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PubMed2001

Extinction and spontaneous recovery of ataxic tolerance to ethanol in rats.

RATIONALE AND OBJECTIVES: Two experiments with rats using an ethanol ataxia method investigated extinction and spontaneous recovery of tolerance. Tolerance extinction has been shown with a variety of drugs and methods, but until now it has not been shown with ethanol ataxia. Extinction was investigated here because of its connection with cue exposure treatments, and also to allow an assessment of spontaneous recovery. Spontaneous recovery is the return of conditioned responses, such as those potentially contributing to tolerance, when time passes after extinction. In terms of response topography it resembles instances of relapse in humans. Its demonstration constitutes one technique for illustrating that the effects of extinction are often temporary. There are no published reports showing a recovery of tolerance to any drug due to the passage of time after extinction. A demonstration of spontaneous recovery contributes to an understanding of the effects and time course of tolerance extinction. It also raises the possibility that spontaneous recovery involving drug tolerance has mechanisms similar those involved in instances of spontaneous recovery studied more extensively with non-drug methods. METHODS: In one experiment, ataxic tolerance was conditioned to a strobelight conditioned stimulus (CS) by exposing rats to the strobelight while experiencing the effects of an ethanol injection. Tolerance was extinguished in 17 or 24 once-daily trials by presenting the strobelight without ethanol (with saline). The effect of those numbers of trials was assessed on the day after extinction in the presence of the strobelight when ethanol was again injected. The effect was compared to the effect of the strobelight and ethanol in naive rats and in rats that had received only tolerance conditioning. In a second experiment, ataxic tolerance was conditioned and then extinguished over 17 trials, just as in the other experiment. Different groups were then tested 1, 12, 18, and 24 days after extinction in the presence of the strobelight when ethanol was again injected. RESULTS: Ataxic tolerance was fully extinguished after either 17 or 24 trials, as shown by comparisons with the naive and conditioning-only controls. Tolerance was greater (it recovered) when the strobelight CS was reintroduced 24, 18, and even 12 days after extinction, compared with testing 1 day after extinction. CONCLUSIONS: Conditioned ataxic tolerance can be extinguished, just as other conditioned tolerances can. More important, the return of tolerance over time after extinction represents spontaneous recovery of ethanol tolerance, and indicates that as in other conditioning preparations, extinction does not result in unlearning of the original conditioning association. The identification of spontaneous recovery of tolerance isolates a robust source of the potential for drug use relapse: the mere passage of time after extinction.

Animals↗
PubMed2006

Experimental and clinical evidence for loss of effect (tolerance) during prolonged treatment with antiepileptic drugs.

Development of tolerance (i.e., the reduction in response to a drug after repeated administration) is an adaptive response of the body to prolonged exposure to the drug, and tolerance to antiepileptic drugs (AEDs) is no exception. Tolerance develops to some drug effects much more rapidly than to others. The extent of tolerance depends on the drug and individual (genetic?) factors. Tolerance may lead to attenuation of side effects but also to loss of efficacy of AEDs and is reversible after discontinuation of drug treatment. Different experimental approaches are used to study tolerance in laboratory animals. Development of tolerance depends on the experimental model, drug, drug dosage, and duration of treatment, so that a battery of experimental protocols is needed to evaluate fully whether tolerance to effect occurs. Two major types of tolerance are known. Pharmacokinetic (metabolic) tolerance, due to induction of AED-metabolizing enzymes has been shown for most first-generation AEDs, and is easy to overcome by increasing dosage. Pharmacodynamic (functional) tolerance is due to "adaptation" of AED targets (e.g., by loss of receptor sensitivity) and has been shown experimentally for all AEDs that lose activity during prolonged treatment. Functional tolerance may lead to complete loss of AED activity and cross-tolerance to other AEDs. Convincing experimental evidence indicates that almost all first-, second-, and third-generation AEDs lose their antiepileptic activity during prolonged treatment, although to a different extent. Because of diverse confounding factors, detecting tolerance in patients with epilepsy is more difficult but can be done with careful assessment of decline during long-term individual patient response. After excluding confounding factors, tolerance to antiepileptic effect for most modern and old AEDs can be shown in small subgroups of responders by assessing individual or group response. Development of tolerance to the antiepileptic activity of an AED may be an important reason for failure of drug treatment. Knowledge of tolerance to AED effects as a mechanism of drug resistance in previous responders is important for patients, physicians, and scientists.

Animals↗
PubMed2004

Tolerance induced by low dose D-penicillamine in the brown Norway rat model of drug-induced autoimmunity is immune-mediated.

Most patients taking drugs associated with idiosyncratic drug reactions tolerate the drug and do not develop adverse reactions. Understanding the mechanism of tolerance to drugs is important as it could provide insight into why some patients develop idiosyncratic reactions and others do not. The Brown Norway rat model of D-penicillamine-induced autoimmunity was used as a model of idiosyncratic drug-induced autoimmunity. Two weeks of low dose (5 mg/day) D-penicillamine pretreatment completely prevented all clinical signs of autoimmunity normally seen in 60-80% of rats treated with high dose (20 mg/day) D-penicillamine. Low dose pretreatment also prevented the increase in IgE and IL-4 mRNA characteristic of the response to high dose D-penicillamine. Experiments were conducted to determine whether low dose tolerance is metabolic or immunological. It was found that low dose tolerance possesses key characteristics of immune-mediated tolerance: memory, splenocytes that adoptively transfer tolerance, and regulatory cytokine production. To provide an understanding of the factors that can prevent or reverse established tolerance, the conditions for inducing and maintaining tolerance were investigated. Tolerance induction was investigated by manipulating the immune system during the period of low dose exposure. The induction of tolerance was partially prevented by depleting the macrophage subset of antigen presenting cells with clodronate-filled liposomes or by inhibiting T cells with tacrolimus during the period of low dose exposure. As well, the induction of tolerance was completely prevented by repeatedly stimulating the immune system throughout the period of low dose pretreatment with poly I:C. To investigate the permanence of tolerance, the immune system was stimulated after tolerance induction in an attempt to break tolerance. Both LPS and poly I:C reversed tolerance in a dose-dependent manner. These results demonstrate that immune tolerance to D-penicillamine autoimmunity can be induced by short-term low dose pretreatment.

Administration, Oral↗
PubMed2002

Induction of bacterial lipoprotein tolerance is associated with suppression of toll-like receptor 2 expression.

Tolerance to bacterial cell wall components including lipopolysaccharide (LPS) may represent an essential regulatory mechanism during bacterial infection. Two members of the Toll-like receptor (TLR) family, TLR2 and TLR4, recognize the specific pattern of bacterial cell wall components. TLR4 has been found to be responsible for LPS tolerance. However, the role of TLR2 in bacterial lipoprotein (BLP) tolerance and LPS tolerance is unclear. Pretreatment of human THP-1 monocytic cells with a synthetic bacterial lipopeptide induced tolerance to a second BLP challenge with diminished tumor necrosis factor-alpha and interleukin-6 production, termed BLP tolerance. Furthermore, BLP-tolerized THP-1 cells no longer responded to LPS stimulation, indicating a cross-tolerance to LPS. Induction of BLP tolerance was CD14-independent, as THP-1 cells that lack membrane-bound CD14 developed tolerance both in serum-free conditions and in the presence of a specific CD14 blocking monoclonal antibody (MEM-18). Pre-exposure of THP-1 cells to BLP suppressed mitogen-activated protein kinase phosphorylation and nuclear factor-kappaB activation in response to subsequent BLP and LPS stimulation, which is comparable with that found in LPS-tolerized cells, indicating that BLP tolerance and LPS tolerance may share similar intracellular pathways. However, BLP strongly enhanced TLR2 expression in non-tolerized THP-1 cells, whereas LPS stimulation had no effect. Furthermore, a specific TLR2 blocking monoclonal antibody (2392) attenuated BLP-induced, but not LPS-induced, tumor necrosis factor-alpha and interleukin-6 production, indicating BLP rather than LPS as a ligand for TLR2 engagement and activation. More importantly, pretreatment of THP-1 cells with BLP strongly inhibited TLR2 activation in response to subsequent BLP stimulation. In contrast, LPS tolerance did not prevent BLP-induced TLR2 overexpression. These results demonstrate that BLP tolerance develops through down-regulation of TLR2 expression.

Bacterial Outer Membrane Proteins↗
PubMed2006

Antibiotic treatment in vitro of phenotypically tolerant bacterial populations.

OBJECTIVES: Most pharmacodynamic models used for design of treatment regimens are based on time-kill data obtained with normal cells in the susceptible state without taking into account the killing kinetics of the antibiotic-tolerant cells in the population. We compared the microbiological efficacy of six antibiotics against tolerant cells and by mathematical modelling explored the potential clinical implications of tolerance. METHODS: Tolerant cells were obtained by filtration of bacterial cultures of Escherichia coli MG1655 after antibiotic exposure. Killing kinetics of the tolerant cells was compared with that of exponentially growing naive cells. To examine the nutrient dependency of the reversion from the tolerant state to the susceptible state, tolerant cells were re-suspended in Luria-Bertani and PBS and re-exposed to antibiotics. A mathematical model was used to explore the clinical implications of antibiotic tolerance. RESULTS: Streptomycin was the most efficient drug against tolerant cells. Ciprofloxacin and ampicillin had intermediate activity against tolerant cells while rifampicin, tetracycline and erythromycin had poor activity against tolerant cells. No correlation could be established between the microbiological efficacies against susceptible and tolerant cells. Reversion from tolerance to susceptibility was dependent on the presence of nutrients and growth. Computer simulations demonstrated that the efficacy of antibiotics against tolerant cell populations has a large influence on treatment outcome. CONCLUSIONS: The in vitro killing kinetics of tolerant cells is antibiotic-dependent and different from that of cells in the susceptible state. This difference in efficacy could have an influence on treatment outcome and tolerance should therefore be studied further in vivo.

Anti-Bacterial Agents↗
PubMed2000

Baseline predictors of tolerability to carvedilol in patients with chronic heart failure.

OBJECTIVE: To determine baseline predictors of tolerance to the alpha/beta blocker carvedilol in everyday clinical practice. DESIGN: Retrospective analysis of tolerance to carvedilol in patients with chronic heart failure. Tolerance was defined as currently on carvedilol or on it at the time of death or heart transplantation. To meet the criteria for tolerance, carvedilol had to be prescribed at a stable dose for >/= 3 months. SETTING: Everyday clinical practice, comprising both hospital specialist practice and private practice. Tolerance was assessed in all patients prescribed carvedilol for chronic heart failure in those practices. PATIENTS: 808 consecutive patients in both hospital specialist (611 patients) and private practice (197 patients). MAIN OUTCOME MEASURES: Baseline predictors of tolerance assessed by proportional hazards analysis. Both univariate and multivariate analyses were performed. RESULTS: Within the entire cohort of 808 patients, 95 had stopped carvedilol, 606 were currently receiving the drug, 50 had died, and 44 had received a heart transplant. Overall, 88% of patients tolerated carvedilol (87% in the hospital specialist group, 92% in the private practitioner group). Factors that indicated impaired tolerance by univariate analysis were increased age in years (hazard ratio 1.01, 95% confidence interval (CI) 1.0 to 1.3), low diastolic blood pressure (hazard ratio 1.04, 95% CI 1.02 to 1.08), and raised plasma urea concentration (hazard ratio 1.04, 95% CI 1.02 to 1.05). New York Heart Association (NYHA) class was also a marker of tolerance (proportion not tolerated: 3% class I; 9% class II; 13% class III, 22% class IV). By multivariate analysis, no single baseline variable was an independent marker of inability to tolerate carvedilol. Tolerance was also assessed in relation to traditional precautions or relative contraindications to beta blockade. Tolerance in these subgroups was: chronic obstructive airways disease/asthma 85% (89 patients), diabetes 86% (127 patients), peripheral vascular disease 84% (58 patients), concomitant amiodarone treatment 83% (230 patients), and heart rate < 70 beats/min 84% (184 patients). CONCLUSIONS: beta Blocker treatment was well tolerated in everyday clinical practice, including non-hospital-based private practice. There was no single predictor of poor tolerance on multivariate analysis, although there was a clear association with NYHA class as well as age, diastolic blood pressure, and plasma urea on univariate analysis. Carvedilol was tolerated well among selected patients with traditional contraindications to beta blockade in this situation.

Adolescent↗
PubMed1990

Induction of transplantation tolerance and development of lymphomas in mice: lack of interdependence.

Neonatal transplantation tolerance was induced in five different H-2-incompatible donor----recipient mouse strain combinations by the iv injection of semiallogeneic (F1 hybrid) spleen cells. The highest degree of tolerance (expressed by the survival time of the specific test skin allografts) was observed in the (CBA X A)F1----CBA combination (approximately 95% permanent tolerance) but some degree of tolerance was achieved in all strain combinations. An increased incidence of malignant lymphoproliferative disorders was observed in all groups of mice which underwent neonatal tolerance induction. The highest incidence of lymphoproliferative malignancies was observed in the (B10 X A)F1----A tolerance induction system, in which approximately 50% of the recipient mice died within 1 year. In further experiments, spleen cells of mice which proved to be permanently tolerant after the neonatal tolerance induction were transferred into syngeneic, normal, adult, ATS-pretreated, allografted recipients; by this method, in approximately 50% of the recipients permanent "adult" tolerance was achieved. The spleen cells of the "adult" tolerant mice were able to transfer the tolerance to other adult, syngeneic, ATS-pretreated recipients. Even the fourth serial transfer resulted in essentially the same degree of tolerance in the new recipients. We consider the serial transfer a classical instance of "infectious tolerance" based on suppressor mechanisms. However, an increasing number (and malignancy) of lymphomas occurred in the course of the serial transfers and prevented the "indefinite" transfer of tolerance after the fourth occasion. We conclude that both the degree of transplantation tolerance and the high frequency of lymphomas are determined by (immuno)genetic factors but the two phenomena are not interrelated. Thus, successful transplantations do not seem to be necessarily accompanied by an increased incidence of malignancies.

Animals↗
PubMed1993

Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. VI. Suppression of adoptively transferred disease and differential effects of oral vs. intravenous tolerization.

Antigen-driven tolerance is an effective method of suppressing cell-mediated immune responses. We have previously shown that oral administration of myelin basic protein (MBP) suppresses experimental autoimmune encephalomyelitis (EAE) when it is actively induced by MBP emulsified in complete Freund's adjuvant. In order to further study antigen-driven tolerance in this model, we investigated the effect of oral tolerization on adoptively transferred EAE and compared oral tolerance to intravenously (i.v.) administered MBP in both actively induced EAE and adoptively transferred EAE. Although orally tolerized animals were not protected from adoptively transferred EAE, spleen cells from orally tolerized animals suppressed adoptively transferred EAE when co-transferred with encephalitogenic cells or when injected into recipient animals at a different site at the time encephalitogenic cells were transferred. This suppression was mediated by CD8+ T cells, correlated with suppression of DTH responses to MBP, and was associated with decreased inflammation in the spinal cord. Unlike oral tolerization, spleen cells from i.v. tolerized animals did not suppress adoptively transferred EAE when co-transferred with encephalitogenic cells although i.v. tolerized animals were protected from adoptively transferred EAE. MBP peptides were then utilized to further characterize differences between i.v. and oral tolerization in the actively induced disease model. Both orally and intravenously administered MBP suppressed actively induced EAE. However, EAE was only suppressed by prior i.v. tolerization with the encephalitogenic MBP peptide 71-90, but not with the non-encephalitogenic peptide 21-40, whereas prior tolerization with 21-40 did suppress actively induced EAE when administered orally. These results suggest a different mechanism of tolerance is initiated by oral vs. intravenous administered antigen. Specifically, oral tolerization suppresses primarily by the generation of active suppression whereas the dominant mechanism of suppression associated with i.v. tolerization appears most consistent with the elicitation of clonal anergy.

Administration, Oral↗
PubMed1998

Attenuation of tolerance to opioid-induced antinociception and protection against morphine-induced decrease of neurofilament proteins by idazoxan and other I2-imidazoline ligands.

1. Agmatine, the proposed endogenous ligand for imidazoline receptors, has been shown to attenuate tolerance to morphine-induced antinociception (Kolesnikov el al., 1996). The main aim of this study was to assess if idazoxan, an alpha2-adrenoceptor antagonist that also interacts with imidazoline receptors, could also modulate opioid tolerance in rats and to establish which type of imidazoline receptors (or other receptors) are involved. 2. Antinociceptive responses to opioid drugs were determined by the tail-flick test. The acute administration of morphine (10 mg kg(-1), i.p., 30 min) or pentazocine (10 mg kg(-1), i.p., 30 min) resulted in marked increases in tail-flick latencies (TFLs). As expected, the initial antinociceptive response to the opiates was lost after chronic (13 days) treatment (tolerance). When idazoxan (10 mg kg(-1), i.p.) was given chronically 30 min before the opiates it completely prevented morphine tolerance and markedly attenuated tolerance to pentazocine (TFLs increased by 71-143% at day 13). Idazoxan alone did not modify TFLs. 3. The concurrent chronic administration (10 mg kg(-1), i.p., 13 days) of 2-BFI, LSL 60101, and LSL 61122 (valldemossine), selective and potent I2-imidazoline receptor ligands, and morphine (10 mg kg(-1), i.p.), also prevented or attenuated morphine tolerance (TFLs increased by 64 172% at day 13). This attenuation of morphine tolerance was still apparent six days after discontinuation of the chronic treatment with LSL 60101-morphine. The acute treatment with these drugs did not potentiate morphine-induced antinociception. These drugs alone did not modify TFLs. Together, these results indicated the specific involvement of I2-imidazoline receptors in the modulation of opioid tolerance. 4. The concurrent chronic (13 days) administration of RX821002 (10 mg kg(-1), i.p.) and RS-15385-197 (1 mg kg(-1), i.p.), selective alpha2-adrenoceptor antagonists, and morphine (10 mg kg(-1), i.p.), did not attenuate morphine tolerance. Similarly, the concurrent chronic treatment of moxonidine (1 mg kg(-1), i.p.), a mixed I(1)-imidazoline receptor and alpha2-adrenoceptor agonist, and morphine (10 mg kg(-1), i.p.), did not alter the development of tolerance to the opiate. These results discounted the involvement of alpha2-adrenoceptors and I(1)-imidazoline receptors in the modulatory effect of idazoxan on opioid tolerance. 5. Idazoxan and other imidazol(ine) drugs fully inhibited [3H]-(+)-MK-801 binding to N-methyl-D-aspartate (NMDA) receptors in the rat cerebral cortex with low potencies (Ki: 37-190 microM). The potencies of the imidazolines idazoxan, RX821002 and moxonidine were similar, indicating a lack of relationship between potency on NMDA receptors and ability to attenuate opioid tolerance. These results suggested that modulation of opioid tolerance by idazoxan is not related to NMDA receptors blockade. 6. Chronic treatment (13 days) with morphine (10 mg kg(-1), i.p.) was associated with a marked decrease (49%) in immunolabelled neurofilament proteins (NF-L) in the frontal cortex of morphine-tolerant rats, suggesting the induction of neuronal damage. Chronic treatment (13 days) with idazoxan (10 mg kg(-1)) and LSL 60101 (10 mg kg(-1)) did not modify the levels of NF-L proteins in brain. Interestingly, the concurrent chronic treatment (13 days) of idazoxan or LSL 60101 and morphine, completely reversed the morphine-induced decrease in NF-L immunoreactivity, suggesting a neuroprotective role for these drugs. 7. Together, the results indicate that chronic treatment with I2-imidazoline ligands attenuates the development of tolerance to opiate drugs and may induce neuroprotective effects on chronic opiate treatment. Moreover, these findings offer the I2-imidazoline ligands as promising therapeutic coadjuvants in the management of chronic pain with opiate drugs.

Adrenergic alpha-Antagonists↗
PubMed1970

Cell to cell interaction in the immune response. V. Target cells for tolerance induction.

Collaboration between thymus-derived lymphocytes, and nonthymus-derived antibody-forming cell precursors occurs during the immune response of mice to sheep erythrocytes (SRBC). The aim of the experiments reported here was to attempt to induce tolerance in each of the two cell populations to determine which cell type dictates the specificity of the response. Adult mice were rendered specifically tolerant to SRBC by treatment with one large dose of SRBC followed by cyclophosphamide. Attempts to restore to normal their anti-SRBC response by injecting lymphoid cells from various sources were unsuccessful. A slight increase in the response was, however, obtained in recipients of thymus or thoracic duct lymphocytes and a more substantial increase in recipients of spleen cells or of a mixture of thymus or thoracic duct cells and normal marrow or spleen cells from thymectomized donors. Thymus cells from tolerant mice were as effective as thymus cells from normal or cyclophosphamide-treated controls in enabling neonatally thymectomized recipients to respond to SRBC and in collaborating with normal marrow cells to allow a response to SRBC in irradiated mice. Tolerance was thus not achieved at the level of thelymphocyte population within the thymus, perhaps because of insufficient penetration of the thymus by the antigens concerned. By contrast, thoracic duct lymphocytes from tolerant mice failed to restore to normal the response of neonatally thymectomized recipients to SRBC. Tolerance is thus a property that can be linked specifically to thymus-derived cells as they exist in the mobile pool of recirculating lymphocytes outside the thymus. Thymus-derived cells are thus considered capable of recognizing and specifically reacting with antigenic determinants. Marrow cells from tolerant mice were as effective as marrow cells from cyclophosphamide-treated or normal controls in collaborating with normal thymus cells to allow a response to SRBC in irradiated recipients. When a mixture of thymus or thoracic duct cells and lymph node cells was given to irradiated mice, the response to SRBC was essentially the same whether the lymph node cells were derived from tolerant donors or from thymectomized irradiated, marrow-protected donors. Attempts to induce tolerance to SRBC in adult thymectomized, irradiated mice 3-4 wk after marrow protection, by treatment with SRBC and cyclophosphamide, were unsuccessful: after injection of thoracic duct cells, a vigorous response to SRBC occurred. The magnitude of the response was the same whether or not thymus cells had been given prior to the tolerization regime. The various experimental designs have thus failed to demonstrate specific tolerance in the nonthymus-derived lymphocyte population. Several alternative possibilities were discussed. Perhaps such a population does not contain cells capable of dictating the specificity of the response. This was considered unlikely. Alternatively, tolerance may have been achieved but soon masked by a rapid, thymus-independent, differentiation of marrow-derived lymphoid stem cells. On the other hand, tolerance may not have occurred simply because the induction of tolerance, like the induction of antibody formation, requires the collaboration of thymus-derived cells. Finally, tolerance in the nonthymus-derived cell population may never be achieved because the SRBC-cyclophosphamide regime specifically eliminates thymus-derived cells leaving the antibody-forming cell precursors intact but unable to react with antigen as there are no thymus-derived cells with which to interact.

Animals↗
PubMed1972

Immunological tolerance in bone marrow-derived lymphocytes. I. Evidence for an intracellular mechanism of inactivation of hapten-specific precursors of antibody-forming cells.

Administration of the 2,4-dinitrophenyl (DNP) derivative of the copolymer of D-glutamic acid and D-lysine (D-GL) to inbred mice induces a state of DNP-specific tolerance in such animals irrespective of their immune status at the time of treatment. Taking advantage of the relative ease with which DNP-D-GL can induce tolerance in an animal previously primed with an immunogenic DNP-carrier conjugate, we have established conditions for tolerance induction in an adoptive cell transfer system. Thus, the adoptive secondary anti-DNP antibody response of DNP-keyhole limpet hemocyanin (KLH)-primed spleen cells was completely, or almost completely, abolished by exposure of such cells to DMP-D-GL either in vivo or in vitro. Tolerance induction in vivo occurred irrespective of whether the DNP-primed cells were exposed to DNP-D-GL in the donor animal before adoptive transfer or in recipient mice after transfer. In the latter situation, it was possible to show that tolerance induction in this model occurs very rapidly (1 hr) and with relatively low doses of tolerogen (50 microg). Incubation of DNP-KLH-primed cells with DNP-D-GL in vitro under varying culture conditions also resulted in depression of the adoptive secondary response of such cells, although the kinetics and degree of tolerance induction in this way were slightly different from that obtained by in vivo tolerization. Utilizing the adoptive transfer tolerance system, it was possible to approach certain questions concerning the mechanism of tolerance induction and fate of tolerant bone marrow-derived (B) lymphocytes in the DNP-D-GL model. The possibility that suppression of anti-DNP antibody from the DNP-D-GL reflects blocking of surface receptor molecules on B lymphocytes has been ruled out by several experimental observations. The most conclusive evidence on this point derives from the failure of enzymatic treatment with trypsin to reverse the tolerant state induced by in vitro exposure of primed cells to DNP-D-GL, whereas trypsinization completely restored the immunocompetence of DNP-KLH-primed cells rendered unresponsive by exposure to DNP-ovalbumin in vitro. The present studies also demonstrate that the tolerant state induced by DNP-D-GL represents a predominantly irreversible inactivation of specific B lymphocytes. This conclusion is derived from experiments in which it was found that tolerance was maintained through as many as two serial adoptive transfers performed over a period of time of at least 24 days from the single exposure of such cells to the tolerogen. Moreover, the possibility that maintenance of tolerance through such serial transfers was due to inadvertent transfer of tolerogenic doses of DNP-D-GL was definitively ruled out. It appears, therefore, that DNP-specific tolerance induced by DNP-D-GL is an example of irreversible inhibition of cell reactivity to antigen reflecting yet-to-be-determined events at the intra- and subcellular levels.

Animals↗
PubMed1996

Pancreatic islet allograft immunity and tolerance: the two-signal hypothesis revisited.

The principle assumption of this discussion is that costimulation (CoS) forms the primary stimulus that compels T cells to mount a response to their specific antigen. However, this response can be either positive or negative, depending on the developmental stage of the T cell and the microenvironment in which the antigen and CoS are received. Thus, both immunity and tolerance may represent different outcomes of a two-signal process. We would emphasize that CoS is a functional term and not a strict molecular definition. While many molecular interactions have been described as providing CoS activity, notably those involving the B-7 family of cell surface molecules, it is not yet clear what combination(s) of non-antigen-specific signals may fulfil this function. This point is important because many studies have achieved tolerance through strategies designed to inhibit specific CoS molecules. However, it may be that differential signaling through distinct CoS molecules, rather than a global inhibition of CoS per se, plays a role in the generation of active tolerance in such studies (Bluestone 1995). A corollary of this notion is that antigen (signal 1) delivery to T cells is a null event and so is not an inherently paralysing signal. Of course, if signal 1 is not itself a tolerogenic signal, then other mechanisms are necessary to explain many empirical observations of tolerance to allogeneic or self antigens. This is best illustrated by those forms of functional tolerance to either alloantigens or self antigens that do not appear to be the result of clonal deletion/inactivation. It would be relatively simple to invoke a model of tolerance whereby the relevant tissue-destructive cell is eliminated or inactivated; such a model would preclude the necessity to suggest active regulatory mechanisms of tolerance. However, in several model systems, including our own observations concerning tolerance induction to APC-depleted islet allografts, tissue-destructive T cells can persist in recipients tolerant to allogeneic or self antigens. Furthermore, there are key examples in which tolerance demonstrates a dominant phenotype; that is, tolerant cells can regulate the activity of naive, non-tolerant cells. This latter observation points to the function of an active, regulatory form of tolerance. As such, we would emphasize that tolerance should not be defined as unresponsiveness since the tolerant state is the consequence of very active immune reactions.

Animals↗
PubMed1985

Tolerance of Haemophilus influenzae to beta-lactam antibiotics.

Two hundred clinical isolates of Haemophilus influenzae were tested for tolerance (MBC/MIC greater than or equal to 32) to ampicillin and cefotaxime by broth dilution tests. Of 200 strains, 9 were tolerant to ampicillin, and 10 were tolerant to cefotaxime. Tolerant organisms were identified in both systemic and nonsystemic infections and among different biotypes and serotypes of H. influenzae. These tolerant isolates were compared with nontolerant isolates by broth dilution and killing curves with log-phase and stationary-phase inocula. Both tolerant and nontolerant bacteria in log phase were killed more rapidly by antibiotics than bacteria in stationary-phase growth. When tested against 11 different beta-lactams, several patterns of tolerance were observed. Six of the ten strains were tolerant to aztreonam, four were tolerant to cefuroxime, three were tolerant to cefamandole, and two were tolerant to cefoxitin. Strain H130 was tolerant to all beta-lactam antibiotics studied. None of the 10 tolerant H. influenzae isolates were tolerant to chloramphenicol, rifampin, tobramycin, ciprofloxacin, enoxacin, and trimethoprim-sulfamethoxazole. Although the clinical significance of tolerance is not determined, this study suggests that the bactericidal activity (MBC) of beta-lactam antibiotics against H. influenzae should be determined in cases of severe infections in which clinical response is slow or unsatisfactory.

Ampicillin↗
PubMed2006

Role of endogenous hydrogen peroxide in the development of nitrate tolerance.

The present study was designed to test the hypothesis that hydrogen peroxide plays a role in the development of nitrate tolerance. Isolated rat aortic rings were suspended in organ chambers for isometric tension recording. The rings were incubated with (tolerant) and without (control) nitroglycerin (10(-4) M) for 90 min, followed by repeated rinsing for 1 h. Hydrogen peroxide release in control and tolerant tissues was measured fluorimetrically using amplex red. Nitroglycerin (10(-9)-10(-4) M) caused concentration-dependent relaxations in control (-logEC50=7.15+/-0.1) and tolerant rings (-logEC50=5.83+/-0.1) contracted with norepinephrine. Nitrate tolerance was evident by a >20-fold rightward shift in the nitroglycerin concentration-response curve in tissues exposed previously to nitroglycerin for 90 min. Incubation of the rings with the superoxide dismutase (SOD)-mimetic, tempol (10(-4) M), during the 90-min exposure period to nitroglycerin caused a leftward shift in the nitroglycerin concentration-response curve in tolerant rings (-logEC50=6.84+/-0.2), but had no effect on the response to nitroglycerin in control rings. Treatment of the rings with catalase (1200 U/ml) or ebselen (1.5x10(-5) M), a glutathione peroxidase-mimetic, during the 90-min exposure period to nitroglycerin resulted in a further rightward shift in the nitroglycerin concentration-response curve in tolerant rings (-logEC50=5.41+/-0.1 and 4.98+/-0.1; catalase and ebselen respectively), without altering the response to nitroglycerin in control rings. In the presence of catalase, the effect of tempol on nitrate tolerance was abolished (-logEC50=5.46+/-0.1). Hydrogen peroxide release was reduced by approximately 64% in nitrate tolerant tissues when compared to control. The decrease in hydrogen peroxide release was completely reversed by treatment with tempol, whereas treatment with ebselen caused a further decrease in hydrogen peroxide release in nitrate tolerant tissues. Addition of hydrogen peroxide (3x10(-5) M) to nitrate tolerant rings caused a leftward shift in the nitroglycerin concentration-response curve in tolerant rings (-logEC50=7.18+/-0.3), but had no effect on the response to nitroglycerin in control rings. These results suggest that nitrate tolerance is associated with decreased endogenous formation of hydrogen peroxide, which attenuates nitrate tolerance development. SOD-mimetics may reduce nitrate tolerance, in part, by increasing the formation of hydrogen peroxide.

Animals↗
PubMed1983

Clonal variation for tolerance to polyethylene glycol-induced water stress in cultured tomato cells.

Cell clones were isolated from a population of cultured tomato (Lycopersicon esculentum Mill cv VFNT-cherry) cells and their tolerance to polyethylene glycol (PEG)-induced water stress was measured. Considerable variation for tolerance among the clones was found. Tolerance differences between clones appeared to be spontaneous and were different from tolerance differences between adapted and unadapted cells. Unlike adapted (selected by exposure to PEG) cells, cell clones retained their relative tolerance for many generations in the absence of selection pressure, and tolerance of both relatively tolerant and intolerant clones was very dependent on growth cycle stage and inoculum density. Analysis of subclones isolated from relatively tolerant and intolerant parent clones revealed that each parent clone gives rise to progeny with tolerances near the mean tolerance of both parents. However, progeny populations of both tolerant and intolerant parents are enriched with individuals with phenotypes nearer the mean response of their respective parent populations. When exposed to PEG, relatively tolerant and intolerant clones alike become adapted to the level of PEG to which they are exposed, and have the same phenotypic level of tolerance. Thus, selection by exposure to stress is unable to discriminate (on the basis of growth) between the innately tolerant and intolerant cell types within the population. This is indicated also by the fact that clones isolated from a population of cells adjusted to growth on 25% PEG do not show an enriched frequency of tolerant phenotypes when grown in the absence of PEG compared to the nonselected normal cell population which has never been adjusted to growth on PEG.

Journal Article↗
PubMed2000

Mecamylamine prevents tolerance but enhances whole brain [3H]epibatidine binding in response to repeated nicotine administration in rats.

RATIONALE: Chronic administration of nicotine in rats results in upregulation of neuronal nicotinic receptors. Upregulation has been proposed to reflect receptor desensitization, which may underlie functional tolerance to nicotine's effects. However, evidence indicates that tolerance and upregulation do not always parallel each other, suggesting that either upregulation does not always reflect desensitization, or mechanisms other than receptor desensitization account for tolerance to nicotine. OBJECTIVES: The present studies examined tolerance to nicotine-induced antinociception and changes in receptor binding after two regimens of intermittent nicotine injections in rats. The role of receptor activation in upregulation and tolerance was also examined by co-administering nicotine with the non-competitive antagonist, mecamylamine. METHODS: Sprague-Dawley rats were administered a short (once-daily, s.c. for 6 days (0.35 mg/kg)) or long (twice-daily for 11 days (0.66 mg/kg)) series of injections and tolerance to nicotine-induced antinociception and [3H]epibatidine binding in whole brain were measured. RESULTS: The short series of injections resulted in tolerance to nicotine-induced antinociception, but failed to increase [3H]epibatidine binding. In contrast, the long series of injections resulted in both tolerance and increased receptor binding. Once-daily pairings of mecamylamine (1 mg/kg, s.c.) with nicotine (0.35 mg/kg) for 6 days blocked the development of tolerance, indicating receptor activation is necessary for tolerance to occur. Pairing mecamylamine with nicotine (0.66 mg/kg) twice daily for 11 days blocked tolerance but produced a greater increase in [3H]epibatidine binding than nicotine alone. CONCLUSIONS: A dissociation of tolerance from receptor upregulation was observed in the present study. The finding that receptor activation may be necessary for tolerance but not upregulation is discussed within the context of possible mechanisms controlling tolerance to nicotine.

Animals↗
PubMed1990

Rats withdrawn from ethanol rapidly re-acquire membrane tolerance after resumption of ethanol feeding.

The time course for the re-acquisition of membrane tolerance to the disordering effects of ethanol in vitro has been determined for liver microsomes obtained from chronically ethanol-fed rats that were withdrawn from ethanol for 2-4 days (during which tolerance is lost) followed by resumption of ethanol feeding. Naive rats require 28-35 days of chronic ethanol feeding to develop membrane tolerance. Microsomal membranes regain partial sensitivity to ethanol disordering after 2-3 days of withdrawal and regain the complete sensitivity observed in membranes from untreated control rats after 4 days of withdrawal. The period of ethanol re-feeding required for the re-acquisition of membrane tolerance was dependent on the withdrawal period, with tolerance appearing sooner if the withdrawal period was shorter. The time course for the re-development of tolerance in previously tolerant animals was considerably faster (4-14 days) than in naive rats being administered the ethanol diet for the first time (35 days). Microsomes from rats that were withdrawn for 2 days (which retained partial tolerance) and then re-fed the ethanolic-diet required only 4 days to re-acquire membrane tolerance. Microsomes from rats withdrawn 3 days required 8 days and those withdrawn 4 days required 15 days for full tolerance to re-develop. The same time-course for the re-acquisition of membrane tolerance was observed in either intact microsomes or in liposomes prepared from extracted microsomal total phospholipids. Phosphatidylinositol (PI) has previously been reported to be responsible for conferring membrane tolerance to liver microsomes in ethanol-fed rats (Taraschi, T.F., Ellingson, J.S., Wu, A., Zimmerman, R. and Rubin, E. (1986) Proc. Natl. Acad. Sci. USA 83, 9398-9402). The time course for re-acquisition of membrane tolerance by liver microsomes following ethanol withdrawal and resumption of ethanol feeding correlated with the ability of PI to confer tolerance.

Animals↗
PubMed1996

Zaprinast, but not dipyridamole, reverses hemodynamic tolerance to nitroglycerin in vivo.

Hemodynamic tolerance to nitroglycerin was developed in spontaneously hypertensive rats following 2-3 days of pretreatment with 100 mg/kg of nitroglycerin administered s.c. 3 times/day. Tolerance was evaluated both in vivo, by administering ascending bolus doses of nitroglycerin of 1-300 micrograms/kg i.v., and ex vivo in isolated, denuded aortic vascular rings by exposure to ascending concentrations of nitroglycerin of 0.0003-100 microM. Tolerance was observed as a significant blunting of the hypotensive and vasorelaxant effect of nitroglycerin. Co-incubation of tolerant aortic rings and pretreatment of tolerant SHR with 10 microM and 0.1-10 mg/kg zaprinast, respectively, resulted in full restoration of the vasorelaxant and hypotensive effect of nitroglycerin. Zaprinast partially reversed hemodynamic tolerance at 0.01 mg/kg. Conversely, dipyridamole (10 microM) reversed tolerance ex vivo, but was ineffective in reversing tolerance in vivo at pretreatment doses of 30 and 60 mg/kg. Following a 100-micrograms/kg i.v. challenge dose of nitroglycerin, aortic cyclic guanosine monophosphate (cGMP) levels were lower in nitroglycerin tolerant SHR when compared to non-tolerant SHR. Pretreatment of tolerant SHR with 10 mg/kg zaprinast restored the increase in cGMP levels to nitroglycerin to that seen in non-tolerant SHR. Conversely, dipyridamole (30 mg/kg) pretreatment was not effective in restoring cGMP levels. These data therefore suggest that reversal of hemodynamic tolerance in vivo is related to restoration of changes in vascular cGMP levels. Zaprinast, a selective cGMP phosphodiesterase inhibitor, effectively reverses tolerance and dipyridamole, a rather non-selective inhibitor, does not.

3',5'-Cyclic-GMP Phosphodiesterases↗