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PubMed2001

Tolerance to NaCl induces changes in plasma membrane lipid composition, fluidity and H+-ATPase activity of tomato calli.

Two tomato (Lycopersicon esculentum Mill. cv. Pera) callus lines tolerant to NaCl were obtained by successive subcultures of NaCl-sensitive calli in 50 and 100 mM NaCl-supplemented medium. Growth and ion content, as well as plasma membrane lipid composition, fluidity and H+-ATPase (EC 3.6.1.35) activity, were studied in both NaCl-sensitive and NaCl-tolerant calli. Although calli tolerant to 100 mM NaCl exhibited a reduced growth relative to calli sensitive to NaCl or tolerant to 50 mM NaCl, growth of calli tolerant to 100 mM NaCl was higher than that of NaCl-sensitive calli grown for one subculture in 100 mM NaCl. Growth in the presence of 100 mM NaCl provoked an increase of Na+ and Cl- content, but no significant changes in K+ and Ca2+. As compared with NaCl-sensitive and 50 mM NaCl-tolerant calli, plasma membrane vesicles isolated from calli tolerant to 100 mM NaCl exhibited a higher phospholipid and sterol content as well as a lower phospholipid/free sterol ratio and a lower double bond index (DBI) of phospholipid fatty acids. The changes in plasma membrane lipid composition were correlated with a decrease of plasma membrane fluidity in calli tolerant to 100 mM NaCl, as indicated by fluorimetric studies using diphenylhexatriene (DPH) as probe. Plasma membrane-enriched vesicles isolated from calli tolerant to 100 mM NaCl showed lower ATP hydrolysis and ATP-dependent H+-pumping activities, as well as a lower passive permeability to H+ than plasma membrane from NaCl-sensitive and 50 mM NaCl-tolerant calli. The involvement of the changes in plasma membrane lipid content and composition, fluidity and H+-ATPase activity in salt tolerance of tomato calli is discussed.

Journal Article↗
PubMed2004

Relationships among vernalization, shoot apex development and frost tolerance in wheat.

BACKGROUND AND AIMS: Frost tolerance of wheat depends primarily upon a strong vernalization requirement, delaying the transition to the reproductive phase. The aim of the present study was to learn how saturation of the vernalization requirement and apical development stage are related to frost tolerance in wheat. METHODS: 'Mironovskaya 808', a winter variety with a long vernalization requirement, and 'Leguan', a spring variety without a vernalization requirement, were acclimated at 2 degrees C at different stages of development. Plant development (morphological stage of the shoot apex), vernalization requirement (days to heading) and frost tolerance (survival of the plants exposed to freezing conditions) were evaluated. KEY RESULTS: 'Mironovskaya 808' increased its frost tolerance more rapidly; it reached a higher level of tolerance and after a longer duration of acclimation at 2 degrees C than was found in 'Leguan'. The frost tolerance of 'Mironovskaya 808' decreased and its ability to re-acclimate a high tolerance was lost after saturation of its vernalization requirement, but before its shoot apex had reached the double-ridge stage. The frost tolerance of 'Leguan' decreased after the plants had reached the floret initiation stage. CONCLUSIONS: The results support the hypothesis that genes for vernalization requirement act as a master switch regulating the duration of low temperature induced frost tolerance. In winter wheat, due to a longer vegetative phase, frost tolerance is maintained for a longer time and at a higher level than in spring wheat. After the saturation of vernalization requirement, winter wheat (as in spring wheat) established only a low level of frost tolerance.

Acclimatization↗
PubMed1999

Tolerance to shock: an exploration of mechanism.

OBJECTIVE: To determine if cross-tolerance to septic shock could be induced by a previous insult with sublethal hemorrhage (SLH) and to characterize the mechanisms involved in this induced protective response. BACKGROUND DATA: It is possible to condition animals by prior SLH such that they tolerate an otherwise lethal hemorrhage. It is also possible to condition animals with low doses of lipopolysaccharide (LPS) so that they survive a "lethal" septic insult. However, a paucity of information exists on cross-tolerance between hemorrhage and sepsis. METHODS: Rats were made tolerant by conditioning SLH or sham operation. Twenty-four hours later, tolerant and sham rats were exposed to a lethal dose of LPS. To explore the mechanism of tolerance induction, rats were given the macrophage (Mphi) inhibitor CNI-1493 or saline carrier before SLH. Survival and pulmonary vascular injury were determined after LPS. Serum tumor necrosis factor (TNF) levels and splenic Mphi TNF gene expression were measured at several time points. RESULTS: Prior SLH indeed made rats tolerant and imparted a significant survival benefit and reduction in pulmonary vascular injury after LPS. The tolerance induced by SLH was reversed by Mphi inhibition. Tolerant animals had low serum TNF levels immediately after SLH and reduced circulating TNF levels after LPS. SLH, however, did not inhibit the augmentation of TNF gene expression after LPS. CONCLUSIONS: Sublethal hemorrhage bestows protection against a lethal LPS challenge. Inhibition of the Mphi attenuated the benefit of the tolerance induced by SLH. Circulating TNF but not TNF gene after LPS is lessened by SLH. This implicates changes in Mphi intracellular signaling in induction of the tolerant state.

Animals↗
PubMed2004

Inhibition of toll-like receptor and cytokine signaling--a unifying theme in ischemic tolerance.

Cerebral ischemia triggers acute inflammation, which exacerbates primary brain damage. Activation of the innate immune system is an important component of this inflammatory response. Inflammation occurs through the action of proinflammatory cytokines, such as TNF, IL-1 beta and IL-6, that alter blood flow and increase vascular permeability, thus leading to secondary ischemia and accumulation of immune cells in the brain. Production of these cytokines is initiated by signaling through Toll-like receptors (TLRs) that recognize host-derived molecules released from injured tissues and cells. Recently, great strides have been made in understanding the regulation of the innate immune system, particularly the signaling mechanisms of TLRs. Negative feedback inhibitors of TLRs and inflammatory cytokines have now been identified and characterized. It is also evident that lipid rafts exist in membranes and play a role in receptor-mediated inflammatory signaling events. In the present review, using this newly available large body of knowledge, we take a fresh look at studies of ischemic tolerance. Based on this analysis, we recognize a striking similarity between ischemic tolerance and endotoxin tolerance, an immune suppressive state characterized by hyporesponsiveness to lipopolysaccharide (LPS). In view of this analogy, and considering recent discoveries related to molecular mechanisms of endotoxin tolerance, we postulate that inhibition of TLR and proinflammatory cytokine signaling contributes critically to ischemic tolerance in the brain and other organs. Ischemic tolerance is a protective mechanism induced by a variety of preconditioning stimuli. Tolerance can be established with two temporal profiles: (i) a rapid form in which the trigger induces tolerance to ischemia within minutes and (ii) a delayed form in which development of protection takes several hours or days and requires de-novo protein synthesis. The rapid form of tolerance is achieved by direct interference with membrane fluidity, causing disruption of lipid rafts leading to inhibition of TLR/cytokine signaling pathways. In the delayed form of tolerance, the preconditioning stimulus first triggers the TLR/cytokine inflammatory pathways, leading not only to inflammation but also to simultaneous upregulation of feedback inhibitors of inflammation. These inhibitors, which include signaling inhibitors, decoy receptors, and anti-inflammatory cytokines, reduce the inflammatory response to a subsequent episode of ischemia. This novel interpretation of the molecular mechanism of ischemic tolerance highlights new avenues for future investigation into the prevention and treatment of stroke and related diseases.

Animals↗
PubMed2003

Evolutionary genetics of resistance and tolerance to natural herbivory in Arabidopsis thaliana.

Resistance and tolerance are widely viewed as two alternative adaptive responses to herbivory. However, the traits underlying resistance and tolerance remain largely unknown, as does the genetic architecture of herbivory responses and the prevalence of genetic trade-offs. To address these issues, we measured resistance and tolerance to natural apical meristem damage (AMD) by rabbits in a large field experiment with recombinant inbred lines (RILs) of Arabidopsis thaliana (developed from a cross between the Columbia x Landsberg erecta ecotypes). We also measured phenological and morphological traits hypothesized to underlie resistance and tolerance to AMD. Recombinant inbred lines differed significantly in resistance (the proportion of replicates within an RIL that resisted herbivory), and early flowering plants with tall apical inflorescences were more likely to experience damage. Tolerance (the difference in fitness between the damaged and undamaged states), also differed significantly among RILs, with some lines overcompensating for damage and producing more fruit in the damaged than undamaged state. Plastic increases in basal branch number, basal branch height, and senescence date in response to damage were all associated with greater tolerance. There was no evidence for a genetic trade-off between resistance and tolerance, an observation consistent with the underlying differences in associated morphological and phenological characters. Selection gradient analysis detected no evidence for direct selection on either resistance or tolerance in this experiment. However, a statistical model indicates that the pattern of selection on resistance depends strongly on the mean level of tolerance, and selection on tolerance depends strongly on the mean level of resistance. These observations are consistent with the hypothesis that selection may act to maintain resistance and tolerance at intermediate levels in spatially or temporally varying environments or those with varying herbivore populations.

Adaptation, Biological↗
PubMed2004

Wheat seedlings as a model to understand desiccation tolerance and sensitivity.

The coleoptiles of wheat (Triticum aestivum L.) seedlings of cultivar Trémie are desiccation tolerant when 3 days old, although the roots are not. Cutting some of the coleoptiles open prior to dehydration rapidly increased the drying rate. This rendered the coleoptiles sensitive to desiccation, providing a useful model with which to study desiccation tolerance. Both sensitive and tolerant seedlings were dehydrated to 0.3 g H(2)O g(-1) dry mass (g.g) and thereafter rehydrated. Sensitive tissues accr- ued the lipid peroxidation products H(2)O(2)and MDA, and substantial subcellular damage was evident in dry tissues. H(2)O(2) and MDA accumulated slightly only in dry tolerant coleoptiles and no subcellular damage was evident. The activity of antioxidant enzymes glutathione reductase (EC1.6.2.4), superoxide dismutase (EC 1.14.1.1) and catalase (EC 1.11.1.6) increased on drying in both tolerant and sensitive tissues, but were sustained on rehydration in only the tolerant tissues. It is proposed that free radical damage sustained during rapid drying exceeded the ameliorating capacity of antioxidant systems, allowed accrual of lethal subcellular damage. Slow drying enabled sufficient detoxification by antioxidants to minimize damage and allow tolerance to drying. Three LEA- (p11 and Asp 52) and dehydrin- (XV8) like proteins were detected by western blots in tolerant coleoptiles dried to 3.0 g.g and below. Only one (Asp 52) was induced at low water content in rapidly dried sensitive coleoptiles. None were present in root tissues. XV8 RNA (northern analyses) was induced on drying only in tolerant coleoptiles and correlated with protein expression. These stress-putative protein protectants (and XV8 transcripts) appear to be down-regulated during germination but wheat seedlings temporarily retain the ability to reproduce them if drying is slow. Sucrose accumulation during dehydration was similar for both sensitive and tolerant tissues, suggesting that this sugar has little role, or is not effective in isolation, in protecting against desiccation damage in wheat seedlings. In summary, the slower rate at which tolerant coleoptiles were dried allowed for the mobilization of protection mechanisms with which to survive desiccation. Rapid drying of tissues precluded induction of some putative stress protein protectants and caused damage in excess of the ameliorating capacity of the antioxidant protection systems.

Journal Article↗
PubMed1980

Effect of storage and changes in bacterial growth phase and antibiotic concentrations on antimicrobial tolerance in Staphylococcus aureus.

Forty clinical isolates of Staphylococcus aureus were tested for tolerance to oxacillin and cephalothin by broth dilution susceptibility tests and killing curves. Most experiments were carried out with stationary-phase inocula, but nine tolerant isolates were retested with log-phase inocula. All 40 isolates were retested in killing curves at double the antibiotic concentrations used in initial tests. Isolates were retested for tolerance to oxacillin after storage at --70 degrees C for 1 year. In broth dilution tests, 23 of 40 (57.5%) and 20 of 40 (50%) isolates were tolerant to oxacillin and cephalothin, respectively. By killing curves, 25 of 40 (62.5%) and 22 of 40 (55%) isolates were tolerant to oxacillin and cephalothin, respectively. When nine tolerant isolates were retested with log-phase inocula, none manifested tolerance. Only 25 to 30% of the isolates were tolerant in killing curves performed with oxacillin and cephalothin at concentrations double those used in initial tests. After storage at --70 degrees C for 1 year, only two-thirds of the isolates remained tolerant. In isolates that remained tolerant, the degree of tolerance diminished to about 25% of that observed in initial tests.

Anti-Bacterial Agents↗
PubMed1999

Drug tolerance in Mycobacterium tuberculosis.

Although Mycobacterium tuberculosis is eradicated rapidly during therapy in some patients with pulmonary tuberculosis, it can persist for many months in others. This study examined the relationship between mycobacterial drug tolerance (delayed killing in vitro), persistence, and relapse. It was performed with 39 fully drug-susceptible isolates from a prospective trial of standard short-course antituberculous therapy with sputum smear-positive, human immunodeficiency virus-uninfected subjects with pulmonary tuberculosis in Brazil and Uganda. The rate of killing in vitro was determined by monitoring the growth index (GI) in BACTEC 12B medium after addition of drug to established cultures and was measured as the number of days required for 99% sterilization. Drugs differed significantly in bactericidal activity, in the following order from greatest to least, rifampin > isoniazid-ethambutol > ethambutol (P < 0.001). Isolates from subjects who had relapses (n = 2) or in whom persistence was prolonged (n = 1) were significantly more tolerant of isoniazid-ethambutol and rifampin than isolates from other subjects (P < 0.01). More generally, the duration of persistence during therapy was predicted by strain tolerance to isoniazid and rifampin (P = 0.012 and 0.026, respectively). Tolerance to isoniazid-ethambutol and tolerance to rifampin were highly correlated (P < 0.001). Tolerant isolates did not differ from others with respect to the MIC of isoniazid; the rate of killing of a tolerant isolate by isoniazid-ethambutol was not increased at higher drug concentrations. These observations suggest that tolerance may not be due to drug-specific mechanisms. Tolerance was of the phenotypic type, although increased tolerance appeared to emerge after prolonged drug exposure in vivo. This study suggests that drug tolerance may be an important determinant of the outcome of therapy for tuberculosis.

Antitubercular Agents↗
PubMed1996

Development of metal tolerance in soil bacterial communities exposed to experimentally increased metal levels.

The development of metal tolerance in soil bacterial communities exposed to different heavy metals was examined under laboratory conditions. An agricultural soil amended with different Zn concentrations was studied most intensively, and measurements were made over a 28-month incubation period by means of the thymidine incorporation technique. Tolerance levels were not affected by metal concentrations lower than 2 mmol of Zn kg (dry weight) of soil(sup-1), but above this value, the level of Zn tolerance increased exponentially with the logarithm of the soil Zn concentration. An increased metal tolerance was detected after only 2 days of Zn exposure. Thereafter, stable tolerance values were observed at different sampling times for bacterial communities exposed to up to 8 mmol of Zn kg (dry weight)(sup-1), indicating no changes in tolerance with time. The tolerance of bacterial communities exposed to 32 mmol of Zn kg (dry weight)(sup-1) increased rapidly within the second week of incubation, but then the values remained unchanged until the end of the experiment. Bacterial communities from soil contaminated with 16 mmol of Zn kg (dry weight)(sup-1) showed an increase of the same magnitude, but the increase started later, after 4 months of incubation, and took place for a much longer period (more than 1 year). Cd, Cu, and Ni addition also resulted in metal-tolerant communities, and the level of tolerance increased with prolonged incubations of the soils. The bacterial community at the end of the incubation period also exhibited a lower pH optimum and an increased tolerance to low osmotic potential. The results suggest that the increase in metal tolerance of the community after adding metals can be attributed to an immediate effect due to the death of sensitive species and a later effect due to different competitive abilities and adaptation of surviving bacteria.

Journal Article↗
PubMed2006

The impact of baseline HR and BP on the tolerability of carvedilol in the elderly: the COLA (Carvedilol Open Label Assessment) II Study.

BACKGROUND: The COLA (Carvedilol Open Label Assessment) II Study prospectively evaluated the tolerability of carvedilol in 1030 patients >70 years of age with chronic heart failure (CHF). Tolerability, defined as patients receiving > or =3 months of carvedilol and achieving a maintenance dosage > or =12.5 mg/day, was 80%. In a multivariate analysis, advanced age, low DBP, left ventricular ejection fraction, obstructive airways disease, and a presence of diabetes mellitus were predictors of tolerability. The aim of this analysis was to evaluate further the relationship between baseline HR, SBP, DBP and tolerability in COLA II. METHODS: Baseline HR, SBP and DBP data were available in 1009 patients (98%). These data were analyzed as both continuous and categorical variables. For the latter analysis, the following categories were created: HR <70, 70 < or = HR <90, HR > or =90 bpm; SBP <120, 120 < or = SBP <160, SBP > or =160 mm Hg; DBP <70, 70 < or = DBP <90, DBP > or =90 mm Hg. RESULTS: Baseline HR did not differ between patients who tolerated carvedilol (T) and those who did not (non-T) [81 +/- 16 vs 79 +/- 16 bpm]. However, SBP and DBP were significantly lower in the non-T versus the T group (131 +/- 20 vs 139 +/- 22 mm Hg for SBP [p < 0.001] and 77 +/- 11 vs 81 +/- 12 mm Hg for DBP [p < 0.001]). Seventy-four percent of patients in the lowest category for baseline HR (<70 bpm tolerated carvedilol versus 82% and 79% of those in the higher categories (p = not significant). Seventy percent of patients in the lowest category of baseline SBP (<120 mm Hg) tolerated carvedilol versus 80% and 89% of those in the upper categories (p < 0.001). Similarly, 73% of patients in the lowest category for DBP (<70 mm Hg) tolerated carvedilol versus 78% and 87% of those in the upper categories (p < 0.005). CONCLUSIONS: Carvedilol is generally well tolerated by elderly patients with CHF, even in those with low baseline BP or HR. However, a low baseline SBP or DBP does identify patients who are less likely to tolerate the drug. Baseline HR does not appear to significantly affect tolerability in this population.

Adrenergic beta-Antagonists↗
PubMed1999

Prevention of graft-versus-host disease by induction of immune tolerance with ultraviolet B-irradiated leukocytes in H-2 disparate bone marrow donor.

Transfusions (Tx) of Ultraviolet B (UVB)-irradiated peripheral blood mononuclear leukocytes (MNL) have been shown to induce humoral immune tolerance to major histocompatability complex (MHC) antigens (Blood 88:4375, 1996). To determine whether cellular immune tolerance to MHC antigens can be induced by the same approach, transplantation of bone marrow and spleen cells from tolerant donors across the H-2 barrier was conducted to study its effect on prevention of graft-versus-host disease (GVHD). After immune tolerance induction by four weekly Tx of UVB-irradiated BALB/c (H-2(d)) peripheral blood MNL into CBA/HT6 (H-2(k)) mice, bone marrow cells (BMC) and spleen MNL from tolerant or naive CBA mice were transplanted into lethally irradiated BALB/c mice. The transplanted mice were followed by measuring body weight, peripheral leukocyte counts, GVHD, survival, and cytokine response. All BALB/c recipient mice were fully engrafted with H-2(k) CBA donor cells after transplantation. The severity of GVHD was significantly attenuated in BALB/c mice transplanted with BMC and spleen MNL from tolerant CBA donor mice. The recovery of peripheral leukocyte and lymphocyte counts were faster and more complete in mice transplanted with cells from the tolerant donors. The serum cytokine profile after transplantation with tolerant donor cells showed increased interleukin-4 and reduced gamma interferon that are consistent with a polarized Th2 response. The results pooled from three separate experiments showed that BALB/c mice transplanted with 5 x 10(6) BMC and 4 x 10(5) spleen MNL from tolerant CBA donors had better overall survival than the control group (72% v 17%, P =.018). The findings show that transplantation with bone marrow and spleen cells from tolerant H-2 disparate donor mice is associated with significant attenuation of GVHD and better outcomes. The results also support that transfusions of UVB-irradiated leukocytes may induce cellular immune tolerance.

Animals↗
PubMed2005

Blood transfers infectious immunologic tolerance in MHC-incompatible heart transplantation in rats.

"Infectious tolerance" or inducing immunologic tolerance of infection in allografts is still poorly understood. We investigated whether transfusing blood from LEW.1A rats tolerant of LEW.1W hearts could transmit tolerance to naive LEW.1A rats. In 4 of 6 cases, transfusing blood from tolerant animals was followed by immunologic tolerance of heart transplants from LEW.1W donor rats in LEW.1A recipient animals, whereas transplanting heart grafts that were tolerated in previous transplantations across MHC barriers did not transfer tolerance in major histocompatibility complex (MHC)-incompatible animals. We conclude that in rat heart transplantation, the transfer of immunologic tolerance can be enhanced by transfusing blood from tolerant animals to naive animals before transplantation across MHC barriers.

Animals↗
PubMed1989

Peripheral tolerance mechanisms prevent the development of autoreactive T cells in chimeras grafted with two minor incompatible thymuses.

The thymus has been shown to play an important role in the generation of T cell tolerance to self antigens. Developing T cells are readily tolerized to antigens which are expressed in the thymus, and it is generally thought that such thymic tolerance occurs by a mechanism of clonal deletion. We sought to examine whether T cells which initially encountered a "self antigen" post-thymically would be rendered tolerant of that antigen, and if so whether the mechanism of tolerance induction would differ from that found for thymic antigens. We constructed bone marrow radiation chimeras which were grafted with two thymus lobes differing in minor histocompatibility antigens. T cells which matured in one thymus would be tolerized to the minor histocompatibility antigens expressed in that thymus but would not encounter, and would therefore have no early opportunity of being tolerized to the minor histocompatibility antigens expressed by the other thymus. The initial encounter with the minor antigens on the second thymus would occur post-thymically. Would these T cells be tolerant or responsive to those minor histocompatibility antigens? We found that tolerance was dominant in these chimeras. The data further suggest that the mechanism responsible for tolerance induction in the periphery may differ from that which operates in the thymus.

Animals↗
PubMed1989

Resistance to experimental autoimmune encephalomyelitis induced by neonatal tolerization to myelin basic protein: clonal elimination vs. regulation of autoaggressive lymphocytes.

The target autoantigen of experimental autoimmune encephalomyelitis (EAE), myelin basic protein (MBP), appears late in ontogeny. In the rat MBP is expressed first on days 2-3 post partum, at a development stage, when self tolerance to most other autoantigens has already developed. To shed light on the cellular mechanisms that lead to immunological self tolerance to MBP, we treated neonatal rats with high doses of MBP before ontogenetic appearance of this autoantigen. We found that high doses are required to confer MBP-specific tolerance lasting until the adult life. Neonatally tolerized, adult rats are completely resistant to induction of EAE by injection of MBP in complete Freund's adjuvant (CFA). Upon MBP CFA challenge, these animals develop a limited humoral response to MBP, but are completely unreactive to MBP on the T cell level. The function of antigen-presenting cells is unchanged by neonatal tolerization, and there is no evidence for the induction of suppressive mechanisms. Transfers of large numbers of tolerized lymphocytes to normal hosts fails to interfere with EAE inducibility. Moreover, neonatally tolerized lymphocytes do not reduce MBP reactivity of primed lymph node cells or T line cells in vitro. Finally, neonatally tolerized rats are susceptible to EAE transferred by activated primed lymphocytes or by in vitro-activated MBP-specific T line cells. The apparent deletion of MBP-specific T lymphocytes in neonatally tolerized rats is in striking contrast to the physiological self tolerance to MBP, which is characterized by the presence of MBP-specific clones in the normal immune repertoire.

Animals↗
PubMed1993

Direct evidence for anergy in T lymphocytes tolerized by oral administration of ovalbumin.

The present study investigated bystander suppression, specific suppression and anergy as mechanisms for oral tolerance. Oral tolerance was induced in mice by a single gastric intubation of 20 mg ovalbumin (OVA) and was evaluated in vitro by the absence of T lymphocyte proliferative responses to OVA after priming by OVA-complete Freund's adjuvant (CFA). T lymphocyte unresponsiveness was antigen specific, systemic and was not affected by the vehicle used for immunization. T lymphocytes derived from tolerant popliteal lymph nodes (PLN) responded to an acetone precipitate (AP) of mycobacteria present in CFA; this response was not suppressed by co-culture with OVA, thereby arguing against a mechanism of bystander suppression in our system. Responses of PLN T lymphocytes derived from OVA-CFA primed, non-tolerant mice, or those of an OVA-specific T lymphocyte line, were not suppressed by PLN or spleen cells derived from OVA tolerant mice. These results excluded the possibility that oral tolerance was induced and maintained by a mechanism of specific suppression. At the cellular level, we found that OVA-tolerant T lymphocytes did not produce interleukin-2 (IL-2) nor express IL-2 receptor in response to OVA stimulation in vitro; both observations are indicative of a state of anergy. Incubation of OVA-tolerant PLN T lymphocytes together with murine recombinant IL-2 for 5 days, released anergic T lymphocytes and a concomitant OVA-specific proliferative response of CD4+ T cells was detected. Taken together, our experimental system excludes the involvement of bystander or specific suppression in the induction of oral tolerance to OVA, and provides direct evidence to show that oral tolerance results from specific T lymphocyte anergy.

Administration, Oral↗
PubMed1994

Different kinetic patterns of cytokine gene expression in vivo in orally tolerant mice.

A biologically relevant mechanism of generating peripheral tolerance in T cells that have escaped thymic deletion is by the oral administration of soluble antigens. Oral tolerance occurs by two distinct mechanisms. Feeding a single high dose of antigen induces anergy of antigen-specific TH1 cells, while multiple low doses of antigen induce regulatory T cells that mediate suppression by producing immunosuppressive cytokines. Although cytokine production orally tolerant animals has been well studied utilizing in vitro assay systems, semi-quantitative characterization of cytokine production in oral tolerance in vivo has not been carried out. In this paper we have developed a system using semi-quantitative RNA polymerase chain reaction to characterize cytokine gene expression in vivo in mice orally tolerized by feeding either a single high dose or multiple low dosages of antigen. We find that measurable differences in interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) gene expression occurred between the tolerized and non-tolerized groups. Qualitatively, IL-4 mRNA was increased in both orally tolerized groups. However, significant differences in IL-4 gene expression between the two groups in both magnitude and kinetics were found. A large but short-lived increase in IL-4 was produced in mice fed a single high dose, while a relatively more moderate, longer-lived increase was produced in mice fed multiple low doses. The increase in IL-4 gene expression was specific only to the draining lymph node following antigen administration. Expression of IFN-gamma was decreased in both orally tolerant groups. These results indicate that tolerance in TH1 cells is induced by both of these feeding regimens while TH2 responses are intact and amplified upon reexposure to antigen.

Administration, Oral↗
PubMed2004

Concomitant airway expression of granulocyte-macrophage colony-stimulating factor and decorin, a natural inhibitor of transforming growth factor-beta, breaks established inhalation tolerance.

We previously showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) breaks tolerance induction. The objective of this study was to determine whether GM-CSF breaks established inhalation tolerance. To induce tolerance, BALB/c mice were exposed to aerosolized ovalbumin (OVA) for 10 consecutive days. A control group was exposed to saline. Subsequently, tolerant and control animals were exposed to OVA in a GM-CSF-enriched airway microenvironment. Tolerant animals, unlike control animals, did not develop airway and peripheral blood eosinophilia, had diminished levels of OVA-specific IgE, and reduced airway hyper-responsiveness. While tolerant animals did not express IL-4, IL-5 and IL-13, levels of the regulatory cytokines IL-10, IFN-gamma and transfoming growth factor (TGF)-beta were similar between tolerant and non-tolerant animals. Lung CD4+ T cells were activated according to CD69, CD25 and T1/ST2 expression, but systemic responses characterized by splenocyte proliferation and Th2 effector function were dramatically reduced. Concurrent expression of GM-CSF and decorin, a natural inhibitor of TGF-beta, reversed eosinophilic unresponsiveness. Our study suggests that the breakdown of tolerance and, by extension, the emergence of eosinophilic inflammation, requires two signals: one that triggers sensitization and one that interferes with negative regulation. Moreover, our study shows that dysregulated expression of an extracellular matrix protein may break established tolerance and lead to eosinophilic airway inflammation.

Administration, Inhalation↗
PubMed1984

A conditioning model of alcohol tolerance.

Tolerance to several effects of ethanol can be learned in a classical conditioning paradigm. In the conditioning model of tolerance, a response compensatory in nature to the effect of ethanol develops in association with the cues that signal the presence of ethanol. Tolerance produced by this procedure (environment-dependent tolerance) differs in several respects from tolerance produced in a paradigm in which learning would not be expected to play a significant role (environment-independent tolerance). Depletion of norepinephrine in the brain blocks the development of both types of tolerance, whereas depletion of serotonin enhances the rate of development of environment-dependent tolerance, but inhibits the development of environment-independent tolerance. Cued alterations in the volume of distribution for ethanol are an important factor in the tolerance displayed in the classical conditioning paradigm. It has been suggested that the conditioned compensatory response comprises the physiological response underlying "craving" for ethanol. This implies that an extinction procedure would be an effective treatment for the prevention of relapse.

Alcohol Drinking↗