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PubMed2000

Effects of the flavoprotein inhibitor, diphenyleneiodonium sulfate, on ex vivo organic nitrate tolerance in the rat.

The flavoprotein inhibitor, diphenyleneiodonium (DPI), inhibits the action of glyceryl trinitrate (GTN) and the D-enantiomer of isoidide dinitrate (IIDN), but not the L-enantiomer (L-IIDN), in isolated rat aorta via inhibition of the bioactivation of these prodrugs. Paradoxically, a vascular NAD(P)H oxidase, which also is inhibited by DPI, has been proposed to generate superoxide that quenches nitric oxide (NO) produced during GTN biotransformation, and increased oxidase levels are proposed to contribute to the phenomenon of organic nitrate tolerance. We examined the effect of DPI on isolated rat aorta using an in vivo model of organic nitrate tolerance. The EC(50) values for GTN-, D-IIDN-, and L-IIDN-induced relaxation of aorta from GTN-tolerant rats were increased 4.5- to 7.5-fold. Treatment of blood vessels with DPI (0.3 microM) increased the EC(50) values for GTN and D-IIDN by the same magnitude in control and tolerant aortae, a result that would not be predicted if DPI and GTN tolerance affected common targets. The expression of NADPH-cytochrome P450 reductase (CPR) during in vivo tolerance was assessed by NADPH-dependent cytochrome c reductase activity of aortic microsomes, immunoblotting, and Northern analysis. By all three determinants, CPR expression was unchanged in aorta from GTN-tolerant rats. Superoxide dismutase-inhibitable NADPH-dependent cytochrome c reductase activity (a measure of superoxide generation) of tolerant rat aortic microsomes was not different from that of controls. Superoxide dismutase-inhibitable NADH-dependent cytochrome c reductase activity was detected only in microsomes from tolerant animals. DPI caused a modest increase in the sensitivity for relaxation by the NO donor DEA NONOate to an equal extent in tolerant and nontolerant tissues, whereas the superoxide scavenger, 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron), had no effect on the sensitivity for relaxation by GTN. These results would not be expected if tolerance-induced increases in superoxide were a causative factor for the reduced relaxation response in tolerance. We conclude that neither reduced flavoprotein-dependent metabolic activation of organic nitrates, such as that mediated by CPR, nor increased superoxide due to increased NAD(P)H oxidase activity can account for the development of in vivo tolerance to GTN.

Animals↗
PubMed2000

Incomplete, asymmetric, and route-dependent cross-tolerance between oxycodone and morphine in the Dark Agouti rat.

Our previous studies indicate that oxycodone is a putative kappa-opioid agonist, whereas morphine is a well documented micro-opioid agonist. Because there is limited information regarding the development of tolerance to oxycodone, this study was designed to 1) document the development of tolerance to the antinociceptive effects of chronically infused i.v. oxycodone relative to that for i. v. morphine and 2) quantify the degree of antinociceptive cross-tolerance between morphine and oxycodone in adult male Dark Agouti (DA) rats. Antinociceptive testing was performed using the tail-flick latency test. Complete antinociceptive tolerance was achieved in 48 to 84 h after chronic infusion of equi-antinociceptive doses of i.v. oxycodone (2.5 mg/24 h and 5 mg/24 h) and i.v. morphine (10 mg/24 h and 20 mg/24 h, respectively). Dose-response curves for bolus doses of i.v. and i.c.v. morphine and oxycodone were produced in naive, morphine-tolerant, and oxycodone-tolerant rats. Consistent with our previous findings that oxycodone and morphine produce their intrinsic antinociceptive effects through distinctly different opioid receptor populations, there was no discernible cross-tolerance when i.c.v. oxycodone was given to morphine-tolerant rats. Similarly, only a low degree of cross-tolerance (approximately 24%) was observed after i.v. oxycodone administration to morphine-tolerant rats. By contrast, both i.v. and i.c.v. morphine showed a high degree of cross-tolerance (approximately 71% and approximately 54%, respectively) in rats rendered tolerant to oxycodone. Taken together, these findings suggest that, after parenteral but not supraspinal administration, oxycodone is metabolized to a mu-opioid agonist metabolite, thereby explaining asymmetric and incomplete cross-tolerance between oxycodone and morphine.

Analgesics, Opioid↗
PubMed2001

Dissociation of nicotine tolerance from tobacco dependence in humans.

Chronic functional tolerance to nicotine generally is believed to be associated with processes responsible for tobacco dependence. The dose-related effects of nicotine (0-20 microg/kg by nasal spray) on subjective, cardiovascular, and performance responses were compared among four groups varying in current or past dependence: dependent smokers (21 cigarettes per day for 20 years; n = 45), nondependent smokers (three cigarettes per day for 14 years; n = 12), former dependent smokers (mean of 7 years quit after smoking 25 cigarettes per day for 19 years; n = 17), and life-long nonsmokers (n = 19). Chronic tolerance was determined by a shift to the right, or flattening, of the dose-response curve relative to the curve for nonsmokers. Responses were corrected for plasma nicotine concentration to rule out dispositional tolerance. Chronic tolerance was observed for most subjective responses, but little or none for cardiovascular and performance effects. Tolerance was substantial and virtually identical between dependent and nondependent smokers, whereas tolerance of former smokers was intermediate between nonsmokers and dependent smokers. Identical chronic tolerance between dependent and nondependent smokers indicates that tolerance is not a linear function of smoking exposure and does not require presence of dependence. Thus, the wide variability in daily smoking rate among smokers cannot be attributed to differences in tolerance and must involve other processes of adaptation to nicotine. The modest reversal of tolerance in long-time former smokers suggests that such tolerance reversal is either limited or extremely slow after extended abstinence, despite loss of dependence. These results suggest there is no close link between nicotine tolerance and dependence and question the utility of tolerance as one of the criteria for defining dependence.

Adult↗
PubMed1992

Basal intermediary metabolism in impaired glucose tolerance and morbid obesity.

The effects of impaired glucose tolerance and obesity, in isolation and in combination, on basal (postabsorptive) intermediary metabolism were examined in four groups of subjects (n = 10 for each) matched for age and gender: Group 1: Non-obese healthy controls with normal glucose tolerance (75 g); Group 2: Non-obese subjects with impaired glucose tolerance; Group 3: Morbidly obese subjects with normal glucose tolerance; Group 4: Morbidly obese subjects with impaired glucose tolerance. While there was no significant difference in fasting blood glucose concentrations between the four groups plasma immuno-reactive insulin concentrations were elevated (p < 0.01 or less) in the obese subjects relative to the non-obese subjects within each category of glucose tolerance. Basal immunoreactive insulin concentrations in non-obese subjects with impaired glucose tolerance were also elevated (p < 0.01) relative to the non-obese healthy controls. Concentrations of glycerol (p < 0.01), non-esterified fatty acids (p < 0.01), and total ketone bodies (p < 0.001) were significantly higher in the obese/normal glucose tolerance and obese/impaired glucose tolerance groups relative to their matched non-obese counterparts. Compared with the subjects with normal glucose tolerance, only lactate (p < 0.05) and pyruvate (p < 0.05) concentrations were elevated in the non-obese/impaired glucose tolerance and obese/impaired glucose tolerance groups, respectively. In conclusion, in addition to fasting hyperinsulinaemia the regulation of lipolysis and ketone body metabolism is abnormal in the basal state in morbid obesity. By contrast, despite normal fasting blood glucose concentrations, impaired glucose tolerance is associated with disturbances of other aspects of basal carbohydrate metabolism.

Adult↗
PubMed1990

Naloxone produces protracted tolerance in mice treated with a single dose of morphine.

Previously we have shown that naloxone (NLX)-induced withdrawal in acutely dependent mice [a single dose of 100 mg/kg of morphine sulfate (MS) s.c.] leads to an increase in the degree and duration of the dependent state. In this study we investigated the modulation of opioid tolerance by NLX in acutely tolerant mice (a single dose of 100 mg/kg of MS s.c.). When acutely tolerant mice were injected 3 hr later with 32 mg/kg of NLX, tolerance to the antinociceptive effect of MS could be observed for at least 12 days after MS injection. The same dose of NLX given 3 days after MS injection also led to the prolongation of MS tolerance whereas 4 mg/kg of NLX had no effect. By using the latter protocol, if the ineffective 4-mg/kg dose of NLX was preceded 2 hr before with 10 mg/kg of MS, tolerance to MS could be detected for at least 6 days. When this protracted tolerance (100 mg/kg of MS followed 3 hr later by 32 mg/kg of NLX) was studied at spinal and supraspinal sites, tolerance to MS at supraspinal sites was greater and more prolonged than at spinal sites. [D-Pen2,D-Pen5]enkephalin did not show cross-tolerance at either site. U50,488H [trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)-cyclohexyl]benzeneacetamide) showed a slowly developing cross-tolerance only at the supraspinal sites. In acutely tolerant animals, the tolerance that developed at supraspinal and spinal sites was of equal magnitude and contributed additively to the total tolerance observed in the animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1986

Membrane defects of the tolerant B cell. IV. Failure to accelerate antigen receptor loss.

Mechanisms of immunologic tolerance affecting antibody responses include conditions extrinsic to the B cell such as dominant suppression by T cells (1), regulation by anti-idiotype (2), and tolerance in T helper cell populations (3). But tolerance can also result from changes in the antigen-reactive B cells such as their deletion (4), or that mysterious process by which they become "intrinsically tolerant", i.e., refractory to stimulation (5). One approach to learning more about the mechanism of intrinsic tolerance at the level of cell physiology is to determine which of the activation events that normally follow antigen contact occur or fail to occur in such cells. An established model of intrinsic B cell tolerance previously exploited in such studies in the trinitrophenyl (TNP)-self-induced tolerance model of Fidler and Golub (6). Having established that BDF1 mice injected with 2,4,6-trinitrobenzene sulfonic acid (TNBS) become tolerant to TNP, they showed by appropriate transfer experiments that the tolerance could be not induce antibody to TNP in such mice (8). cells (7). They also showed that lipopolysaccharide could not induce antibody to TNP in such mice (8). Together, these data indicated that in this example, tolerance is intrinsic to the B cells. B cells with receptors for TNP remain in these mice (9), providing an opportunity to study activation events in intrinsically tolerant B cells. This paper is part of an ongoing series of studies of activation events in TNP-antibody-binding cells (ABC)2 using this tolerance model (9-11). It shows that a TNP-antigen that normally induces rapid loss of antigen receptors on TNP-ABC cannot do so in mice rendered tolerant to TNP.

Animals↗
PubMed1982

Mechanisms of tolerance of the Ia antigen disparate skin allografts.

Transplantation tolerance was induced in A.TL mice to donors having disparity in the Ia antigens and identity at the H-2K, H-2D and non-H-2 antigens. After neonatal injection of 12 X 10(6) semiallogeneic lymphoid cells, permanent survival of A.TH skin allografts was observed in more than 90% of the recipients. Adoptive transfer of 50 X 10(6) lymphoid cells from normal A.TL donors to tolerant mice resulted in rejection of the tolerated grafts only in half of the animals. When cells from tolerant mice were tested in MLC and GVH assays, they reacted positively as did cells from normal mice. After sensitization in vitro, cells from tolerant mice were cytotoxic to A.TH antigens. Serum from tolerant mice did not inhibit cell proliferation in MLC assay nor blocked cytotoxic reaction in vitro and also did not enhance survival of A.TH skin grafts in normal A.TL mice. When the enhancing effect of this serum was tested in the recipients treated with ALS, prolonged survival of allografts was observed. Attempts to prolong survival of A.TH skin allografts by transfer of spleen cells from tolerant donors failed in normal A.TL recipients, while they were successful in the recipients treated with ALS. Long-term tolerated A.TH allografts, when transferred to normal A.TL recipients, were rejected. The findings show that loss of antigenicity of the tolerated skin allografts is not the mechanism of tolerance in this model and that cells capable of recognizing antigens of the tolerated allografts and reacting against them are still present in tolerant animals. Tolerance of skin allografts disparate only in Ia antigens, as has been shown at least for the strain combination tested, is probably mediated by the positive serum and cell suppressor mechanisms that block in vivo the effector phase of allotransplantation reaction.

Animals↗
PubMed1994

Cross-tolerance between mu- and kappa-opioid agonists in the guinea pig ileum myenteric plexus.

The present investigation was aimed at elucidating if chronic activation of mu opioid receptor induces development of tolerance to mu (specific tolerance) and kappa agonists (cross-tolerance) in the guinea pig ileum myenteric plexus-longitudinal muscle strip. Morphine (prototype of mu agonist), [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO) and sufentanil (selective mu-agonists) and U-50,488H (selective kappa agonist) were selected. Tolerance to morphine was induced by subcutaneous implantation of morphine pellets (75 mg per pellet) for 7 days. Tolerance to sufentanil was induced by subcutaneous implantation of osmotic minipumps for 7 days, which deliver at a rate of 2 micrograms/microliters/hr. Control groups received placebo pellets or minipumps of vehicle. Tolerance to morphine and DAMGO was observed after chronic treatment with morphine or sufentanil and was revealed as a rightward shift of the concentration-response curve. In addition, a decrease in maximal response was observed. Preparations from morphine-pelleted guinea pigs were also tolerant to the kappa-selective agonist trans-(+-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidynyl)- cyclohexyl]benzeneacetamide (U-50,488H); that is, there was cross-tolerance to the kappa agonist. The development of tolerance to U-50,488H was characterized by a parallel rightward shift of the concentration-response curve, but the maximal response was unchanged. Sufentanil-tolerant tissues were also tolerant to the inhibitory effects of U-50,488H (cross-tolerance). These data indicate that alterations occur during chronic mu opioid administration that are not receptor specific and suggest that tolerance would be associated with a functional change in the myenteric neurons that is unrelated to individual receptor system.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Metamorphosis in the summer flounder, Paralichthys dentatus: thyroidal status influences salinity tolerance.

Metamorphosis in the summer flounder (Paralichthys dentatus) is controlled by thyroid hormones (TH) and takes place as the larvae move from a salinity of about 35 parts per thousand (ppt) in the ocean to salinity ranging from 0-35 ppt in estuaries. Historically, the role of TH in juvenile and adult teleost osmoregulation has been ambiguous, and it is not known if TH influences larval teleost osmoregulatory development. This study addresses the influence of thyroxine (T4) on the development of tolerance to low (5 ppt) and high salinity (45 and 50 ppt) as determined by salinity tolerance tests. In untreated larvae, tolerance to both low and high salinity was high during early premetamorphosis (early pre-M) and decreased or was very low from late prometamorphosis (late pro-M) through mid-metamorphic climax (mid-MC). Salinity tolerance increased 2-3-fold during late MC when whole-animal T4 levels are highest, and reached maximum tolerance at the juvenile stage. The early induction of metamorphosis by exposing larvae in pre-M to exogenous T4 reduced tolerance to low salinity during early and mid-MC, though tolerance of fish that had developed into juveniles was not impaired. In contrast, T4 increased high salinity tolerance during early and mid-MC, and the juvenile stage. This T4-induced heterochrony in salinity tolerance with regards to developmental stage suggests that the effects of T4 on salinity tolerance may be uncoupled from accelerated metamorphosis. Treatment of larvae with thiourea (TU, an inhibitor of T4 synthesis) inhibited metamorphosis and reduced tolerance to high salinity, but did not affect tolerance to low salinity. Reduced tolerance to high salinity by TU was only partially counteracted by T4 treatment, suggesting that TU also affects hypoosmoregulatory activity by an extrathyroidal mechanism. Our findings suggest that in the summer flounder T4 plays a more important role in the development of hypoosmoregulatory ability than hyperosmoregulatory ability. J. Exp. Zool. 284:414-424, 1999.

Adaptation, Physiological↗
PubMed2006

Role of gender norms and group identification on hypothetical and experimental pain tolerance.

Previous research indicates that men typically tolerate more pain in experimental settings than women. One likely explanation for these group differences in pain tolerance is conformity to traditional, gender group social norms (i.e., the ideal man is masculine and tolerates more pain; the ideal woman is feminine and tolerates less pain). According to self-categorization theory, norms guide behavior to the degree that group members adopt the group identity. Therefore, high-identifying men are expected to conform to gender norms and tolerate more pain than high-identifying women who conform to different gender norms as a guide for their behavior. We conducted two studies to investigate whether gender group identification moderates individuals' conformity to pain tolerance and reporting norms. In the first study, participants indicated their gender identification and expected tolerance of a hypothetical painful stimulus. As anticipated, high-identifying men reported significantly greater pain tolerance than high-identifying women. No differences existed between low-identifying men and women. To determine if self-reported pain tolerance in a role-playing scenario corresponds to actual pain tolerance in an experimental setting, the second study examined pain tolerance to a noxious stimulus induced by electrical stimulation of the index finger. The experimental outcome revealed that high-identifying men tolerated more painful stimulation than high-identifying women. Further, high-identifying men tolerated more pain than low-identifying men. These results highlight the influence of social norms on behavior and suggest the need to further explore the role of norms in pain reporting behaviors.

Adaptation, Psychological↗
PubMed2003

Climatic variability and the evolution of insect freeze tolerance.

Insects may survive subzero temperatures by two general strategies: Freeze-tolerant insects withstand the formation of internal ice, while freeze-avoiding insects die upon freezing. While it is widely recognized that these represent alternative strategies to survive low temperatures, and mechanistic understanding of the physical and molecular process of cold tolerance are becoming well elucidated, the reasons why one strategy or the other is adopted remain unclear. Freeze avoidance is clearly basal within the arthropod lineages, and it seems that freeze tolerance has evolved convergently at least six times among the insects (in the Blattaria, Orthoptera, Coleoptera, Hymenoptera, Diptera and Lepidoptera). Of the pterygote insect species whose cold-tolerance strategy has been reported in the literature, 29% (69 of 241 species studied) of those in the Northern Hemisphere, whereas 85 % (11 of 13 species) in the Southern Hemisphere exhibit freeze tolerance. A randomization test indicates that this predominance of freeze tolerance in the Southern Hemisphere is too great to be due to chance, and there is no evidence of a recent publication bias in favour of new reports of freeze-tolerant species. We conclude from this that the specific nature of cold insect habitats in the Southern Hemisphere, which are characterized by oceanic influence and climate variability must lead to strong selection in favour of freeze tolerance in this hemisphere. We envisage two main scenarios where it would prove advantageous for insects to be freeze tolerant. In the first, characteristic of cold continental habitats of the Northern Hemisphere, freeze tolerance allows insects to survive very low temperatures for long periods of time, and to avoid desiccation. These responses tend to be strongly seasonal, and insects in these habitats are only freeze tolerant for the overwintering period. By contrast, in mild and unpredictable environments, characteristic of habitats influenced by the Southern Ocean, freeze tolerance allows insects which habitually have ice nucleators in their guts to survive summer cold snaps, and to take advantage of mild winter periods without the need for extensive seasonal cold hardening. Thus, we conclude that the climates of the two hemispheres have led to the parallel evolution of freeze tolerance for very different reasons, and that this hemispheric difference is symptomatic of many wide-scale disparities in Northern and Southern ecological processes.

Acclimatization↗
PubMed1998

Endogenous orphanin FQ: evidence for a role in the modulation of electroacupuncture analgesia and the development of tolerance to analgesia produced by morphine and electroacupuncture.

1. Our previous work has demonstrated that exogenously administered orphanin FQ (OFQ) antagonizes morphine analgesia and electroacupuncture analgesia (EAA) in the brain and potentiates morphine analgesia and EAA in the spinal cord of the rat. In the present study we evaluated the role of endogenously released OFQ in the development of tolerance to morphine and electroacupuncture (EA) and the analgesia produced by electroacupuncture, by use of the IgG fraction of an anti-OFQ antibody (OFQ-Ab) microinjected into the rat central nervous system (CNS). 2. EAA was produced by stimulating rats at a frequency of 100 Hz. Rats were classified as either high responders (HR) or low responders (LR) based on the analgesic effects of EA. LRs could be converted into HRs by the intracerebroventricular (i.c.v.) microinjection of OFQ-Ab at both 1:1 and 1:10 dilutions but not 1:100. HRs could be changed into LRs by the intrathecal (i.t.) injection of OFQ-Ab at both 1:1 and 1:10 dilutions, but not 1:100. 3. Acute morphine tolerance was induced in rats by repeated subcutaneous (s.c.) injections of morphine (5 mg kg, every 2 h) for 16 h. When injected i.c.v. the OFQ-Ab (1:1 dilution) had no effect on the development of acute morphine tolerance. 4. Chronic morphine tolerance was produced in rats by repeated injection of morphine (5-60 mg kg, s.c., 3 x a day) for 6 days. I.c.v. injection of OFQ-Ab (1:1 dilution) reversed this type of morphine tolerance in rats by 50% (P < 0.01). 5. Acute tolerance to the analgesia produced by EA developed after 6 h of continuous (100 Hz, 3 mA) stimulation. This tolerance was almost completely reversed by the i.c.v. injection of OFQ-Ab (1:1 dilution) (P < 0.05). 6. Chronic tolerance to the analgesic effect of EA was produced by repeatedly administering increasing current (1, 2 and 3 mA, each lasting for 10 min, for a total of 30 min) at a frequency of 100 Hz once a day for 6 days. I.c.v. injection of OFQ-Ab (1:1 dilution) reversed this kind of tolerance by 50% (P < 0.01). 7. Together these results suggest that 100 Hz EA may enhance the release of endogenous OFQ in the CNS of the rat, which in turn may act to antagonize EA-produced analgesia in the brain but potentiate EA produced analgesia in the spinal cord. Therefore, OFQ appears to play an important role in the development of tolerance to the analgesic effects produced by EA. 8. The mechanisms underlying the development of acute morphine tolerance and chronic morphine tolerance appear to be different. Central OFQ may play an important role in the development of tolerance after chronic morphine administration.

Adaptation, Physiological↗
PubMed2002

Chloroxylenol- and triclosan-tolerant bacteria from industrial sources.

Potential development of bacterial tolerance to biocides in the industrial environment is examined in this study. Bacteria tolerant to the phenolic-type agent para-chloro-meta-xylenol (PCMX) and the bis-phenol 2,4,4'-trichloro-2'-hydroxydiphenylether (triclosan) were isolated from industrial sources and identified. Minimum inhibitory concentrations (MICs) were determined and compared with those of culture collection (standard) strains. Of around 100 isolates originally obtained, most were naturally tolerant species such as Pseudomonas spp., or showed low tolerance levels. PCMX-tolerant isolates of Pseudomonas stutzeri and triclosan-tolerant isolates of Citrobacter freundii and Acinetobacter johnsonii were retained for further study. Of these, only P. stutzeri and A. johnsonii showed elevated tolerance compared with the standard strains. There was no evidence of tolerance to the other biocide except for Pseudomonas aeruginosa (an intrinsically tolerant microorganism), and tolerances were stable in the absence of selective pressure except for A. johnsonii. Attempts to select or generate increased tolerance in the standard strains were unsuccessful. High tolerances in terms of MIC were not reflected in terms of lethal effects. This study did not produce any evidence suggesting that the presence of residual biocide concentrations in the industrial environment promotes the emergence of bacterial tolerance for them.

Bacteria↗
PubMed2001

Enhanced copper tolerance in Silene vulgaris (Moench) Garcke populations from copper mines is associated with increased transcript levels of a 2b-type metallothionein gene.

Silene vulgaris (Moench) Garcke has evolved populations with extremely high levels of copper tolerance. To evaluate the role of metallothioneins (MTs) in copper tolerance in S. vulgaris, we screened a cDNA library derived from a highly copper-tolerant population using Arabidopsis-based MT probes and identified an MT2b-like gene. When expressed in yeast, this gene, SvMT2b, restored cadmium and copper tolerance in different hypersensitive strains. Northern-blot analysis and quantitative reverse transcriptase-PCR showed that plants from the copper-tolerant S. vulgaris populations had significantly higher transcript levels of SvMT2b than plants from the copper-sensitive populations, both in roots and shoots and with and without copper exposure. Southern-blot analysis suggested that the higher expression of the latter allele was caused by gene amplification. Segregating families of crosses between copper-sensitive and copper-tolerant plants exhibited a 1 to 3 segregation for SvMT2b expression. Allele-specific PCR showed that low-expression F(3) plants were homozygous for the allele inherited from the copper-sensitive parent, whereas high-expression plants possessed at least one allele from the tolerant parent. SvMT2b expression did not cosegregate with copper tolerance in crosses between sensitive and tolerant plants. However, a significant cosegregation with copper tolerance did occur in families derived from crosses between moderately tolerant F(3) plants with different SvMT2b genotypes. Thus, overexpression of SvMT2b conferred copper tolerance although only within the genetic background of a copper tolerant plant.

Adaptation, Physiological↗
PubMed1987

Tolerance induced by grafting semi-allogeneic adult skin to larval Xenopus laevis: possible involvement of specific suppressor cell activity.

Major histocompatibility complex (MHC)-homozygous Xenopus laevis were rendered tolerant to semi-allogeneic antigens by grafting skins of adult frogs during larval stages (larvally induced tolerance), and this tolerant state was compared with the tolerance induced in early thymectomized frogs by the grafting of semi-allogeneic nonlymphoid thymuses (thymus-reconstituted tolerance). In contrast to a total inability of thymus-reconstituted frogs both to reject skins and to exhibit a mixed leukocyte reaction (MLR) against the semi-allogeneic donor, larvally induced tolerant frogs showed a strong MLR against leukocytes of the tolerizing skin donor (split tolerance). Breakdown of the tolerant state in thymus-reconstituted frogs were easily accomplished by inoculation with syngeneic splenocytes, but this breakdown was extremely difficult to achieve in frogs with larvally induced tolerance. The injection of splenocytes from larvally induced tolerant frogs into normal frogs significantly suppressed semi-allogeneic graft rejection in the latter group; no suppression was obtained when splenocytes from thymus-reconstituted frogs were used. In addition, in the thymectomized frogs, recovery of allograft rejection capacity against the pertinent semi-allogeneic antigens were suppressed by the injection of splenocytes from larvally induced tolerant frogs, with the degree of suppression depending on the splenocyte dose. These results indicate that the larvally induced tolerant state is maintained by specifically induced suppressor cells affecting the in vivo allograft response but not the MLR.

Animals↗
PubMed1995

Quantification of tolerance to lower body negative pressure in a healthy population.

Subtolerance and presyncopal lower body negative pressure (LBNP) has been used extensively to investigate the effect of various forms of exercise training on central hypovolemic tolerance. However, there are no population data concerning LBNP tolerance, and the validity of common LBNP tolerance indices has not been investigated. LBNP tolerance data from 86 males and 33 females were analyzed. All LBNP exposures were terminated with the onset of presyncopal signs and/or symptoms. LBNP tolerance was quantified using duration of exposure (DNP), maximal negative pressure tolerated (MNP, cumulative stress index (CSI), and the LBNP tolerance index (LTI). Average (+/- SD) LBNP tolerance was 22.12 +/- 5.01 min (DNP), -77 +/- 16 mm Hg (MNP), 975 +/- 402 mm Hg.min-1 (CSI), or 222 +/- 50 mm Hg.min-1 (LTI). All cardiovascular parameters exhibited the same responses as have been documented in the literature. While DNP, MNP, and LTI were normally distributed, CSI in this population was not normally distributed. Age, weight, height, gender, and VO2peak were not associated with LBNP tolerance. Compared to this population, it appears that the subjects that have participated in previous LBNP tolerance studies have had abnormally high LBNP tolerances and that the LTI is the most valid index of LBNP tolerance. Furthermore, in this population LBNP tolerance could not be predicted from physical characteristics.

Adult↗
PubMed1991

Influence of I-E expression on induction of neonatal transplantation tolerance.

Neonatal transplantation tolerance was one of the first experimental systems to reveal that tolerance could be achieved to non-self antigens in living animals. Functional and direct evidence (obtained by the use of monoclonal antibodies directed at T cell receptors specifically reactive with I-E molecules) confirm that tolerance is achieved, at least in part, via clonal elimination of developing thymocytes. In this report, we show that induction of tolerance of class I alloantigens in neonatal mice is governed by expression of I-E molecules. Neonatal I-E non-expressor mice proved to be highly resistant to the acquisition of class I tolerance if the donor inoculum expressed disparate class I antigens as well as I-E molecules. The spleens of the few class I-tolerant, I-E non-expressor mice that were generated were found to be depleted of I-E-reactive (RR315+) T cells, whereas no such depletion was observed in their neonatally injected, but non-tolerant littermates. By contrast we found no resistance to tolerance of I-A alloantigens when neonatal I-E non-expressor mice received injections of I-A-disparate, I-E-bearing donor cells. In these tolerant mice, splenic I-E-reactive T cells were readily detected in apparently normal amounts. These results indicate that lack of I-E expression in newborn mice confers resistance to tolerance induction to class I alloantigens, especially when the latter are expressed on donor cells that also display I-E molecules. The possible mechanisms operating to produce resistance to tolerance induction in neonatal mice are discussed, including the possibilities that (a) I-E may act as a restricting element during tolerance induction (an ontogenic process), and (b) the expression of I-E on H-2-disparate, I-E-expressing test skin allografts may provide a source of "help" for CD8+ cytotoxic T cell precursors, leading to graft rejection.

Animals↗
PubMed1999

Liver-associated lymphocytes expressing NK1.1 are essential for oral immune tolerance induction in a murine model.

Oral tolerance is the induction of immunological hyporesponsiveness towards orally administered antigens. Tolerance initiation involves induction of anti-inflammatory (Th2) lymphocytes, with downregulation of pro-inflammatory (Th1) lymphocytes. The liver was previously shown to play a critical role in oral tolerance induction. The aim of the present study was to test whether liver-associated-lymphocytes expressing the NK1.1 marker (NK1.1+ LAL) are substantial for induction of oral tolerance in an experimental colitis model. Colitis was induced in C57 mice by intracolonic instillation of trinitrobenzensulfonic acid (TNBS). Mice received five oral doses of colonic proteins extracted from TNBS-colitis colonic wall. Anti-NK1.1 monoclonal antibodies were injected before tolerance induction. Colitis was assessed by standard clinical, macroscopic, and microscopic scores. Serum IFN-gamma, TGF-beta1, and IL4 levels were measured by enzyme-linked immunosorbent assay. To evaluate the role of NK1.1+ LAL in keeping the balance between immunogenic and tolerogenic subsets of cells, we tested whether peripheral lymphocytes harvested from tolerized and NK1.1-depleted nontolerized mice can adoptively transfer the tolerance into naive irradiated rats. Depletion of NK1.1+ LAL prevented immune tolerance induction in the experimental colitis model. NK1.1+ LAL-depleted nontolerized mice, disclosed severe clinical, macroscopic, and microscopic parameters of colitis. These mice had significantly lower TGF-beta1, IL4, and higher IFN-gamma serum levels, and their lymphocytes failed to transfer the tolerance into naive animals. In contrast, the feeding of colitis-extracted proteins, without NK1.1+ LAL depletion, markedly alleviated the disease. Tolerized mice had higher IL4 and TGF-beta1 and lower IFN-gamma serum levels, and adoptive transfer of their suppressor splenocytes markedly alleviated colitis in naive recipients. NK1.1+ LAL plays a critical role in oral tolerance induction. Depletion of this subset of LAL prevents a shift from Th1 to a Th2 type of immune response, hindering the ability to induce immune tolerance.

Administration, Oral↗