Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia

Immune mechanisms contribute to cerebral ischemic injury. Therapeutic immunosuppressive options are limited due to systemic side effects. We attempted to achieve immunosuppression in the brain through oral tolerance to myelin basic protein (MBP). Lewis rats were fed low-dose bovine MBP or ovalbumin (1 mg, five times) before 3 h of middle cerebral artery occlusion (MCAO). A third group of animals was sensitized to MBP but did not survive the post-stroke period. Infarct size at 24 and 96 h after ischemia was significantly less in tolerized animals. Tolerance to MBP was confirmed in vivo by a decrease in delayed-type hypersensitivity to MBP. Systemic immune responses, characterized in vitro by spleen cell proliferation to Con A, lipopolysaccharide, and MBP, again confirmed antigen-specific immunologic tolerance. Immunohistochemistry revealed transforming growth factor β1 production by T cells in the brains of tolerized but not control animals. Systemic transforming growth factor β1 levels were equivalent in both groups. Corticosterone levels 24 h after surgery were elevated in all sham-operated animals and ischemic control animals but not in ischemic tolerized animals. These results demonstrate that antigen-specific modulation of the immune response decreases infarct size after focal cerebral ischemia and that sensitization to the same antigen may actually worsen outcome.

An Arabidopsis mutant that requires increased calcium for potassium nutrition and salt tolerance

Potassium (K+) nutrition and salt tolerance are key factors controlling plant productivity. However, the mechanisms by which plants regulate K+ nutrition and salt tolerance are poorly understood. We report here the identification of an Arabidopsis thaliana mutant, sos3 (salt-overly-sensitive 3), which is hypersensitive to Na+ and Li+ stresses. The mutation is recessive and is in a nuclear gene that maps to chromosome V. The sos3 mutation also renders the plant unable to grow on low K+. Surprisingly, increased extracellular Ca2+ suppresses the growth defect of sos3 plants on low K+ or 50 mM NaCl. In contrast, high concentrations of external Ca2+ do not rescue the growth of the salt-hypersensitive sos1 mutant on low K+ or 50 mM NaCl. Under NaCl stress, sos3 seedlings accumulated more Na+ and less K+ than the wild type. Increased external Ca2+ improved K+/Na+ selectivity of both sos3 and wild-type plants. However, this Ca2+ effect in sos3 is more than twice as much as that in the wild type. In addition to defining the first plant mutant with an altered calcium response, these results demonstrate that the SOS3 locus is essential for K+ nutrition, K+/Na+ selectivity, and salt tolerance in higher plants.

Human V delta 2+ gamma delta T-cell tolerance to foreign antigens of Toxoplasma gondii.

Little is known about the mechanisms involved in human gammadelta T-cell tolerance to self or to foreign antigens. Patients with congenital toxoplasmosis offer a unique opportunity to examine Vdelta2+ gammadelta T-cell tolerance. Analysis of gammadelta T cells in patients with congenital toxoplasmosis revealed evidence for anergy of these cells with or without clonal Vdelta2+ gammadelta T-cell expansion in the acute phase of the Toxoplasma infection. T cells in general were unresponsive and did not proliferate upon exposure to mitogens or to Toxoplasma lysate antigens or in response to live Toxoplasma-infected cells when the congenitally infected infants were 1 month of age, and they exhibited selective anergy to Toxoplasma lysate antigens and live Toxoplasma-infected cells when the infants were aged 5 months. During the chronic phase of congenital toxoplasmosis in the patients who were more than I year of age, the repertoires of the gammadelta T-cell receptors were found to be within normal ranges. In addition, in the chronic phase, the gammadelta T cells proliferated and secreted gamma-interferon in response to exposure to live Toxoplasmia-infected cells. By contrast, alphabeta T cells remained anergic. Vdelta2+ gammadelta T cells have been considered to undergo extrathymic maturation and thus to be subject to development of peripheral tolerance. Our findings indicate that Vdelta2+ gammadelta T-cell tolerance was lost in these infected infants earlier than alphabeta T-cell tolerance. These findings suggest that gammadelta T cells play a role in protection against Toxoplasma gondii in the chronic phase when congenitally infected children are more than 1 year of age, especially in those in whom alphabeta T cells continue to exhibit deficits in specific immune responses to Toxoplasma antigens.

Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires.

Immunological self-tolerance is ensured by eliminating or inhibiting self-reactive lymphocyte clones, creating physical or functional holes in the B- and T-lymphocyte antigen receptor repertoires. The nature and size of these gaps in our immune defenses must be balanced against the necessity of mounting rapid immune responses to an everchanging array of foreign pathogens. To achieve this balance, only a fraction of particularly hazardous self-reactive clones appears to be physically eliminated from the repertoire in a manner that fully prevents their recruitment into an antimicrobial immune response. Many self-reactive cells are retained with a variety of conditional and potentially flexible restraints: (i) their ability to be triggered by antigen is diminished by mechanisms that tune down signaling by their antigen receptors, (ii) their ability to carry out inflammatory effector functions can be inhibited, and (iii) their capacity to migrate and persist is constrained. This balance between tolerance and immunity can be shifted, altering susceptibility to autoimmune disease and to infection by genetic or environmental differences either in the way antigens are presented, in the tuning molecules that adjust triggering set points for lymphocyte responses to antigen, or in the effector molecules that eliminate, retain, or expand particular clones.

Oral tolerance in myelin basic protein T-cell receptor transgenic mice: suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells.

Orally administered antigens induce a state of immunologic hyporesponsiveness termed oral tolerance. Different mechanisms are involved in mediating oral tolerance depending on the dose fed. Low doses of antigen generate cytokine-secreting regulatory cells, whereas high doses induce anergy or deletion. We used mice transgenic for a T-cell receptor (TCR) derived from an encephalitogenic T-cell clone specific for the acetylated N-terminal peptide of myelin basic protein (MBP) Ac-1-11 plus I-Au to test whether a regulatory T cell could be generated from the same precursor cell as that of an encephalitogenic Th1 cell and whether the induction was dose dependent. The MBP TCR transgenic mice primarily have T cells of a precursor phenotype that produce interleukin 2 (IL-2) with little interferon gamma (IFN-gamma), IL-4, or transforming growth factor beta (TGF-beta). We fed transgenic animals a low-dose (1 mg x 5) or high-dose (25 mg x 1) regimen of mouse MBP and without further immunization spleen cells were tested for cytokine production. Low-dose feeding induced prominent secretion of IL-4, IL-10, and TGF-beta, whereas minimal secretion of these cytokines was observed with high-dose feeding. Little or no change was seen in proliferation or IL-2/IFN-gamma secretion in fed animals irrespective of the dose. To demonstrate in vivo functional activity of the cytokine-secreting cells generated by oral antigen, spleen cells from low-dose-fed animals were adoptively transferred into naive (PLJ x SJL)F1 mice that were then immunized for the development of experimental autoimmune encephalomyelitis (EAE). Marked suppression of EAE was observed when T cells were transferred from MBP-fed transgenic animals but not from animals that were not fed. In contrast to oral tolerization, s.c. immunization of transgenic animals with MBP in complete Freund's adjuvant induced IFN-gamma-secreting Th1 cells in vitro and experimental encephalomyelitis in vivo. Despite the large number of cells reactive to MBP in the transgenic animals, EAE was also suppressed by low-dose feeding of MBP prior to immunization. These results demonstrate that MBP-specific T cells can differentiate in vivo into encephalitogenic or regulatory T cells depending upon the context by which they are exposed to antigen.

Aod1, the immunoregulatory locus controlling abrogation of tolerance in neonatal thymectomy-induced autoimmune ovarian dysgenesis, maps to mouse chromosome 16.

Mice thymectomized at three days of age (D3Tx) develop during adulthood a variety of organ-specific autoimmune diseases, including autoimmune ovarian dysgenesis (AOD). The phenotypic spectrum of AOD is characterized by the development of anti-ovarian autoantibodies, oophoritis, and atrophy. The D3Tx model of AOD is unique in that disease induction depends exclusively on perturbation of the normal developing immune system, is T-cell-mediated, and is strain specific. For example, D3Tx A/J mice are highly susceptible to AOD, whereas C57BL/6J mice are resistant. After D3Tx, self ovarian antigens, expressed at physiological levels, trigger an autoimmune response capable of eliciting disease. The D3Tx model provides, therefore, the opportunity to focus on the mechanisms of self-tolerance that are relevant to disease pathogenesis. Previous studies indicate that the principal mechanisms involved in AOD susceptibility are genetically controlled and govern developmental processes associated with the induction and maintenance of peripheral tolerance. We report here the mapping of the Aod1 locus to mouse chromosome 16 within a region encoding several loci of immunologic relevance, including scid, Igl1, VpreB, Igll, Igl1r, Mtv6 (Mls-3), Ly-7, Ifnar, and Ifgt.

Evidence for a role of endothelin 1 and protein kinase C in nitroglycerin tolerance.

We sought to examine mechanisms responsible for increased vasoconstriction that occurs during development of nitroglycerin tolerance. Rabbits were treated for 3 days with nitroglycerin patches (0.4 mg/hr), and their aortic segments were studied in organ chambers. This treatment resulted in attenuated in vitro relaxations to nitroglycerin and increased contractile sensitivity to angiotensin II, serotonin, phenylephrine, KCl, and a direct activator of protein kinase C, the phorbol ester phorbol 12,13-dibutyrate. The protein kinase C antagonists calphostin C (100 nM) and staurosporine (10 nM) corrected the hypersensitivity to constrictors in tolerant vessels, yet had minimal effects on constrictions in control vessels. Paradoxically, constrictions caused by endothelin 1 were decreased in nitrate-tolerant vessels. Immunocytochemical analysis revealed intense endothelin 1-like and big endothelin 1-like immunoreactivity in the media of nitroglycerin-tolerant but not of control aortas. The enhanced vasoconstriction to angiotensin II, serotonin, KCl, and phenylephrine could be mimicked in normal vessels by addition of subthreshold concentrations of endothelin 1, and this effect was prevented by calphostin C. We propose that increased autocrine production of endothelin 1 in nitrate tolerance sensitizes vascular smooth muscle to a variety of vasoconstrictors through a protein kinase C-mediated mechanism.

Induction and transmission of Bacillus thuringiensis tolerance in the flour moth Ephestia kuehniella

The use of Bacillus thuringiensis (Bt) endotoxins to control insect vectors of human diseases and agricultural pests is threatened by the possible evolution of resistance in major pest species. In addition to high levels of resistance produced by receptor insensitivity (5, 16, 17), several cases of tolerance to low to medium levels of toxin have been reported in laboratory colonies of lepidopteran species (3, 18). Because the molecular basis of some of these cases of tolerance to the toxin are not known, we explored alternative mechanisms. Here, we present evidence that tolerance to a Bt formulation in a laboratory colony of the flour moth Ephestia kuehniella can be induced by preexposure to a low concentration of the Bt formulation and that the tolerance correlates with an elevated immune response. The data also indicate that both immune induction and Bt tolerance can be transmitted to offspring by a maternal effect and that their magnitudes are determined by more than one gene.

Deletion of guanine nucleotide binding protein az subunit in mice induces a gene dose dependent tolerance to morphine

The Mechanism Underlying the development of tolerance to morphine, is still incompletely understood. Morphine binds to opioid receptors, Which in turn activates downstream second messenger cascades through heterotrimeric guanine nucleotide binding proteins (G proteins). In this paper, we show that G(z), a member of the inhibitory G protein family, plays an important role in mediating the analgesic and lethality effects of morphine after tolerance development. We blocked signaling through the G(z) second messenger cascade by genetic ablation of the alpha subunit of the G protein in mice. The Galpha(z) knockout Mouse develops significantly increased tolerance to morphine. which depends oil Galpha(z), gene dosage. Further experiments demonstrate that the enhanced morphine tolerance is not caused by pharmacokinetic and behavioural learning mechanisms. The results suggest that G(z) signaling pathways are involved ill transducing the analgesic and lethality effects of morphine following chronic morphine treatment. (C) 2004 Elsevier Ltd. All rights reserved.

Boron nutrition and chilling tolerance of warm climate crop species

Background Field observations and glasshouse studies have suggested links between boron (B)-deficiency and leaf damage induced by low temperature in crop plants, but causal relationships between these two stresses at physiological, biochemical and molecular levels have yet to be explored. Limited evidence at the whole-plant level suggests that chilling temperature in the root zone restricts B uptake capacity and/or B distribution/utilization efficiency in the shoot, but the nature of this interaction depends on chilling tolerance of species concerned, the mode of low temperature treatment (abrupt versus gradual temperature decline) and growth conditions (e.g. photon flux density and relative humidity) that may exacerbate chilling stress. Scope This review explores roles of B nutrition in chilling tolerance of continual root or transient shoot chills in crop species adapted to warm season conditions. It reviews current research on combined effects of chilling temperature (ranging from > 0 to 20 degrees C) and B deficiency on growth and B nutrition responses in crop species differing in chilling tolerance. Conclusion For subtropical/tropical species (e.g. cucumber, cassava, sunflower), root chilling at 10-17 degrees C decreases B uptake efficiency and B utilization in the shoot and increases the shoot : root ratio, but chilling-tolerant temperate species (e.g. oilseed rape, wheat) require much lower root chill temperatures (2-5 degrees C) to achieve the same responses. Boron deficiency exacerbates chilling injuries in leaf tissues, particularly under high photon flux density. Suggested mechanisms for B x chilling interactions in plants are: (a) chilling-induced reduction in plasmalemma hydraulic conductivity, membrane fluidity, water channel activity and root pressure, which contribute to the decrease in root hydraulic conductance, water uptake and associated B uptake; (b) chilling-induced stomatal dysfunction affecting B transport from root to shoot and B partitioning in the shoot; and (c) B deficiency induced sensitivity to photo-oxidative damage in leaf cells. However, specific evidence for each of the mechanisms is still lacking. Impacts of B status on chilling tolerance in crop species have important implications for the management of B supply during sensitive stages of growth, such as early growth after planting and early reproductive development, both of which can coincide with the occurrence of chilling temperatures in the field.

Improving drought tolerance in rainfed lowland rice: An example from Thailand

A large portion of the world's poor farm in rainfed systems where the water supply is unpredictable and droughts are common. In Thailand there are approximately 6.2 million ha of rain fed lowland rice, which account for 67% of the country's total rice-growing area. This rice system is often characterised by too much and too little water in the same season. Farmers' estimates of their annual losses to drought are as high as 45% in the upper parts of the toposequence. In contrast to irrigated rice systems, gains from crop improvement of rainfed rice have been modest, in part because there has been little effort to breed and select for drought tolerance for the target rainfed environments. The crop improvement strategy being used in Thailand considers three mechanisms that influence yield in the drought prone targets: yield potential as an important mechanism for mild drought (where yield loss is less than 50%), drought escape (appropriate phenology) and drought tolerance traits of leaf water potential, sterility, flower delay and drought response index for more severe drought conditions. Genotypes are exposed to managed drought environments for selection of drought tolerant genotypes. A marker assisted selection (MAS) scheme has been developed and applied for selection of progenies in the backcrossing program. The plant breeding program uses rapid generation advance techniques that enable early yield testing in the target population of environments (TPE) through inter-station (multi-location yield testing) and on-farm trials. A farmer participatory approach has been used to identify the TPE for the breeding program. Four terrace paddy levels have been identified, upper (drought), middle (drought prone to favorable) and lower (flooded). This paper reports the change in the breeding program for the drought prone tainted lowland rice environments of North and Northeast Thailand by incorporating our knowledge on adaptation and on response of rice to drought. (c) 2005 Elsevier B.V. All rights reserved.

Proprioceptive neuromuscular facilitation stretching - Mechanisms and clinical implications

Proprioceptive neuromuscular facilitation (PNF) stretching techniques are commonly used in the athletic and clinical environments to enhance both active and passive range of motion (ROM) with a view to optimising motor performance and rehabilitation. PNF stretching is positioned in the literature as the most effective stretching technique when the aim is to increase ROM, particularly in respect to short-term changes in ROM. With due consideration of the heterogeneity across the applied PNF stretching research, a summary of the findings suggests that an 'active' PNF stretching technique achieves the greatest gains in ROM, e.g. utilising a shortening contraction of the opposing muscle to place the target muscle on stretch, followed by a static contraction of the target muscle. The inclusion of a shortening contraction of the opposing muscle appears to have the greatest impact on enhancing ROM. When including a static contraction of the target muscle, this needs to be held for approximately 3 seconds at no more than 20% of a maximum voluntary contraction. The greatest changes in ROM generally occur after the first repetition and in order to achieve more lasting changes in ROM, PNF stretching needs to be performed once or twice per week. The superior changes in ROM that PNF stretching often produces compared with other stretching techniques has traditionally been attributed to autogenic and/or reciprocal inhibition, although the literature does not support this hypothesis. Instead, and in the absence of a biomechanical explanation, the contemporary view proposes that PNF stretching influences the point at which stretch is perceived or tolerated. The mechanism(s) underpinning the change in stretch perception or tolerance are not known, although pain modulation has been suggested.

Improving drought tolerance in rainfed lowland rice: an example from Thailand

A large portion of the world’s poor farm in rainfed systems where the water supply is unpredictable and droughts are common. In Thailand there are approximately 6.2 million ha of rain fed lowland rice which account for 67% of the country’s total rice-growing area. This rice system is often characterised by too much and too little water in the same season. Farmers’ estimates of their annual losses to drought are as high as 45% in the upper parts of the toposequence. In contrast to irrigated rice systems, gains from crop improvement of rainfed rice have been modest, in part because there has been little effort to breed and select for drought tolerance for the target rainfed environments. The crop improvement strategy being used in Thailand considers three mechanisms that influence yield in the drought prone targets: yield potential as an important mechanism for mild drought (where yield loss is less than 50%), drought escape (appropriate phenology) and drought tolerance traits of leaf water potential, sterility, flower delay and drought response index for more severe drought conditions. Genotypes are exposed to managed drought environments for selection of drought tolerant genotypes. A marker assisted selection (MAS) scheme has been developed and applied for selection of progenies in the backcrossing program. The plant breeding program uses rapid generation advance techniques that enable early yield testing in the target population of environments (TPE) through inter-station (multi-location yield testing) and on-farm trials. A farmer participatory approach has been used to identify the TPE for the breeding program. Four terrace paddy levels have been identified, upper (drought), middle (drought prone to favorable) and lower (flooded). This paper reports the change in the breeding program for the drought prone rainfed lowland rice environments of North and Northeast Thailand by incorporating our knowledge on adaptation and on response of rice to drought.

Contribution of potential yield, drought tolerance and escape to adaptation of 15 rice varieties in rainfed lowlands in Cambodia

In Cambodia, grain yield in rainfed lowland rice is often affected by drought during late vegetative or reproductive stage. Several experiments were conducted to quantify the contribution of potential yield, drought tolerance and drought escape mechanisms to yield under water stress conditions. In total nine pairs of well irrigated and simulated drought (by draining water) experiments were conducted. Potential yield was obtained under irrigation. Grain yields and flowering dates were recorded in 15 varieties. Drought tolerance was quantified by using drought response index (DRI), which is grain yield under drought adjusted for potential yield and flowering date of the variety. Drought escape is expressed as days to flower under drought conditions. Mean yield reduction due to drought of nine experiments was 27 % (range 12-44). The relative contribution of yield potential, flowering date and DRI to observe yield under drought were evaluated by multiple regression for each experiment. Potential yield accounted for 54% (with a range of 10-80) of the variation in actual yield under drought. This was followed by DRI and flowering date with 34 (with a range of 0-60) and 12 (with a range of 0-30) of the contribution, respectively. It is concluded that selecting for drought tolerance as well as for high yield potential would be important in developing cultivars for rainfed lowlands in Cambodia. Although flowering dates are important for drought escape, it had a small contribution probably because drought developed slowly in these experiments in Cambodia.

Corrosion mechanisms of duplex stainless steels in the petrochemical industry

The recent search for new sources of hydrocarbons has led to production from very severe environments which can contain considerable amounts of carbon dioxide, hydrogen sulphide, and chloride ions, combined with temperatures which can exceed 100°C. Oil and gas production from such wells requires highly corrosion-resistant materials. The traditional solution of using carbon steel with additional protection is generally inadequate in these very-aggressive environments. Duplex stainless steels (DSS) are attractive candidates because of their high strength, good general corrosion resistance, excellent resistance to chloride-induced stress corrosion cracking, and good weldability. Although duplex stainless steels have a very good reputation in both subsea and topsides pipework, it is recognized that the tolerance of these materials to variations in microstructure and chemical composition are still not fully understood. The object of this paper is to review the corrosion behaviour of duplex stainless steels in the petrochemical industry, with particular emphasis on microstructures and the effect of changes in chemical composition.