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PubMed1980

Immunological tolerance of the mouse IgE system: dissociation between T cell tolerance and suppressor cell activity.

Immunological tolerance was induced in CBA mice with respect to both anti-hapten and anti-carrier IgE antibody production, following pretreatment of the animals with deaggregated ovalbumin. IgG antibody production was also affected. The tolerance was antigen-specific, was stable upon adoptive transfer to irradiated syngeneic recipients, but was reversed following booster. The extent and duration of the tolerant state depended on the dosage and number of tolerogen injections. Tolerogen administered after the initiation of the primary response was without effect. The pattern and duration of this tolerance suggested that T suppressor cells were not involved. The adoptive transfer of spleen cells from tolerogen-treated donors while being themselves unresponsive, failed to interfere with the induction of an immune response in the recipient. Evidence of T suppressor cell function was found in adoptive transfers, only after prolonged pretreatment of donors with a combination of tolerogenic and immunogenic forms of the carrier. These results suggested that T cell-dependent tolerance of the IgE antibody response operates via two distinct mechanisms, of which only one is provided by suppressor cell function.

Animals↗
PubMed1990

The requirement of intrathymic mixed chimerism and clonal deletion for a long-lasting skin allograft tolerance in cyclophosphamide-induced tolerance.

Mechanisms of cyclophosphamide (CY)-induced tolerance were studied. When C3H/He Slc (C3H; H-2k, Mls-1b) mice were primed i.v. with 1 x 10(8) viable spleen cells from H-2-identical AKR/J Sea (AKR; H-2k, Mls-1a) mice and treated with 200 mg/kg of CY 2 days later, a long-lasting skin allograft tolerance to AKR was established. When [C57BL/6 Sea (B6; H-2b, Mls-1b) x AKR]F1 (B6AKF1) cells were used as the tolerogen, however, only a moderate, but not long-lasting, skin tolerance to AKR was observed. In the C3H mice treated with AKR cells and CY, the intrathymic clonal deletion of V beta 6+ T cells, which are strongly correlated with reactivity to Mls-1a antigens, was observed in the chimeric thymus on day 35, although neither the clonal deletion of V beta 6-bearing T cells nor the mixed chimerism was observed in the thymus on day 14. In the C3H mice treated with B6AFKF1 cells followed by CY, however, neither the clonal deletion of V beta 6+ T cells nor the mixed chimerism was observed in the thymus throughout the test period. In the lymph nodes of the C3H mice treated with AKR cells and CY, only CD4+ V beta 6+ T cells, bur not CD8+V beta 6+ T cells, had selectively decreased by day 14, and they were hardly detectable on day 35. The selective decrease of CD4+V beta 6+ T cells in the lymph nodes was also observed by day 14 when B6AKF1 cells were used as the tolerogen, although CD4+V beta 6+ T cells gradually increased on day 35, at which time almost all skin grafts from AKR had already been rejected. These results strongly support the necessity of the intrathymic mixed chimerism and clonal deletion of donor-reactive T cells for a long-lasting skin allograft tolerance in CY-induced tolerance.

Animals↗
PubMed1991

Mechanisms of IgE tolerance: dual regulatory T cell lesions in perinatal IgE tolerance.

The mechanisms of genetic control of IgE responses are exercised at different immuno-physiological levels. This study centered upon the development of IgE lineage-specific regulatory T cells. Herein, we demonstrate the following points: (a) perinatal administration of soluble self IgE molecule or self IgE complexed with foreign antigen induces IgE tolerance as manifested by antigen-specific IgE unresponsiveness and a generalized IgE immunodeficiency, and the induction of IgE tolerance does not affect antigen-specific IgG1, IgG, and IgA responses; (b) inducibility of perinatal IgE tolerance is correlated with complete absence of endogenously secreted IgE in the neonates; and the state of persistent IgE tolerance also does not correlate with the presence of high levels of circulating anti-IgE autoantibodies; (c) The lesions induced during the ontogeny of IgE antibody system do not appear to result from an imbalance of production of interleukin 4 and interferon-gamma by T helper Th2 and Th1 cells in antigen-stimulated cultures; the dual immunoregulatory lesions in T cell subsets are demonstrated: clonal anergy/deletion of CD4+ IgE Th cells and the presence of CD8+ IgE suppressor cells induced by perinatal IgE treatment. We propose that antigen/interleukin 4 activated B cells are controlled by IgE lineage-specific regulatory T cells which recognize self IgE determinant(s) on IgE committed B cells. Life-long IgE tolerance ensues as a result of a new steady state of IgE lineage-specific CD4+ and CD8+ T cell subsets.

Animals↗
PubMed2006

Gene array analysis of a rat model of liver transplant tolerance identifies increased complement C3 and the STAT-1/IRF-1 pathway during tolerance induction.

This study aimed to define the molecular mechanism during induction of spontaneous liver transplant tolerance using microarrays and to focus on molecular pathways associated with tolerance by meta-analysis with published studies. The differences in the early immune response between PVG to DA liver transplant recipients that are spontaneously tolerant (TOL) and PVG to Lewis liver transplants that reject (REJ) were examined. Spleens from TOL and REJ on days 1 and 3 were compared by 2 color microarray. Forty-six of 199 genes differentially expressed between TOL and REJ had an immunological function. More immune genes were increased in TOL vs. REJ on day 1, including STAT-1, IRF-1 and complement C3. Differential expression of selected genes was confirmed by quantitative RT-PCR. The results were compared to two published high-throughput studies of rat liver transplant tolerance and showed that C3 was increased in all three models, while STAT-1 and IRF-1 were increased in two models. The early increases in immune genes in TOL confirmed previous reports of an active early immune response in TOL. In conclusion, the increase in STAT-1, IRF-1 and complement component C3 in several models of liver transplant tolerance suggests that the STAT-1/IRF-1 apoptotic pathway and C3 may be involved in the tolerogenic mechanism.

Animals↗
PubMed1992

Factors involved in peripheral T cell tolerance: the extent of clonal deletion or clonal anergy depends on the age of the tolerized lymphocytes.

After injection of SEB (staphylococcus enterotoxin B), normal adult mice, or thymectomized irradiated mice (TX irr.) reconstituted with lymphocytes taken from normal adult mice became specifically tolerant of SEB. At the same time the percentage of Vbeta8 positive CD4 lymphocytes known to be responsive to SEB was almost 50% decreased, indicating that a high level of clonal deletion was realized. In contrast, mice with an exclusively old T cell compartment (old thymectomized mice, TX irr. mice reconstituted several months previously) became tolerant of SEB without deleting their Vbeta8 + CD4 + cells, indicating that clonal anergy was the major mechanism in play in the induction of tolerance. Finally, TX irr. mice reconstituted with single positive thymocytes known to become recent thymic emigrants developed tolerance for SEB together with a high level (70%) of clonal deletion. Altogether these results indicated that the mechanism involved in peripheral tolerance depended on the age of the lymphocyte: very young lymphocytes underwent mainly clonal deletion whereas long lived lymphocytes underwent predominantly clonal anergy.

Animals↗
PubMed1987

Learnt tolerance to sedative effects of chlordiazepoxide on self-stimulation performance, but no tolerance to facilitatory effects after 80 days.

Sedative and facilitatory effects on variable-interval hypothalamic self-stimulation were monitored during chronic treatment with chlordiazepoxide (CDP; 7.5 mg/kg IP), given at 48-h intervals in two groups of rats. Group 1 was injected immediately before each of 40 1-h self-stimulation sessions ("drugged responding"); Group 2 was injected after self-stimulation for the first 20 sessions ("undrugged responding"), and before self-stimulation for a further 20 sessions ("drugged responding"). Significant sedation occurred in both groups in initial sessions of drugged responding, even though Group 2 had already received 20 injections of CDP (after undrugged sessions). Sedative effects showed very rapid tolerance, and disappeared after 1-3 sessions, but only in rats which had been responding while drugged (and which thus had had opportunities to develop coping strategies against the sedative effects). After further sessions of drugged responding, sedation was replaced by apparently stimulant effects. Stimulant effects showed no tolerance at all in either group even after 40 injections, thus differing from anti-conflict (and other) effects of BZDs, which generally show gradual tolerance. These results show that coping strategies acquired by instrumental learning can account for rapid and selective tolerance to sedative effects. Coping strategies do not account for the differing rates of tolerance to stimulant and to other effects of BZDs; these differences may indicate pharmacologically distinct brain systems downstream from the BZD receptor.

Adaptation, Psychological↗
PubMed1987

Tolerance to antinociceptive effects of morphine without tolerance to its effects on schedule-controlled behavior.

The development of tolerance to behavioral effects of morphine was investigated in rats that responded on a two-lever, multiple-trial, multiple differential-reinforcement-of-low-rate fixed-ratio (mult DRL FR) schedule of food presentation. Stable performances were maintained when sessions were conducted just twice per week. The effects of cumulative doses of morphine (1.0-8.0 mg/kg) or chlordiazepoxide (CDP; 4.0-32.0 mg/kg) were evaluated once per week; saline injections were given in the intervening sessions. The effects of saline and morphine on nociception were also evaluated in hot-plate tests conducted on the same subjects 15 min after selected operant sessions. Initially, morphine produced dose-related decreases in response rates and reinforcement rates in the DRL and FR components as well as significant increases in hot-plate response latencies. Following weekly administration of morphine (1.0-8.0 mg/kg) for 10 weeks, there was little or no tolerance to its effects on operant behavior. In contrast, complete tolerance developed to the antinociceptive effects of morphine. These results suggest that tolerance to various behavioral effects of morphine may be dissociated, and that the loss of reinforcement may be insufficient by itself to produce tolerance to effects of morphine on operant behavior. Additionally, whereas CDP initially produced only dose-related decreases in DRL and FR response rates, following weekly morphine the smaller doses of CDP (4.0-16.0 mg/kg) produced increases in response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

Temporal relationship of the induction of tolerance and physical dependence after continuous intoxication with maximum tolerable doses of ethanol in rats.

Rats were treated by intragastric intubation of a 20% ethanol solution in doses of 9-15 g/kg in 3-5 fractions for 1-7 days. Both tolerance and physical dependence were demonstrated after this treatment with the maximum tolerable doses to only a few days. Tolerance was assessed by signs of severity of intoxication: coma, loss of righting reflex, ataxia-3, ataxia-2, ataxia-1, sedation, and neutrality. During withdrawal, as blood ethanol concentrations approached 100 mg/dl the ethanol dependence phase was characterized by the onset of signs and responses of progressive severity: hyperactivity, tremors, spastic rigidity, and spontaneous convulsive seizures. A significant degree of tolerance was demonstrated for all signs of intoxication after 4 days of treatment, but did not reach maximum level even after 7 days. The severity of the withdrawal reactions intensified progressively to a maximum intensity after 4 days of treatment when as many as 72% of animals exhibited severe withdrawal signs and reactions including convulsive seizures. These different time courses suggest that tolerance and physical dependence are mediated through different mechanisms.

Alcoholism↗
PubMed1989

Kappa antagonist properties of buprenorphine in non-tolerant and morphine-tolerant rats.

Buprenorphine was evaluated for its ability to act as a kappa opioid antagonist in rats responding under a fixed-ratio 30 schedule of food presentation both before and after the induction of morphine tolerance. Before the induction of morphine tolerance, both buprenorphine and the selective kappa agonist bremazocine decreased rates of responding in a dose-dependent manner, and buprenorphine (0.03 and 0.3 mg/kg) failed to antagonize bremazocine's rate-decreasing effects. Following the induction of morphine tolerance, the bremazocine dose-effect curve was unaffected, but a profound cross-tolerance developed to buprenorphine. Furthermore, buprenorphine (0.03, 0.3 and 1.0 mg/kg) produced a dose-dependent antagonism of the rate-decreasing effects of bremazocine in the morphine-tolerant rats. These results support the hypothesis that buprenorphine has antagonist activity at kappa opioid receptors.

Animals↗
PubMed1982

Recovery from lorazepam tolerance and the effects of a benzodiazepine antagonist (RO 15-1788) on the development of tolerance.

After 3 days of dosing rats with lorazepam (0.25 mg/kg), tolerance developed to its sedative effects. Recovery from this tolerance was rapid. No differences could be detected in undrugged behaviour 24 h after the last dose and no differences in response to a probe injection could be found when 2 drug-free days intervened between the chronic treatment and test dose. RO 15-1788 (1-4 mg/kg) antagonised the sedative effects of acute lorazepam (0.5 and 0.25 mg/kg), but chronic treatment with these doses concomitantly with lorazepam did not prevent the development of tolerance. However, 4 mg/kg RO 15-1788 administered for 5 days at the same time as lorazepam (0.5 mg/kg) and again 45 min later attenuated the development of tolerance. Plasma concentrations after acute and chronic treatment did not differ for 0.25 mg/kg lorazepam, but they were lower following chronic treatment with 0.5 mg/kg. Therefore the development of behavioural tolerance in rats to the sedative effects of benzodiazepines probably involves changes in benzodiazepine receptors, in addition to a pharmacokinetic contribution after treatment with high doses.

Animals↗
PubMed1992

Comparison of the metabolic effects of mixed meal and standard oral glucose tolerance test on glucose, insulin and C-peptide response in healthy, impaired glucose tolerance, mild and severe non-insulin-dependent diabetic subjects.

Dietary constituents other than glucose can influence insulin secretion in non-insulin-dependent diabetes mellitus and administration of a standard mixed meal has been proposed as a more physiological test in regard to human diet for evaluating the patient both at the time of diagnosis and during follow-up. This study was carried out to compare the effects of a standard meal and the oral glucose tolerance test on glucose, insulin and C-peptide plasma levels in four groups of subjects: healthy controls, subjects with impaired glucose tolerance, patients with mild non-insulin-dependent diabetes, and non-insulin-dependent diabetic patients with secondary failure to oral agents. Plasma glucose values were significantly higher after the oral glucose tolerance test than after the mixed meal in all four groups of subjects. Plasma insulin and C-peptide values were similar during the two tests in all groups of subjects except in non-insulin-dependent diabetics with secondary failure (flattened curves). Insulin and C-peptide responses per unit rise in blood glucose were significantly higher after the oral glucose tolerance test than after the mixed meal both in mild non-insulin-dependent diabetics (P less than 0.05 and P less than 0.05) and in non-insulin-dependent diabetics in secondary failure (P less than 0.01 and P less than 0.05). There was significant correlation between oral glucose tolerance test and mixed meal glucose incremental areas (r = 0.511, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1991

Differential cross-tolerance to mu and kappa opioid agonists in morphine-tolerant rats responding under a schedule of food presentation.

If different populations of opioid receptors mediate the actions of mu and kappa opioid agonists, then tolerance induced by the chronic administration of a mu agonist should confer cross-tolerance to other mu agonists but not necessarily to those compounds whose effects are mediated by the kappa receptor. This hypothesis was evaluated in the present investigation by examining the effects of the mu agonists morphine, l-methadone and fentanyl, the kappa agonists U50,488 and bremazocine, and the mixed kappa/mu agonist ethylketocyclazocine in rats responding under a fixed-ratio 30 schedule of food presentation before, during and after exposure to a regimen of chronic morphine administration. For comparison, naloxone was evaluated as a representative mu antagonist and the phenothiazine chlorpromazine as a control drug. During all phases of the experiment, each of these compounds produced dose-related decreases in rate of responding. During the daily administration of 40 mg/kg morphine, tolerance developed to the rate-decreasing effects of morphine, l-methadone and fentanyl, and an enhanced sensitivity to the effects of naloxone. In contrast to the effects obtained with these mu opioids, there was no evidence that chronic morphine administration produced tolerance or enhanced sensitivity to the rate-decreasing effects of U50,488, bremazocine, ethylketocyclazocine and chlorpromazine. The present findings demonstrate that the chronic administration of morphine results in the selective development of tolerance to other mu agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

Tolerance, cross-tolerance and dependence measured by operant responding in rats treated with triazolam via osmotic pumps.

Previous research has found that drugs with affinity for omega (benzodiazepine) sites differ in their abilities to produce tolerance and dependence. The present study therefore investigated the effects of ligands of omega (BZ) sites in rats that had been rendered tolerant to a benzodiazepine. Two experiments were carried out in separate groups of rats. Behavioral changes induced by chronic infusion of triazolam (3 mg/kg/day, SC, for 14 days) via osmotic pumps were studied in animals trained on a fixed ratio 10 schedule of food presentation. Control animals were implanted with pumps containing the vehicle. Test drugs were administered IP using cumulative dosing. In one experiment triazolam decreased response rates on days 1, 2 and 3 after implantation of the pumps and tolerance developed to this depressant effect. In the other experiment, vehicle and triazolam treated rats differed in their responding during chronic infusion but differences were not statistically significant on any particular day. Flumazenil (3.0-30 mg/kg) greatly decreased rates of responding on day 11 in triazolam treated rats. This effect may represent a precipitated withdrawal syndrome. However, no withdrawal effects on operant performance were observed upon pump removal. Chronic infusion of triazolam did not affect the sensitivity of rats to alpidem on day 11 (10-100 mg/kg) whereas it abolished the stimulant effect of bretazenil (0.1-1.0 mg/kg). Chronic triazolam treatment produced tolerance to the depressant effects of triazolam (1.0-3.0 mg/kg), lorazepam (0.3-3.0 mg/kg) and zopiclone (10 mg/kg) but no tolerance to those of CL 218,872 (3.0-30 mg/kg) and zolpidem (0.3-3.0 mg/kg) when tested 3-14 days after pump removal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Incidence of diabetes mellitus in women following impaired glucose tolerance in pregnancy is lower than following impaired glucose tolerance in the non-pregnant state.

Impaired glucose tolerance (IGT), which is asymptomatic and requires a glucose tolerance test for detection, is a well-known risk factor for diabetes mellitus. Outside the research setting it is rarely identified in people who lack specific risk factors for diabetes except during pregnancy, at which time screening with an oral glucose challenge is a routine procedure. A 75-g oral glucose tolerance test was performed during the latter part of pregnancy or during a routine epidemiology survey in 15-39-year-old Pima Indian women with no history of abnormal glucose tolerance. Those with IGT by World Health Organization criteria were included in this study. Diabetes incidence in women was compared between those whose IGT was first detected during pregnancy and those who were not pregnant when IGT was first recognized. Seventeen of 73 pregnant women and 114 of 244 non-pregnant women developed diabetes within 10 years. When controlled for plasma glucose concentration, age, body mass index, parity and duration of follow-up, those who were not pregnant were at higher risk of developing diabetes than those who were pregnant (hazard rate ratio = 1.71, 95% confidence interval = 1.01-2.91). Previous studies had reported that women with IGT during pregnancy are at higher risk of diabetes than women with normal glucose tolerance. This study suggests that women with IGT during pregnancy are at lower risk than non-pregnant women with a similar plasma glucose concentration who, in the clinical setting, are likely to remain unrecognized.

Adolescent↗
PubMed1983

Cellular events in tolerance IX: maintenance of immunological tolerance in the presence of normal b-cell precursors and in the absence of demonstrable suppression.

The cellular events involved in immunological tolerance to fluoresceinated sheep gammaglobulin (FL-SGG) were analyzed at the level of hapten-specific B cells. One single iv injection of FL-SGG induced tolerance as measured by challenge with thymus-dependent (FL-KLH) or thymus-independent (FL-Ficoll) antigens in vivo or thymus-independent (FL-LPS) antigen in vitro. As noted earlier, unresponsiveness was maintained until 6-8 weeks after tolerance induction. Limiting-dilution precursor analysis demonstrated a reduction in B-cell precursors on Day 7 after tolerogen treatment; precursor frequencies returned to control levels by 3-4 weeks. This recovery of precursors in the presence of stable tolerance was not due to suppressor activity. Rather, results show that tolerant hapten-specific B cells are clonally anergic and display a reduced burst size in response to antigen. Hence, unresponsiveness is maintained in the presence of apparently normal precursor levels by an intrinsic defect in antigen-specific B cells.

Animals↗
PubMed1986

The role of macrophages in B cell tolerance. I. Antigen-specific failure of Thy-1, Ly-2 negative adherent cells from tolerant mice to reconstitute immunocompetence in adherent cell deficient spleen cells.

T-Cell-independent B-cell tolerance to the hapten derivatives of carboxymethyl cellulose (CMC) or methyl cellulose (MC) appears to be controlled by Thy-1-, Ly-2- adherent (A) cells contained in the spleen or peritoneal fluid. Immunocompetence in nonadherent (NA) normal spleen cells could be restored in vitro by irradiated A cells from normal mice. However, NA cells reconstituted with irradiated A cells derived from hapten specifically tolerant mice failed to respond to the same hapten, but responded normally to an immunogenic challenge with another unrelated antigen. A cells that had been preincubated at 4 degrees C with hapten derivatized MC also failed to restore immunocompetence. While preincubation of unfractionated spleen cells with the tolerogen under the same conditions resulted in B-cell unresponsiveness, such treatment of NA cells failed to render B cells tolerant. Treatment of A cells from tolerant mice with the reducing agent potassium iodide (KI) in vitro restored their capacity to render cultures of NA cells immunocompetent to the relevant hapten. Moreover, treatment with KI of spleen cells from mice injected with the tolerogen was shown to render them responsive. We suggest that B-cell tolerance induced by hapten derivatives of CMC and MC is mediated by suppressive macrophages contained among A cells. Certain subpopulations of macrophages are known to exert cytotoxic effects upon target cells by the release at close range of oxidating agents. We postulate that hapten derivatized CMC and MC, through unique properties of the carrier, bind to and possibly activate macrophages rendering them specifically suppressive for hapten binding B cells.

Animals↗
PubMed1993

Tolerance and cross-tolerance to the antinociceptive effects of [D-Arg2]-dermorphin tetrapeptide analogue and morphine.

Rats were given repeated subcutaneous injections of [D-Arg2, Sar4]-dermorphin (1-4) [DAS-DER-(1-4)] and/or morphine over a period of 4 or 7 days. Antinociception was determined at 90 min for DAS-DER (1-4) and 30 min for morphine after each morning injection (9:00 a.m.), using the tail-flick and digit pinching tests in rats. Subcutaneous administration of DAS-DER (1-4) and morphine produced the development of antinociceptive tolerance, respectively. A marked tolerance to DAS-DER (1-4) and morphine was seen in rats made tolerant to morphine. However, administration of morphine produced no significant decrement in the antinociceptive activity in rats made tolerant to DAS-DER (1-4). These results suggest that the site of action of DAS-DER (1-4) may be more limited than that of morphine in the nociceptive pathways, for lack of its antinociceptive efficacy in morphine-tolerant rats.

Amino Acid Sequence↗
PubMed1985

Acquired immunological tolerance in aged mice. II. The cellular basis of the loss of tolerance sensitivity.

Aged C57Bl/6 mice (12 and 24 month) become resistant to tolerance induction with deaggregated human IgG (DHGG). The cellular basis for this tolerance resistance was investigated using adoptive transfer systems and challenged with endotoxin and antigen in the form of heat aggregated HGG. DHGG induced antigen specific suppressor cells in the spleens of aged mice although not in young mice and aged normal splenocytes were more sensitive to suppression. Low dose cyclophosphamide treatment to ablate suppressor cells did not curtail tolerance induction in aged animals. These observations coupled with the transient nature of B cell tolerance in aged mice suggest that the tolerance defect of senescence lies in the B cell compartment.

Aging↗