Regulatory T cells in transplantation tolerance

The identification and characterization of regulatory T (T(Reg)) cells that can control immune responsiveness to alloantigens have opened up exciting opportunities for new therapies in transplantation. After exposure to alloantigens in vivo, alloantigen-specific immunoregulatory activity is enriched in a population of CD4+ T cells that express high levels of CD25. In vivo, common mechanisms seem to underpin the activity of CD4+CD25+ T(Reg) cells in both naive and manipulated hosts. However, the origin, allorecognition properties and molecular basis for the suppressive activity of CD4+CD25+ T(Reg) cells, as well as their relationship to other populations of regulatory cells that exist after transplantation, remain a matter of debate..     

Naturally arising CD25+CD4+ regulatory T cells in maintaining immunologic self-tolerance and preventing autoimmune disease

A large body of evidence indicates that T cell-mediated dominant suppression of self-reactive T cells is indispensable for maintaining immunologic unresponsiveness to self-constituents (i.e., self-tolerance) and preventing autoimmune disease. CD25+CD4+ regulatory T cells naturally present in normal animals, in particular, engage in this function, as their reduction or functional abnormality leads to the development of autoimmune disease in otherwise normal animals. They are at least in part produced by the normal thymus as a functionally mature and distinct subpopulation of T cells. Recent studies have demonstrated that CD25+CD4+ regulatory T cells control not only autoimmune reactions but also other immune responses, including tumor immunity, transplantation tolerance and microbial infection. Thus, this unique population of regulatory T cells can be exploited to control pathological as well as physiological immune responses.     

Double antisense plants lacking ascorbate peroxidase and catalase are less sensitive to oxidative stress than single antisense plants lacking ascorbate peroxidase or catalase

The plant genome is a highly redundant and dynamic genome. Here, we show that double antisense plants lacking the two major hydrogen peroxide-detoxifying enzymes, ascorbate peroxidase (APX) and catalase (CAT), activate an alternative/redundant defense mechanism that compensates for the lack of APX and CAT. A similar mechanism was not activated in single antisense plants that lacked APX or CAT, paradoxically rendering these plants more sensitive to oxidative stress compared to double antisense plants. The reduced susceptibility of double antisense plants to oxidative stress correlated with suppressed photosynthetic activity, the induction of metabolic genes belonging to the pentose phosphate pathway, the induction of monodehydroascorbate reductase, and the induction of IMMUTANS, a chloroplastic homologue of mitochondrial alternative oxidase. Our results suggest that a co-ordinated induction of metabolic and defense genes, coupled with the suppression of photosynthetic activity, can compensate for the lack of APX and CAT. In addition, our findings demonstrate that the plant genome has a high degree of plasticity and will respond differently to different stressful conditions, namely, lack of APX, lack of CAT, or lack of both APX and CAT.     

Reactive Oxygen Species and Induction of Lignin Peroxidase in Phanerochaete chrysosporium

We studied oxidative stress in lignin peroxidase (LIP)-producing cultures (cultures flushed with pure O₂) of Phanerochaete chrysosporium by comparing levels of reactive oxygen species (ROS), cumulative oxidative damage, and antioxidant enzymes with those found in non-LIP-producing cultures (cultures grown with free exchange of atmospheric air [control cultures]). A significant increase in the intracellular peroxide concentration and the degree of oxidative damage to macromolecules, e.g., DNA, lipids, and proteins, was observed when the fungus was exposed to pure O₂ gas. The specific activities of manganese superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase and the consumption of glutathione were all higher in cultures exposed to pure O₂ (oxygenated cultures) than in cultures grown with atmospheric air. Significantly higher gene expression of the LIP-H2 isozyme occurred in the oxygenated cultures. A hydroxyl radical scavenger, dimethyl sulfoxide (50 mM), added to the culture every 12 h, completely abolished LIP expression at the mRNA and protein levels. This effect was confirmed by in situ generation of hydroxyl radicals via the Fenton reaction, which significantly enhanced LIP expression. The level of intracellular cyclic AMP (cAMP) was correlated with the starvation conditions regardless of the oxygenation regimen applied, and similar cAMP levels were obtained at high O₂ concentrations and in cultures grown with atmospheric air. These results suggest that even though cAMP is a prerequisite for LIP expression, high levels of ROS, preferentially hydroxyl radicals, are required to trigger LIP synthesis. Thus, the induction of LIP expression by O₂ is at least partially mediated by the intracellular ROS.     

Unusual ethylene-related behavior in senescing flowers of the carnation Sandrosa

The time course of ethylene production by senescing carnation ( Dianthus caryophyllus L. cv. Sandrosa) flowers was studied. These flowers are unusual in that they do not exhibit an autocatalytic increase in ethylene production nor do they develop petal in-rolling. Exposure of the flowers to exogenous ethylene resulted in a rise in their ethylene-forming enzyme (EFE) activity and ethylene production, and at the same time a marked decline in their fresh weight. Natural senescence was also accompanied by a rise in EFE activity, but with no concomitant rise in 1-amino cyclopropane carboxylic acid synthase activity nor in ethylene production. A shift in responsiveness to ethylene was observed, with young flowers more responsive to exogenous ethylene than older flowers. The results are discussed in terms of a proposed mechanism allowing for the decline in competence of this cultivar to respond to ethylene during senescence.     

Bacterial toxicity of cyclodextrins: Luminuous Escherichia coli as a model

The effect of various concentrations of natural and chemically modified cyclodextrins on the luminescence of an Escherichia coli suspension was investigated. All cyclodextrins were found to reduce, albeit to a varying degree, the luminescence level of the bacterial cells, thus suggesting a direct interaction between the cyclodextrins and cells. The inhibitory concentrations IC₂₀ and IC₅₀ of the various cyclodextrins were determined and taken to represent their toxicity effects upon the bacterial cells. Among the natural cyclodextrins, - and -CD interfered minimally with the bacterial luminescence and consequently were essentially non-toxic. The following descending order of toxicity was observed: -CD -CD > -CD. Among the chemically modified cyclodextrins, Dimeb was clearly toxic while Trimeb and the hydroxylated derivatives (hydroxypropyl-ga-CD, HPACD;--CD, HPBCD;--CD, HPGCD) were essentially non-toxic. The following descending order of toxicity was observed: Dimeb HPBCD > Trimeb > HPACD > HPGCD.     

Endogenous opioid ligands may mediate stress-induced changes in the affective properties of pain related behavior in rats

The effect of a single or repeated daily sessions of immobilization stress on hot plate-induced paw lick and escape responses was studied in rats. Immobilization prior to testing resulted in increased latency to escape while having no effect on paw lick response. Naloxone pretreatment reversed the effect of immobilization on escape behavior. The data suggest that immobilization-induced changes in pain related behavior may be mediated by an opiate receptor ligand system. Furthermore, they suggest that this endogenous system may be mediating the affective but not the sensory properties of pain related behavior.     

Flicker noise of ion-selective membranes and turbulent convection in the depleted layer

Flicker noise of electric currents through ion-selective membranes is explained. It is attributed to the depletion of salt on one side of the membrane, which creates a thin layer of high resistance. Joule heating in this depletion layer and the ensuing temperature gradient, as well as the concentration gradient, give rise to buoyant forces which may create a turbulent convection current. The turbulence mixes the depletion layer so that the electric resistance fluctuates, and consequently the current flickers.Experiments with ion-selective membranes support this conjecture. They show that 1) Noise is coincident with the increase of the electric resistance by the depletion process. 2) When the current density is reduced, it reaches a critical value, below which the convection current changes from turbulent to laminar, and the noise disappears. 3) Noise reduces with temperature, because the expansion coefficient of water decreases with temperature, and its viscosity increases. 4) A non-ionic water-soluble polymer added to the compartment on the side of the depletion layer reduces the noise, by increasing the bulk viscosity of the solution. 5) Noise depends on the membrane's orientation in the gravitational field. 6) The convection-current in the depletion layer can be observed directly, using a laser-beam, by adding latex particles which create optical noise as they drift with the convection current across the beam. The optical noise is observed only coincidently with the current noise.A. Katzir-Katchalsky Fellow