correlated to germination was
examined; in this context, chitin synthase activity was inhibited by
both compounds, confirming the im****tance of chitin biosynthesis in C.
albicans germination [PMID 6357077]
SSRIs are an effective antifungal [PMID 11733460]
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