Who cares?
Marcus
On Jul 19, 11:31=A0pm, Kofi <k...@[EMAIL PROTECTED]
> wrote:
> 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. =A0IDO is indoleamine 2,3-dioxygenase. =A0It degrades
> tryptophan which is essential to T-cell survival.
>
> Of particular interest is butyrate, the bacterial byproduct of fiber
> digestion in the GI tract. =A0It=B9s an HDAC inhibitor. =A0Many of these
> autoimmune problems may be the result of a combining a sugary, low-fiber
> American diet with antibiotics - something that=B9s 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. =A0There's
> evidence Epstein Barr, responsible for chronic fatigue, HIV/AIDS and
> hepatatis upregulate IDO - perhaps to escape from certain T-cell
> attacks. =A0Other viruses like the measles can be damaged by IDO.
=A0This
> 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. =A0Perhaps 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) =8B 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:
>
> =A0APA
> =A0MLA
>
> =A0J 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.
> * =A0Reddy P,
> * =A0Sun Y,
> * =A0Toubai T,
> * =A0Duran-Struuck R,
> * =A0Clouthier SG,
> * =A0Weisiger E,
> * =A0Maeda Y,
> * =A0Tawara I,
> * =A0Krijanovski O,
> * =A0Gatza E,
> * =A0Liu C,
> * =A0Malter C,
> * =A0Mascagni P,
> * =A0Dinarello CA,
> * =A0Ferrara 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 doesn=B9t 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 =3D
> 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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