The predisposition of nonobese diabetic (NOD) mice to develop autoimmunity reflects deficiencies in both peripheral and central tolerance. Several defects have been described in these mice, among ...which aberrant antigen-presenting cell function and peroxynitrite formation. Prediabetes and diabetes in NOD mice have been targeted with different outcomes by a variety of immunotherapies, including interferon (IFN)-gamma. This cytokine may be instrumental in specific forms of tolerance by virtue of its ability to activate immunosuppressive tryptophan catabolism. Here, we provide evidence that IFN-gamma fails to induce tolerizing properties in dendritic cells from highly susceptible female mice early in prediabetes. This effect is associated with impaired tryptophan catabolism, is related to transient blockade of the Stat1 pathway of intracellular signaling by IFN-gamma, and is caused by peroxynitrite production. However, the use of a peroxynitrite inhibitor can rescue tryptophan catabolism and tolerance in those mice. This is the first report of an experimental autoimmune disease in which defective tolerance is causally linked to impaired tryptophan catabolism.
Type I diabetes mellitus is caused by autoimmune destruction of pancreatic beta cells, and effective treatment of the disease might require rescuing beta cell function in a context of reinstalled ...immune tolerance. Sertoli cells (SCs) are found in the testes, where their main task is to provide local immunological protection and nourishment to developing germ cells. SCs engraft, self-protect, and coprotect allogeneic and xenogeneic grafts from immune destruction in different experimental settings. SCs have also been successfully implanted into the central nervous system to create a regulatory environment to the surrounding tissue which is trophic and counter-inflammatory. We report that isolated neonatal porcine SC, administered alone in highly biocompatible microcapsules, led to diabetes prevention and reversion in the respective 88 and 81% of overtly diabetic (nonobese diabetic NOD) mice, with no need for additional beta cell or insulin therapy. The effect was associated with restoration of systemic immune tolerance and detection of functional pancreatic islets that consisted of glucose-responsive and insulin-secreting cells. Curative effects by SC were strictly dependent on efficient tryptophan metabolism in the xenografts, leading to TGF-beta-dependent emergence of autoantigen-specific regulatory T cells and recovery of beta cell function in the diabetic recipients.
Prediabetes and diabetes in nonobese diabetic (NOD) mice have been targeted by a variety of immunotherapies, including the use of a soluble form of cytotoxic T lymphocyte antigen 4 (CTLA-4) and ...interferon (IFN)-gamma. The cytokine, however, fails to activate tolerogenic properties in dendritic cells (DCs) from highly susceptible female mice early in prediabetes. The defect is characterized by impaired induction of immunosuppressive tryptophan catabolism, is related to transient blockade of the signal transducer and activator of transcription (STAT)1 pathway of intracellular signaling by IFN-gamma, and is caused by peroxynitrite production. Here, we show that soluble CTLA-4 imparts suppressive properties to DCs from early prediabetic NOD female mice through mechanisms that rely on autocrine signaling by IFN-gamma. Although phosphorylation of STAT1 in response to IFN-gamma is compromised in those mice, CTLA-4 obviates the defect. IFN-gamma-driven expression of tryptophan catabolism by CTLA-4-immunoglobulin is made possible through the concomitant activation of the Forkhead Box class O (FOXO) transcription factor FOXO3a, induction of the superoxide dismutase gene, and prevention of peroxynitrite formation.
Functional constipation is a common problem in childhood and has a great impact on social, physical, and emotional functioning of affected children and their caregivers. No organic cause of the ...constipation can be found in approximately 95% of children, defining the "so-called" chronic functional constipation. Its prevalence has been reported to range from 0.7 to 29.6%, with a median of 12%. The diagnosis of functional constipation is exclusively clinical based on the pediatric diagnostic Rome criteria for functional gastrointestinal disorders and does not routinely require laboratory and/or radiological investigations. In case of alarm signs and symptoms that may suggest organic diseases, further investigations can be required. The therapeutic management is based on non-pharmacological and pharmacological approaches. Education, demystification of constipation and reward-based toilet training represent the cornerstones of nonpharmacological management. Disimpaction, maintenance treatment and weaning of medication are all elements of pharmacological treatment. Osmotic laxatives, mainly polyethylene glycol (PEG), are considered the first-choice laxative for both disimpaction and maintenance treatment. The aim of this review is to provide pediatric gastroenterologists with a practical tool to support the clinical and therapeutic management of children and adolescents affected by chronic functional constipation.
Immunoregulatory antigen-presenting cells (APC) play an important role in maintaining T cell homeostasis and self-tolerance. In particular, recent evidence demonstrates a role for inhibition of T ...cell proliferation by macrophage tryptophan catabolism involving the activity of the enzyme indoleamine 2,3-dioxygenase (IDO). Dendritic cells (DC) have also been shown to exert immunoregulatory effects mediated by tryptophan catabolism and to cause T cell apoptosis. In the present study, we have comparatively analyzed the expression of IDO activity by murine macrophages and splenic DC. By means of PCR, Western blotting and measurements of enzyme functional activity, we obtained evidence that, different from macrophages, DC constitutively express IDO. Following activation by IFN-γ, the latter cells, in particular the CD8α+ subset, exhibit high functional activity and, unlike macrophages, mediate apoptosis of Th cells in vitro. Therefore, in the mouse, CD8α+ DC may be unique APC capable of fully expressing the IDO mechanism functionally.
Murine dendritic cells (DCs) can present Ag in an immunogenic or tolerogenic fashion, the distinction depending on either the occurrence of specialized DC subsets or the maturation or activation ...state of the DC. Although DC subsets may be programmed to direct either tolerance or immunity, it is not known whether appropriate environmental stimulation can result in complete flexibility of a basic program. Using splenic CD8(-) and CD8(+) DCs that mediate the respective immunogenic and tolerogenic presentation of self peptides, we show that both the in vivo and in vitro activities of either subset can be altered by ligation of specific surface receptors. Otherwise immunogenic CD8(-) DCs become tolerogenic upon B7 ligation by soluble CTLA-4, a maneuver that initiates immunosuppressive tryptophan catabolism. In contrast, CD40 ligation on tolerogenic CD8(+) DCs makes these cells capable of immunogenic presentation. Thus, environmental conditioning by T cell ligands may alter the default function of DC subsets to meet the needs of flexibility and redundancy.
Almahata Sitta (AhS), an anomalous polymict ureilite, is the first meteorite observed to originate from a spectrally classified asteroid (2008 TC3). However, correlating properties of the meteorite ...with those of the asteroid is not straightforward because the AhS stones are diverse types. Of those studied prior to this work, 70–80% are ureilites (achondrites) and 20–30% are various types of chondrites. Asteroid 2008 TC3 was a heterogeneous breccia that disintegrated in the atmosphere, with its clasts landing on Earth as individual stones and most of its mass lost. We describe AhS 91A and AhS 671, which are the first AhS stones to show contacts between ureilitic and chondritic materials and provide direct information about the structure and composition of asteroid 2008 TC3. AhS 91A and AhS 671 are friable breccias, consisting of a C1 lithology that encloses rounded to angular clasts (<10 μm to 3 mm) of olivine, pyroxenes, plagioclase, graphite, and metal‐sulfide, as well as chondrules (~130–600 μm) and chondrule fragments. The C1 material consists of fine‐grained phyllosilicates (serpentine and saponite) and amorphous material, magnetite, breunnerite, dolomite, fayalitic olivine (Fo 28‐42), an unidentified Ca‐rich silicate phase, Fe,Ni sulfides, and minor Ca‐phosphate and ilmenite. It has similarities to CI1 but shows evidence of heterogeneous thermal metamorphism. Its bulk oxygen isotope composition (δ18O = 13.53‰, δ17O = 8.93‰) is unlike that of any known chondrite, but similar to compositions of several CC‐like clasts in typical polymict ureilites. Its Cr isotope composition is unlike that of any known meteorite. The enclosed clasts and chondrules do not belong to the C1 lithology. The olivine (Fo 75‐88), pyroxenes (pigeonite of Wo ~10 and orthopyroxene of Wo ~4.6), plagioclase, graphite, and some metal‐sulfide are ureilitic, based on mineral compositions, textures, and oxygen isotope compositions, and represent at least six distinct ureilitic lithologies. The chondrules are probably derived from type 3 OC and/or CC, based on mineral and oxygen isotope compositions. Some of the metal‐sulfide clasts are derived from EC. AhS 91A and AhS 671 are plausible representatives of the bulk of the asteroid that was lost. Reflectance spectra of AhS 91A are dark (reflectance ~0.04–0.05) and relatively featureless in VNIR, and have an ~2.7 μm absorption band due to OH− in phyllosilicates. Spectral modeling, using mixtures of laboratory VNIR reflectance spectra of AhS stones to fit the F‐type spectrum of the asteroid, suggests that 2008 TC3 consisted mainly of ureilitic and AhS 91A‐like materials, with as much as 40–70% of the latter, and <10% of OC, EC, and other meteorite types. The bulk density of AhS 91A (2.35 ± 0.05 g cm−3) is lower than bulk densities of other AhS stones, and closer to estimates for the asteroid (~1.7–2.2 g cm−3). Its porosity (36%) is near the low end of estimates for the asteroid (33–50%), suggesting significant macroporosity. The textures of AhS 91A and AhS 671 (finely comminuted clasts of disparate materials intimately mixed) support formation of 2008 TC3 in a regolith environment. AhS 91A and AhS 671 could represent a volume of regolith formed when a CC‐like body impacted into already well‐gardened ureilitic + impactor‐derived debris. AhS 91A bulk samples do not show a solar wind component, so they represent subsurface layers. AhS 91A has a lower cosmic ray exposure (CRE) age (~5–9 Ma) than previously studied AhS stones (11–22 Ma). The spread in CRE ages argues for irradiation in a regolith environment. AhS 91A and AhS 671 show that ureilitic asteroids could have detectable ~2.7 μm absorption bands.
T cell apoptosis by kynurenines Fallarino, Francesca; Grohmann, Ursula; Vacca, Carmine ...
Advances in experimental medicine and biology,
2003, Volume:
527
Journal Article
Peer reviewed
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that, expressed by different cell types, has regulatory effects on T cells resulting from tryptophan depletion in specific local ...tissue microenvironments. The discovery that inhibition of IDO activity reduces the survival of MHC-mismatched fetuses in mice and that the risk of fetal allograft rejection correlates with the degree of parental tissue incompatibility has led to the hypothesis that IDO activity protects fetal allografts from maternal T cell-mediated immunity. Different mechanisms, however, might contribute to IDO-dependent immune regulation. We have found that tryptophan metabolites in the kynurenine pathway, such as 3-hydroxyanthranilic and quinolinic acids, will induce the selective apoptosis in vitro of murine thymocytes and Th1 but not Th2 cells. T cell apoptosis was observed at relatively low concentrations of kynurenines, did not require Fas/Fas ligand interactions and was associated with the activation of casapase-8 and the release of cytochrome c from mitochondria. In vivo, the two kynurenines caused depletion of specific thymocyte subsets in a fashion qualitatively similar to dexamethasone. These data may represent the first experimental evidence for the involvement of tryptophan catabolism in the regulation of T cell apoptosis and maintenance of peripheral T cell tolerance.
► Greater mycorrhizal colonization in the C
3
Leymus than in C
4 genotypes. ► Among the native genotypes, greatest mycorrhizal colonization in
P. vaginatum. ► Unabated mycorrhizal colonization in ...defoliated plants of all study genotypes.
Pappophorum vaginatum is the most abundant C
4, warm-season perennial grass in rangelands of northeastern, arid Patagonia, which is often exposed to continuous grazing.
Eragrostis curvula is the only naturalized, C
4 warm-season genotype that has successfully established from seed during moist years in the study region, that is characterized by a scarce forage availability to livestock during the spring and summer. Successful introduction of perennial forage genotypes is then critical in that region. No studies have yet been conducted to determine the greater abundance of
P. vaginatum compared to that of other native C
4 grass genotypes (
Aristida subulata,
A. spegazzinii,
Sporobolus cryptandrus) in the study area. The effect of defoliation on arbuscular mycorrhizal colonization was investigated on the four native, one naturalized and five introduced, C
3 perennial grass genotypes (
Leymus cinereus cvs. “Magnar” and “Trailhead”, and
Achnatherum hymenoides cvs. “Paloma”, “Rimrock” and “Nezpar”) growing at the field. We hypothesized that the magnitude of mycorrhizal colonization (1) is similar on defoliated than on undefoliated plants of the native and naturalized genotypes, (2) is greater in the native and naturalized than in the introduced genotypes, and (3) is greatest in
P. vaginatum than in all remaining genotypes. Plants of all ten genotypes were either exposed or not to a severe defoliation twice in the growing seasons of 2007/2008 and 2008/2009. The results showed that all studied genotypes maintained arbuscular mycorrhizal colonization levels following defoliation similar to undefoliated controls. The greatest arbuscular mycorrhizal colonization was often found on both cultivars of
L. cinereus among all genotypes. The greatest arbuscular mycorrhizal colonization in
P. vaginatum than in the other native genotypes at the end of the study, parameter that contributes to defoliation tolerance, could help to explain its greater abundance in rangelands of central Argentina. The higher arbuscular mycorrhizal colonization in both cultivars of
L. cinereus might contribute to their successful establishment and survival in rangelands of northeastern, arid Patagonia. Genotype introduction in these rangelands is likely to affect community dynamics because of variable effects of the mycorrhizal symbiosis on the various plant genotypes.
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