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PubMed1994

Chronic and acute tolerance to subjective, behavioral and cardiovascular effects of nicotine in humans.

Understanding tolerance to effects of nicotine in humans may elucidate processes involved in the onset and maintenance of tobacco dependence. Subjective, behavioral and cardiovascular responses to nicotine were examined as a function of past history of nicotine exposure (i.e., smokers vs. nonsmokers, chronic tolerance) and of immediately preceding nicotine exposure (acute tolerance). Dose-effect relationships between nicotine (0-2 micrograms/kg via measured-dose nasal spray) and each response were determined in male and female smokers (n = 17) and nonsmokers (n = 18), with different doses presented on different days. Each day, subjects also received a challenge dose of 20 micrograms/kg 30 min after the previous dosing to assess acute tolerance. Plasma nicotine concentrations were 30% lower in nonsmokers compared with smokers and analyses were adjusted to control for this difference. Results showed significant changes in nearly all responses as a function of nicotine dose. Dose-effect curves were shifted to the right or dampened in smokers relative to nonsmokers for most subjective and some behavioral responses, consistent with chronic tolerance, but there was less evidence of chronic tolerance to other behavioral effects or to cardiovascular responses. A pattern of acute tolerance generally similar to that of chronic tolerance was observed across response domains (i.e., clear acute tolerance to subjective measures but less to behavioral or cardiovascular effects). These results support the notions that regular use of nicotine is associated with chronic functional tolerance and that repeated nicotine exposure during a single episode produces acute tolerance. A similar pattern of chronic vs. acute tolerance suggests similarity of mechanisms responsible for both "types" of tolerance. However, variability in tolerance magnitude across subjective, behavioral and cardiovascular response domains indicates that different mechanisms may be responsible for these different effects of nicotine.

Adult↗
PubMed2004

A major QTL conditioning salt tolerance in S-100 soybean and descendent cultivars.

Deployment of salt tolerant cultivars is an effective approach to minimize yield loss in a saline soil. In soybean, Glycine max (L.) Merr., substantial genetic variation exists for salt response. However, breeding for salt tolerance is hampered because no economically viable screening method has been developed for practical breeding. To facilitate the development of an effective screening method for salt tolerance in soybean, the present study was conducted to determine the heritability of salt tolerance and to identify associated quantitative trait loci (QTL). F2:5 lines from the cross of 'S-100' (salt tolerant) x 'Tokyo' (salt sensitive) were evaluated in a saline field in Hyde County, N.C., USA, in 1999 and in a greenhouse located in Raleigh, N.C., USA, in 2001. S-100 and Tokyo are ancestors of popular soybean cultivars released for the southern USA. The visual salt tolerance ratings of the F2:5 lines ranged from 0 (complete death) to 5 (normal healthy appearance). The entry-mean heritability for salt tolerance was 0.85, 0.48, and 0.57 in the field (four replications), greenhouse (two replications), and combined environments, respectively. The genotypic correlation between field and greenhouse ratings was 0.55, indicating reasonably good agreement between the two screening environments. To identify QTL associated with salt tolerance, each line was characterized with RFLP markers and an initial QTL single-factor analysis was completed. These results were used to identify genomic regions associated with the trait and to saturate the selected genomic regions with SSR markers to improve mapping precision. Subsequently, a major QTL for salt tolerance was discovered near the Sat_091 SSR marker on linkage group (LG) N, accounting for 41, 60, and 79% of the total genetic variation for salt tolerance in the field, greenhouse, and combined environments, respectively. The QTL allele associated with tolerance was derived from S-100. Pedigree tracking was used to examine the association between the salt tolerance QTL and flanking SSR marker alleles in U.S. cultivars descended from S-100 or Tokyo through 60 years of breeding. The presence of alleles from S-100 at the Sat_091 and Satt237 marker loci was always associated with salt tolerance in descendants. Alleles from Tokyo for these same markers were generally associated with salt sensitivity in descendent cultivars. The strong relationship between the SSR marker alleles and salt tolerance suggests that these markers could be used for marker-assisted selection in commercial breeding.

Adaptation, Physiological↗
PubMed2004

Improving crop salt tolerance.

Salinity is an ever-present threat to crop yields, especially in countries where irrigation is an essential aid to agriculture. Although the tolerance of saline conditions by plants is variable, crop species are generally intolerant of one-third of the concentration of salts found in seawater. Attempts to improve the salt tolerance of crops through conventional breeding programmes have met with very limited success, due to the complexity of the trait: salt tolerance is complex genetically and physiologically. Tolerance often shows the characteristics of a multigenic trait, with quantitative trait loci (QTLs) associated with tolerance identified in barley, citrus, rice, and tomato and with ion transport under saline conditions in barley, citrus and rice. Physiologically salt tolerance is also complex, with halophytes and less tolerant plants showing a wide range of adaptations. Attempts to enhance tolerance have involved conventional breeding programmes, the use of in vitro selection, pooling physiological traits, interspecific hybridization, using halophytes as alternative crops, the use of marker-aided selection, and the use of transgenic plants. It is surprising that, in spite of the complexity of salt tolerance, there are commonly claims in the literature that the transfer of a single or a few genes can increase the tolerance of plants to saline conditions. Evaluation of such claims reveals that, of the 68 papers produced between 1993 and early 2003, only 19 report quantitative estimates of plant growth. Of these, four papers contain quantitative data on the response of transformants and wild-type of six species without and with salinity applied in an appropriate manner. About half of all the papers report data on experiments conducted under conditions where there is little or no transpiration: such experiments may provide insights into components of tolerance, but are not grounds for claims of enhanced tolerance at the whole plant level. Whether enhanced tolerance, where properly established, is due to the chance alteration of a factor that is limiting in a complex chain or an effect on signalling remains to be elucidated. After ten years of research using transgenic plants to alter salt tolerance, the value of this approach has yet to be established in the field.

Crops, Agricultural↗
PubMed2001

Co-existence of salt and drought tolerance in Triticeae.

Cell membrane stability (CMS) technique was used to screen for drought tolerance, salt tolerant accessions of three Aegilops species, Ae. tauschii, Ae. cylindrica, Ae. geniculata and two hexaploid wheat (Tricitum aestivum L.) cultivars comprising salt tolerant LU-26 and drought tolerant Chakwal-86. The objectives were to see how valid it is for a salt tolerant plant to be drought tolerant as well and to identify the character(s) that may contribute to drought tolerance. Three moisture levels equal to 100, 50 and 25% saturation capacity of the soil were used for plant cultivation. Injury percentage (IP) based on in-vitro desiccation induced by polyethylene glycol (PEG) in leaf tissue was measured through the conductivity of the electrolyte leakage. Injury percentage decreased in all the test material with decrease in soil moisture contents. Ae. cylindrica exhibited minimum injury at 100% soil moisture level followed by Ae. tauschii and Ae. geniculata while drought tolerant wheat cultivars exhibited the maximum. The wheat cultivar Chakwal-86 has been developed for dry areas, with low soil moisture levels, and high water potential enhances the injury percentage. Aegilops cylindrica is a salt tolerant species and can thus tolerate water deficit conditions created due to low osmotic potential. Potassium appeared to play an important role in drought tolerance which was evident from high K+ contents and low K+ leakage from Aegilops cylindrica and drought tolerant wheat cultivar Chakwal-86. It was inferred from the study that salt tolerant species might prove drought tolerant in the areas where water deficit prevails due to the ability to create low intracellular osmotic potentials.

Acclimatization↗
PubMed2000

Gender differences in tolerance to lower body negative pressure.

BACKGROUND: Previous studies suggest that women have lower tolerance than men do to lower body negative pressure (LBNP). The mechanism(s) responsible has not been determined. HYPOTHESES: Women would be less tolerant to presyncopal LBNP than men as determined by several indices of LBNP tolerance. Additionally, men and women, regardless of LBNP tolerance, would have similar cardiovascular responses to LBNP as presyncope was reached. METHODS: The subjects were 18 men and 18 women (average age 25) of similar fitness levels who volunteered for the study. A step-wise LBNP protocol to presyncope was employed. HR, stroke volume (SV), cardiac output (Q), BP, and systemic vascular resistance (SVR) were measured before and throughout the LBNP stress. Data from women were compared with those from all men, and to men with similar and higher LBNP tolerance. RESULTS: Women had significantly less LBNP tolerance than men regardless of index used: 30% less by duration of LBNP, 21% less by maximal LBNP tolerated, 44% less by a cumulative stress index, and 27% less by a linear tolerance index. Cardiovascular responses to LBNP were similar for women and men as presyncope was approached, whether the men were low-tolerant (LT) or high-tolerant (HT). In the 2 min pre-presyncope, HR increased by 80 +/- 6% in women, 72 +/- 7% in LT men and 96 +/- 14% in HT men; Q decreased by 47 +/- 3% in women, 52 +/- 6% in LT men and 55 +/- 2% in HT men. Similar comparisons occurred for the decline in BP and the rise in SVR. CONCLUSION: Women have lower LBNP tolerance than do men, although there is considerable gender overlap in tolerances. The cardiovascular response to LBNP is similar regardless of gender or tolerance level as presyncope is approached. Understanding the gender differences in LBNP tolerance may lie in determining how the LBNP stress is translated into a "trigger" for cardiovascular decompensation.

Adult↗
PubMed1990

[Effects of exercise tolerance on electrocardiogram (ECG) with emphasis laid on younger generation].

Effects of Exercise Tolerance on young healthy adults were studied. The results obtained were as follows. The subjects selected were non-smoking 100 volunteers aged 20 to 25 years old, without anamnesis in respiratory and circulatory systems. Exercise was conducted in an amount 3 times (test 1) or 4 times (test 2) of that in a going up and down test stipulated in the Master two step method. The results were subjected to determine changes in heart rate (HR) and ST, QT time, QT ratio and QX/QT immediately after and 5 minutes after tolerance, using ECG taken prior to the tolerance as a control. 1. Changes in each determination 1) Heart rate (HR) (HR before tolerance: 100%) Hardly any change was observed in test 1. But test 2 showed a marked increase in HR, that is 201.8% and 150.1% immediately after and 5 minutes after tolerance respectively. 2) ST change Test 2 showed ST changes of 0.4mm and 0.1mm immediately after and 5 minutes after tolerance respectively. 3) QT time and QT ratio Test 2 showed QT time of 0.29 sec. and 0.34 sec. immediately after and 5 minutes after tolerance respectively. The ratio tended to decrease as exercise tolerance increases, that is 0.92 and 0.98 in test 1 and 0.77 and 0.93 in test 2 immediately after and 5 minutes after tolerance respectively. 4) QX/QT Test 1 showed QX/QT of 0.48 and 0.49 immediately after and 5 minutes after tolerance respectively. Test 2 showed QX/QT of 0.44 and 0.47 immediately after and 5 minutes after tolerance respectively in ST change. 2. Correlation between HR and each determination HR was significantly correlated with ST changing, that is in test 2 r = -0.410 (p less than 0.01) immediately after tolerance (p less than 0.01). HR was significantly correlated with QT ratio, that is in test 1, r = -0.629, r = -0.653 and r = -0.553 control, immediately after and 5 minutes after tolerance respectively, and in test 2 r = -0.712, r = -0.708 and r = -0.785 control, immediately after and 5 minutes after tolerance respectively (p less than 0.01). 3. Correlation between HR-changing and ST-changing rate. Primary formula, that is, ST = -0.379 + 0.0174x (HR) was obtained in r = 0.672 (p less than 0.01), suggesting that ST-changing rate decreases as HR increases.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1982

Development and loss of tolerance to morphine in the rat.

The development of a differential tolerance to morphine was investigated with respect to the mean effective dose, the threshold dose of tolerance, the degree of tolerance after a fixed dose, and the speed of tolerance loss. The mean effective doses, the threshold doses of tolerance, and the degree of tolerance differed considerably from effect to effect, whereas in all tests tolerance loss remained the same. The mean effective doses were not correlated to threshold doses of tolerance, degree of tolerance, or to the loss of tolerance, but a strong correlation exists between threshold doses of tolerance and degree of tolerance to all effects measured. Consequences of these results upon current theories of tolerance are discussed.

Animals↗
PubMed1982

Differences among 'serotonergic' anorectics in a cross-tolerance paradigm: do they all act on serotonin systems?

Rats on a 4 hr/day feeding schedule showed anorexia after i.p. injections of several 'serotonergic' agents. Tolerance developed within a few days of daily administration of all drugs except fluoxetine. The tolerant animals were then given a cross-tolerance test with a different agent, either the next day or after a drug free washout period. Rats which were tolerant to quipazine or MK 212 showed no cross-tolerance to fenfluramine or norfenfluramine. In contrast, rats which were tolerant to fenfluramine showed good cross-tolerance to quipazine or MK 212. However, after a washout period between the end of the chronic fenfluramine regimen and the cross-tolerance test, quipazine regained its full anorectic potency. The development of tolerance to fenfluramine was dependent upon the number of injections, not on their spacing. Fenfluramine-tolerant animals showed a partial decay of tolerance after a 3 day washout, but still retained some tolerance after 12 days. These findings imply that the mechanisms underlying the development of tolerance may differ from those which mediate its maintenance. Our data further suggest that not all of the agents act on the same neural system(s), and raise the possibility that non-serotonergic and/or non-cerebral systems may be involved in the mode of action of these agents.

Animals↗
PubMed1984

Heterogeneity of oral tolerance defects in autoimmune mice.

Three strains of mice, BXSB, MRL-lpr/lpr, and NZB, which spontaneously develop autoimmune syndromes, all fail to become tolerant to challenge with bovine gamma-globulin (BGG) in adjuvant by prior intraperitoneal (ip) injection of BGG in tolerogenic form. In the present study, these three strains were examined for the ability of a single enteric dose of BGG or ovalbumin (OVA) to tolerize to subsequent challenge with the corresponding antigen in adjuvant. In contrast to lack of ip tolerance to BGG, BXSB mice were tolerant to gastrointestinal (GI) BGG as well as to GI OVA, suggesting that ip and GI forms of tolerance to BGG operate through distinct mechanisms in these mice. MRL-lpr/lpr mice had normal tolerance to GI OVA but not GI BGG. The presence of enteric tolerance to one antigen but not another suggests that the responsible cellular defects vary from one antigen to another. NZB mice lacked tolerance to both GI BGG and GI OVA. Splenectomy of NZB mice allowed normal tolerance to enteric BGG; spleen cells administered to splenectomized NZB mice interfered with BGG tolerance. Congenic NZB.xid mice were tolerant only to OVA. These results suggest that in NZB mice Lyb 5+ cells interfere with tolerance to enteric OVA and Lyb 5- spleen cells interfere with tolerance to enteric BGG.

Animals↗
PubMed1987

A blood marker for pharmacodynamic tolerance to alcohol.

The treatment of alcoholism may be delayed because of the difficulty in confirming a diagnosis. There are currently no direct blood tests to objectively determine the presence of pharmacodynamic tolerance to alcohol. The state of the membrane fluidity of the peripheral blood erythrocyte may provide a biophysical measurement of the pharmacodynamic tolerance to alcohol. This discussion proposes methods that potentially may be applied to the clinical purpose of diagnosing alcoholism in humans. The methods have been used to successfully measure pharmacodynamic tolerance in animals and humans. The development of the physiologic state of acquired tolerance and dependence is related to alcohol intake. Chronic alcohol consumption that leads to pharmacodynamic tolerance may be assessed by measuring the membrane fluidity of the peripheral blood erythrocyte. Physiologic recovery from tolerance and dependence to alcohol may also be assessed during withdrawal in which the reversal of changes in membrane fluidity is measured in the abstinent state. Relapse to drinking may be detected in the state of the membrane fluidity of the peripheral blood erythrocytes that reflect the return of tolerance and dependence. Tolerance to alcohol may be a manifestation of the inheritability to alcoholism. Alcoholics and high risk individuals appear to have an increased, innate (genetic) tolerance to alcohol. High risk individuals are nonalcoholic, blood relatives of alcoholics. Animal studies suggest that innate (genetic) tolerance and dependence to alcohol may be related to the biophysical state of erythrocyte membrane fluidity. The assessment of these changes in membrane fluidity of the erythrocyte may be performed in the peripheral blood in humans. A trait marker (in the genetically predisposed) for high risk individuals and a state (in the actively drinking) marker for pharmacodynamic tolerance in the erythrocyte might be developed. In this way, a blood test may be used to detect the inheritability for alcoholism and the development of pharmacodynamic tolerance to alcohol. No blood test for pharmacodynamic tolerance is currently available. This article represents an extrapolation from animal and human research data. The proposals contained therein may not be considered readily, clinically applicable.

Alcohol Drinking↗
PubMed2003

The expression of a high level of morphine antinociceptive tolerance in mice involves both PKC and PKA.

We have previously reported that intracerebroventricular (i.c.v.) injection of either a PKC or PKA inhibitor completely reversed the expression of 5- to 8-fold morphine antinociceptive tolerance. We developed a model of 45-fold morphine tolerance that included a 75-mg morphine pellet and twice daily morphine injections. PKC inhibitor doses of bisindolylmaleimide I and Gö-7874 that completely reversed 8-fold tolerance only partly reversed the 45-fold level of antinociceptive tolerance. A component of tolerance was resistant to PKC inhibition, since even higher inhibitor doses failed to further reverse the high level of morphine tolerance. In addition, the 45-fold tolerance was only partly reversed by the PKA inhibitor KT-5720 at a dose previously cited by others to reverse 5-fold tolerance. Another PKA inhibitor 4-cyano-3-methylisoquinoline only partly reversed the morphine tolerance as well. In other experiments PKC and PKA inhibitors were co-administered together to determine their effectiveness for completely reversing the 45-fold level of morphine tolerance. Co-administering either bisindolylmaleimide I with KT-5720, or Gö-7874 with KT-5720, completely reversed the high level of tolerance. The high level of morphine tolerance was also completely reversed by co-administering Gö-7874 with 4-cyano-3-methylisoquinoline. Thus, high levels of morphine tolerance may reflect increases in protein phosphorylation by the terminal kinases of both the adenylyl cyclase and phosphatidylinositol cascades in brain and spinal cord areas critical to the expression of antinociception.

Analgesics↗
PubMed2000

Possible mechanisms of action in melatonin reversal of morphine tolerance and dependence in mice.

In our earlier study, we reported the ability of melatonin to reverse the development of morphine tolerance and dependence in mice. In the present study, we attempted to analyse the possible involvement of putative melatonin receptors, central and peripheral benzodiazepine receptors and the nitric oxide (NO) system in the mechanism of melatonin reversal of morphine tolerance and dependence in mice. Co-administration of L-N(G)-nitro arginine methyl ester (L-NAME) or melatonin with morphine during the induction phase (days 1-9) delayed the development of tolerance to the anti-nociceptive action of morphine and also reversed naloxone precipitated withdrawal jumpings. L-arginine administration during the induction phase enhanced the development of tolerance to the anti-nociceptive effect of morphine but had no effect on the naloxone-precipitated withdrawal response. During the expression phase (day 10), acute administration of melatonin or L-NAME reversed, whereas L-arginine facilitated, naloxone-precipitated withdrawal jumping in morphine-tolerant mice, but none of these drugs affected the nociceptive threshold in morphine-tolerant mice. Further, co-administration of melatonin or L-NAME with L-arginine during the induction phase antagonized later the effects on the development of morphine tolerance. Also, prior administration of melatonin or L-NAME reversed the L-arginine potentiation of naloxone-precipitated withdrawal jumping in morphine tolerant mice. Among the antagonists for putative melatonin receptors studied, neither luzindole (melatonin MT1 and MT2 receptor antagonist) nor prazosin (melatonin MT3 receptor antagonist) antagonized the melatonin reversal of morphine tolerance and dependence. 1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK11195), a peripheral but not central benzodiazepine receptor antagonist, flumazenil, partially antagonized the melatonin reversal of naloxone-precipitated withdrawal jumping in morphine-dependent mice, but had no effect on the reversal of morphine tolerance induced by melatonin. Overall, the present observations suggest that the melatonin-induced reversal of morphine tolerance and dependence may involve its ability to suppress nitric oxide synthase (NOS) activity. Further, the melatonin-induced reversal of morphine tolerance and dependence is not mediated through its actions via putative melatonin receptors. The agonistic activity of melatonin towards peripheral benzodiazepine receptors may partially contribute to the suppression of morphine dependence but not to the reversal of tolerance to the analgesic activity of morphine.

Animals↗
PubMed2000

Induction of oral tolerance towards hepatitis B envelope antigens in a murine model.

BACKGROUND: Hepatitis B virus (HBV) is a non-cytopathic virus, and the hepatocellular injury that occurs as a consequence of HBV infection is mediated by the host antiviral immune response. Subjects with natural tolerance to HBV have minimal or no liver injury despite chronic viremia. We have shown that immune tolerance towards viruses can be induced by oral administration of viral proteins. AIMS: To test whether oral induction of tolerance can be induced towards HBV antigens, and whether oral tolerance induction downregulates preexisting anti-HBV immune response. METHODS: Oral tolerance was induced via feeding of five low oral doses of HBV proteins (HBsAg+preS1+preS2, BioHepB). This was followed by two inoculations with the BioHepB vaccine. Humoral immune tolerance was evaluated by measuring serum levels of anti-HBs antibody titers at monthly intervals. To determine if oral tolerance induction downregulates pre-existing anti-HBs immunity, mice were inoculated twice with the BioHepB vaccine, followed by feeding of BioHepB-HBV proteins. RESULTS: Feeding of HBV proteins markedly inhibited production of anti-HBs antibodies in naive mice. Anti-HBs titers were 45 versus 135 mIU/ml, in tolerized versus non-tolerized controls (P<0.005). Moreover, oral tolerance induction effectively down-regulated pre-existing immunity and reduced the anti-HBs titers in previously immunized mice to 112 versus 223 mIU/ml, in tolerized compared with non-tolerized controls (P<0.01). CONCLUSIONS: Induction of oral tolerance towards HBV proteins downregulates the antiviral humoral immune response in naive mice, and in the presence of preexisting anti-HBV immunity. This approach should be further investigated as a method for alleviation of antiviral-mediated liver injury in chronic HBV hepatitis.

Administration, Oral↗
PubMed1996

MHC class II tolerant T cells undergo apoptosis upon re-exposure to tolerogen in vivo.

Tolerance of MHC class II alloantigens can be achieved by intravenous injection of semiallogeneic hematopoietic cells into neonatal mice. Lymphoid cells of tolerant mice fail to proliferate or secrete interleukins IL-2 or IL-4 when stimulated in vitro with tolerogen. Since the lymphoid organs of B10.T(6R) tolerant mice contain normal levels of I-E reactive (V beta 11+) CD4+ T cells, deletion of alloreactive T cells does not appear to be the mechanism involved in the tolerance induction. To test whether T cells from tolerant animals can become activated under conditions that do not involve alloantigen stimulation, we stimulated these cells with immobilized anti-V beta 11 antibodies. Spleen cells from grafted tolerant and rejector mice proliferated in response to anti-V beta 11+ antibodies, suggesting they were not inert. We then tested whether V beta 11+ T cells from grafted mice can be induced to proliferate following stimulation with alloantigen in vivo. We adoptively transferred T cells from grafted tolerant and rejector mice into irradiated (B10.AQR x B10.T(6R))F1 mice and harvested the lymphoid organs after 65 h. Cells from both grafted tolerant and rejector mice underwent blast transformation, but only cells from rejector mice proliferated when exposed to immobilized anti-V beta 11 antibodies. The failure of V beta 11+ cells from tolerant mice to proliferate after in vivo stimulation may be because they are apoptotic. To test this hypothesis, spleen cells from naive or neonatally tolerized (with (B10.AQR x B10.T(6R))F1 cells) B10.T(6R) mice were adoptively transferred into irradiated (B10.AQR x B10.T(6R))F1 mice and bcl-2 expression was analysed in harvested V beta 11+ cells. Large cells recovered from recipients of naive 6R cells expressed bcl-2 mRNA. By contrast, large cells harvested from recipients of tolerized 6R cells did not express bcl-2 mRNA, suggesting bcl-2 mRNA expression was downregulated in these mice. Moreover, in another experiment, large V beta 11+ cells from grafted tolerant animals recovered after transfer into irradiated (B10.AQR x B10.T(6R))F1 mice did not express the bcl-2 protein as determined by flow cytometry, and contained fragmented DNA as assessed by the TUNEL method. Taken together, these data suggest that MHC class II tolerant T cells undergo apoptosis upon re-exposure to tolerogen in vivo.

Animals↗
PubMed2003

Repeated inhalation exposures to the bioactivated cytotoxicant naphthalene (NA) produce airway-specific Clara cell tolerance in mice.

Repeated exposures to bioactivated cytotoxicants such as naphthalene (NA) render the target population, Clara cells, resistant to further injury through a glutathione-dependent mechanism. The current studies were designed to test the hypothesis that the mechanism for tolerance is localized in Clara cells. We used three approaches to test this hypothesis. First, using airway explants from tolerant mice maintained in culture, we sought to determine if the mechanism of Clara cell tolerance was airway-specific. Second, using inhalation as the route of exposure, we sought to determine if Clara cells at all airways levels become tolerant to repeated inhalation exposures of NA. Third, by measuring gamma-glutamylcysteine synthetase (gamma-GCS) activity and expression we determined if tolerance to inhaled NA resulted from shifts in phase-II metabolism. Our results indicate that Clara cells in explants from tolerant mice remained tolerant to NA injury in culture. When mice were exposed to repeated inhalation exposures of NA (15 ppm), we found that Clara cells at all airway levels became tolerant. Expression and activity analysis revealed that gamma-GCS, the rate-limiting enzyme in glutathione synthesis, is induced in tolerant Clara cells. Buthionine sulfoximine, a gamma-GCS inhibitor, was able to eliminate the resistance of these tolerant cells. We conclude: (1) the mechanism of NA tolerance in Clara cells is airway specific, (2) the specific mechanism allows Clara cells to become tolerant to NA vapor at levels relevant to human exposure, and (3) the mechanism of tolerance to inhaled NA is highly dependent on induction of the catalytic enzyme, gamma-GCS.

Administration, Inhalation↗
PubMed1989

Lymphokine production by MLR-reactive reaction lymphocytes obtained from normal mice and mice rendered tolerant of class II MHC antigens.

A large proportion of mice rendered neonatally tolerant of class II MHC antigens respond to the tolerogen in vitro in an MLR, while simultaneously maintaining tolerance in vivo as evidenced by acceptance of a skin graft bearing the tolerated antigens. To determine whether this discrepancy between in vivo and in vitro tolerance is reflective of differences in the amount and/or type of lymphokines produced by tolerant lymphocytes, we have examined the ability of tolerogen-reactive lymphocytes to produce IL-2, IL-4/5, and IFN in vitro in an MLR. Our results demonstrate that when stimulated with the tolerogen, lymphocytes from both normal and tolerant responders produce IL-2 and interferon. However, in comparison to normal cells, 2 alterations in the tolerogen-specific responses of lymphocytes obtained from tolerant mice were identified. (1) The amount of IL-2 in the supernatants derived from tolerant cultures declines prematurely compared to normal cultures. This premature decline in IL-2 production was due neither to a lower frequency of Th cells as judged by limit dilution analysis nor to an increase in IL-2R expression on tolerant lymphocytes as measured by FACS analysis. (2) IL-4 and presumably IL-5 can be demonstrated in supernatants of tolerant, but not normal, lymphocytes stimulated by the tolerogen. Thus although lymphocytes from MLR-positive tolerant mice generate substantial quantities of lymphokines in response to the tolerogen, the pattern of lymphokine production is unusual when compared to that of normal lymphocytes. These results are inconsistent with the notion that a global lack of helper activity, per se, is responsible for the maintenance of tolerance in these mice and furthermore suggest that tolerance could be the result of "inappropriate" lymphokine production.

Animals↗
PubMed2005

Oral tolerance and inflammatory bowel disease.

PURPOSE OF REVIEW: Oral tolerance refers to the ability of the mucosal immune system to actively inhibit systemic immune responses to fed antigens. Recently, clinical trials have used oral tolerance as a therapy for certain chronic inflammatory and autoimmune diseases such as multiple sclerosis and type I diabetes. Inflammatory bowel disease is now widely thought to be caused by the breakdown of oral tolerance through a combination of genetic and environmental factors. Therefore, it seems incongruous that clinicians would try to use oral tolerance therapy to alleviate the symptoms of inflammatory bowel disease. Yet, armed with the results of select animal models, trials have begun for oral tolerance therapy for Crohn's disease. This review will outline the recent advances in understanding oral tolerance, explore the relation between oral tolerance and inflammatory bowel disease, and comment on the likelihood of successful oral tolerance therapy for inflammatory bowel disease. RECENT FINDINGS: The results of an oral tolerance trial in Crohn's disease patients in Israel have shown some promising results, whereas the results of studies of experimentally induced oral tolerance in patients with inflammatory bowel disease from the authors' laboratory have shown that feeding a neoantigen in an attempt to induce oral tolerance is not successful in patients with inflammatory bowel disease. SUMMARY: The fundamental difference in the mechanisms of oral tolerance in mice and humans requires a more focused effort to understand the human mucosal immune system before oral tolerance therapy for autoimmune and chronic inflammatory disorders reaches its full potential.

Animals↗
PubMed1981

Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose.

The quantitative contributions of pancreatic responsiveness and insulin sensitivity to glucose tolerance were measured using the "minimal modeling technique" in 18 lean and obese subjects (88-206% ideal body wt). The individual contributions of insulin secretion and action were measured by interpreting the dynamics of plasma glucose and insulin during the intravenous glucose tolerance test in terms of two mathematical models. One, the insulin kinetics model, yields parameters of first-phase (phi 1) and second-phase (phi 2) responsivity of the beta-cells to glucose. The other glucose kinetics model yields the insulin sensitivity parameters, SI. Lean and obese subjects were subdivided into good (KG greater than 1.5) and lower (KG less than 1.5) glucose tolerance groups. The etiology of lower glucose tolerance was entirely different in lean and obese subjects. Lean, lower tolerance was related to pancreatic insufficiency (phi 2 77% lower than in good tolerance controls [P less than 0.03]), but insulin sensitivity was normal (P greater than 0.5). In contrast, obese lower tolerance was entirely due to insulin resistance (SI diminished 60% [P less than 0.01]); pancreatic responsiveness was not different from lean, good tolerance controls (phi 1: P greater than 0.06; phi 2: P greater than 0.40). Subjects (regardless of weight) could be segregated into good and lower tolerance by the product of second-phase beta-cell responsivity and insulin sensitivity (phi 2 . SI). Thus, these two factors were primarily responsible for overall determination of glucose tolerance. The effect of phi 1 was to modulate the KG value within those groups whose overall tolerance was determined by phi 2 . SI. This phi 1 modulating influence was more pronounced among insulin sensitive (phi 1 vs. KG, r = 0.79) than insulin resistant (obese, low tolerance; phi 1 vs. KG, r = 0.91) subjects. This study demonstrates the feasibility of the minimal model technique to determine the etiology of impaired glucose tolerance.

Body Weight↗