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Results for “Tolerability”

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PubMed1990

Importance of suppressor T cells in cyclophosphamide-induced tolerance to the non-H-2-encoded alloantigens. Is mixed chimerism really required in maintaining a skin allograft tolerance?

Mechanisms of cyclophosphamide (CP)-induced tolerance were studied. When AKR/J Sea (AKR: H-2k) mice were primed i.v. with 5 x 10(7) spleen cells plus 1 x 10(7) bone marrow cells from [C57BL/6 Slc (B6; H-2b) x C3H/He Slc (C3H; H-2k)]F1 (B6C3F1) mice and treated i.p. with 200 mg/kg CP 2 days later, the survival of C3H skin was moderately prolonged, but the survival of either B6 or B6C3F1 skin was not prolonged. By this treatment, however, mixed chimerism of B6C3F1 cells in the AKR mice was not established. When C3H cells were used as the tolerogen, a minimal degree of mixed chimerism associated with profound tolerance to C3H skin was established. Similar results were observed in various donor-recipient combinations. When C3H skin was grafted in the AKR mice 12 wk after the treatment with C3H cells and CP, or B6C3F1 cells and CP, survival of the grafted C3H skin was prolonged remarkably or moderately, respectively, although mixed chimerism was not detectable at the timing of grafting in either of the groups. In this late stage of tolerance, a strong level of tolerogen-specific suppressor cell activity was observed in those tolerant AKR mice. The suppressor activity was mainly attributable to T cells. These results suggest that the role of Ts cells in order to maintain skin tolerance is important in our CP-induced tolerance system, especially in the late stage of tolerance. Moreover, the generation of the Ts cells does not necessarily require the establishment of a long term mixed chimeric state.

Animals↗

PubMed1999

Analysis of peripheral immune tolerance uncovers a mouse strain-dependent in situ type of graft tolerance.

We screened various mouse strains [C57BL/6, BALB/c, DBA/2, CBA/Ca, (CBAxC57L/6)F1, SJL, C3H] for induction of peripheral immune tolerance. Only CBA/Ca mice treated with anti-CD4 + CD8 monoclonal antibodies and grafted with allogeneic skin showed long-term graft survival (150 to >200 days). Interestingly, T cells from the tolerant CBA/Ca mice rejected bone marrow/spleen cells of the skin graft donor strain and caused lethal graft-versus-host disease when transplanted to the donor strain. Furthermore, peripheral tolerance was easily broken: CBA/Ca mice could be reactivated to reject their tolerated grafts via immunization with (graft donor x recipient strain)F1 bone marrow cells. Thus, in contrast to the generalized nature of central tolerance, our experiments show that peripheral immune tolerance is strain dependent and locally restricted to graft tissue.

Animals↗

PubMed1975

B cell tolerance induced by polymeric antigens. III. Dissociation of antibody formation and memory generation in tolerant mice.

Hapten (2,4-dinitrophenyl (DNP))-substituted type 3 pneumococcal polysaccharide (DNP-lys-S3) effectively suppresses both primary and secondary anti-DNP antibody responses to DNP-proteins. The present experiments show that tolerizing doses of DNP-lys-S3 have much less effect on B cell memory (re)generation in three distinct situations: (i) in serial transfers of DNP-protein-primed cells, (ii) in virgin mice tolerized before priming with DNP-hemocyanin, and (iii) in tolerized, hemocyanin-primed mice boosted with DNP-hemocyanin. Under some conditions tolerized mice developed 10-50% of normal memory in the absence of significant antibody formation. Isoelectric focusing analyses revealed that many B cell clones proliferate in tolerant mice, but produce very little antibody until transferred to further hosts. Clones that escape suppression in partially tolerant mice do not appear to be resistant to DNP-lys-S3, when retested. Since there is independent evidence that the generation of B memory cells is less T cell-dependent than the development of antibody-forming cells, these data are best explained by assuming that DNP-lys-S3 blocks lymphocyte cooperation. This would be expected to preferentially suppress antibody formation, and to spare memory generation.

Adoptive Transfer↗

PubMed1981

The effect of second signals on the induction of B cell tolerance: failure of helper T cells to block tolerance induction.

The effect of carrier-primed helper T (Th) cells and T cell-replacing factors on the induction of hapten-specific tolerance in B cells from adult mice has been tested. The 2,4,6-trinitrophenyl conjugate of human gamma-globulin (TNP17HGG) was used as tolerogen in an in vitro tolerance induction system. Tolerance was assessed by the subsequent induction of plaque-forming cell responses using TNP-Brucella abortus and trinitrophenylated sheep red blood cells (TNP-SRBC) plus SRBC-primed Th cells as T-independent (TI) and T-dependent (TD) forms of TNP, respectively. B cells that respond to the different forms of TNP appear to be distinct B cell subpopulations. TNP17HGG induced TNP-specific tolerance in B cells responsive to TI and TD forms of the antigen, although more tolerogen was required to induce unresponsiveness in the TD antigen-reactive B cells. The presence of antigen nonspecific T cell-replacing factors during tolerance induction had no effect on the induction of unresponsiveness in either TI or TD antigen-responsive B cells, although these factors were able to support primary anti-TNP responses in T-depleted B cell populations to subtolerogenic doses of TNP-HGG. Populations of irradiated lymphocytes enriched for HGG-specific Th cells also had no effect on tolerogenesis in TI or TD antigen-responsive B cells, although priming of TD antigen-responsive B cells occurred at subtolerogenic doses of tolerogen. The inability of these Th cells to modulate B cell unresponsiveness was not due to their inability to exert helper function at higher concentrations of HGG. Thus, in this system, tolerance susceptibility is an intrinsic property of B lymphocytes, i.e. immunogenicity vs. tolerogenicity of signals is not determined by a "second signal" provided by Th cells.

Animals↗

PubMed1993

Split tolerance of Th1 and Th2 cells in tolerance to Theiler's murine encephalomyelitis virus.

Theiler's murine encephalomyelitis virus (TMEV) produces a chronic, inflammatory demyelinating disease in susceptible mouse strains that is used as a model for multiple sclerosis. Because disease susceptibility correlates temporally with the development of virus-specific delayed-type hypersensitivity (DTH) responses, we studied methods and mechanisms by which virus-specific DTH could be specifically inhibited. The intravenous injection of UV-inactivated TMEV coupled to syngeneic splenocytes via a carbodiimide linkage (TMEV-SP), prior to immunization, induced a significant degree of tolerance in virus-specific helper (Th) cells as determined by decreased DTH and T cell proliferative responses, and decreased interleukin (IL)-2 and interferon (IFN)-gamma protein and mRNA levels. In contrast to the reduced levels of Th1-specific lymphokine mRNA levels, IL-4-specific mRNA levels in response to virus stimulation were not affected in tolerant mice. Surprisingly, the total anti-TMEV antibody response in DTH tolerant mice was enhanced 20-100-fold over sham-tolerized controls and was composed of reduced levels of anti-virus IgG2a, but dramatically increased levels of anti-virus IgG1. The "split-tolerance" was antigen specific, dependent on the concentrations of TMEV and carbodiimide used in the coupling procedure, and varied with the number of coupled syngeneic splenocytes administered. The fixative effects of carbodiimide on antigen-presenting function were necessary for the induction of DTH tolerance with TMEV-SP, since intravenous administration of virus coupled to splenocytes via a biotin-avidin linkage led to enhanced virus-specific antibody responses, but was unable to inhibit DTH unless concomitantly fixed with carbodiimide. Collectively, the data indicate that Th1 cells (mediating DTH, IL-2 and IFN-gamma production, and helper function for IgG2a production) were specifically anergized, with concomitant stimulation of Th2 cells (producing IL-4 and mediating helper function for IgG1 antibody production).

Animals↗

PubMed2005

Split peripheral tolerance: CD40 ligation blocks tolerance induction for CD8 T cells but not for CD4 T cells in response to intestinal antigens.

The role of antigen-presenting cells in the balance between immunity and tolerance to intestinal antigens remains poorly understood. In this study, we examined whether CD40 ligation affects the induction of CD4 and CD8 T cell tolerance in response to intestinal antigens. We show that an agonistic anti-CD40 mAb treatment did not block the induction of OVA-specific CD4 T cell tolerance, whereas this approach enabled strong priming of OVA-specific cytotoxic T cells (CTL), preventing CTL tolerance to intestinal antigen. Such CTL priming was independent of CD4 T cell help but required B7 costimulation. Co-administration of anti-CD40 mAb increased the synthesis of IL-2 and the expression of CD25 by CD8 T cells, but neither IL-2 production nor CD25 expression by CD4 T cells was enhanced by anti-CD40 mAb. However, neutralization of TGF-beta together with addition of agonistic anti-CD40 mAb was able to reverse CD4 T cell tolerance. These findings suggest that the induction of tolerance versus immunity against intestinal antigens is determined by the status of the antigen-presenting cells and that signals via CD40 differently regulate the outcome of CD4 and CD8 T cells in vivo.

Administration, Oral↗

PubMed1986

Behavioural tolerance to arecoline in rats: cross-tolerance to oxotremorine and prevention by pretreatment with atropine.

In two experiments tolerance development to the effects of arecoline on operant responding for a water reward was shown to be dose-dependent, complete tolerance developing to a daily dose of 4 mg/kg, but only partial tolerance developing to a daily dose of 8 mg/kg. However, rats chronically treated with the higher dose of arecoline were least affected by a challenge dose of oxotremorine (0.2 mg/kg); i.e. the high dose group exhibited the greatest cross-tolerance to oxotremorine. Moreover, atropine (4 mg/kg) pretreatment prior to arecoline (4 mg/kg) prevented cross-tolerance to oxotremorine, indicating that dispositional mechanisms are unlikely to be involved in tolerance to arecoline.

Animals↗

PubMed1975

Electroencephalographic studies on the development of tolerance and cross tolerance to mescaline in the rat.

Recordings of the electroencephalogram (EEG) and the electromyogram (EMG) were collected continuously from rats equipped with permanent cortical and temporalis muscle electrodes. Automatic injections of mescaline were administered through indwelling i.p. cannulas at an initial dose of 30 mg/kg every 6 hrs for the first 2 days. This dose was then increased to 60 mg/kg 6 hr which was given for the duration of the study. The initial injections of the mescaline induced an immediate desynchronization of the EEG and behavioral arousal of the rat, which endured for 2-3 hrs. After this time, slow wave (SW) sleep and rapid eye movement (REM) sleep episodes reappeared, with the return of regular alternations of the sleep-wakefulness cycle. Upon continued administration of the drug, partial tolerance to the arousal effects of mescaline developed, which was reflected by a gradual reduction in the latencies to onset of SW sleep and REM sleep. Rats rendered tolerant to mescaline in this manner were found to be cross tolerant to lysergic acid diethylamide (LSD) and N,N-diethyl-tryptamine (DET). In contrast, cross tolerance did not occur to amphetamine, which exerts similar arousal and EEG desynchronizing effects. These results agree with physiological and behavioral studies of tolerance and cross tolerance among hallucinogens and support the usefulness of the EEG as a quantitative indicator of central nervous system function.

Amphetamine↗

PubMed1982

Morphine- and methadone-tolerant mice differ in cross-tolerance to other opiates. Heterogeneity in opioid mechanisms indicated.

Mice were rendered tolerant to morphine or 1-methadone by subcutaneous injections for 4 days. The antinociceptive activities of morphine, codeine, l-methadone and d-propoxyphene were determined in tolerant and control mice using the hot-plate test, and the respective ED50's were calculated by the up-and-down procedure of Dixon. An asymmetry in cross-tolerance patterns was found: While morphine-pretreated mice were tolerant to morphine only (with a dose-ratio tolerant: control of 5.2), methadone-pretreated mice were tolerant to all analgesics tested, and more so to morphine 5.2; l-methadone 3.0; codeine 2.7 and d-propoxyphene 1.9). The results are discussed in terms of heterogeneity in opioid receptor mechanisms.

Analgesia↗

PubMed1999

Context-specific morphine tolerance on the paw-pressure and tail-shock vocalization tests: evidence of associative tolerance without conditioned compensatory responding.

RATIONALE: Demonstrations of associative tolerance to the analgesic effects of morphine, not confounded by practice or novelty effects, have been restricted to the tail-flick and flinch-jump tests. OBJECTIVES: Experiment 1 investigated whether associative tolerance would be found on two other nociceptive assessment methods: the paw-pressure withdrawal and tail-shock vocalization thresholds. Experiment 2 tested the hypothesis that conditioned compensatory behavioral responses are the substrate of associative morphine tolerance in the paw-pressure, tail-shock, and tail-flick tests. METHODS: Rats were given eight morphine injections (20 mg/kg, i.p.) explicitly paired or unpaired with a distinctive context. Control animals were given saline injections over the course of conditioning. Animals were then tested after morphine (experiment 1) or placebo injections (experiment 2) in the context. RESULTS: There was evidence of context-specific tolerance across both testing methods, with a rightward shift of dose-response curves of paired relative to unpaired animals. No evidence of conditioned compensatory responding was found on any of the three testing methods. CONCLUSIONS: The data indicated that, although Pavlovian processes can play a major role in tolerance acquisition, there was little support for the thesis that the conditioned tolerance response is a behavioral effect that is opposite in direction to the direct effects of the drug.

Analgesics, Opioid↗

PubMed1987

Tolerance to morphine microinjections in the periaqueductal gray (PAG) induces tolerance to systemic, but not intrathecal morphine.

The acquisition and retention of tolerance to the antinociceptive effect of supraspinal morphine on the tail withdrawal reflex was assessed in rats implanted with unilateral cannulae in the periaqueductal gray (PAG). Development of tolerance to daily microinjections of morphine was indicated by the return of the tail flick response within 4 days, followed by the recovery of analgesic sensitivity one week later. After tolerance had developed, the effect of an acute systemic (1.5-4.5 mg/kg) or intrathecal (5-15 micrograms) morphine injection was determined. 'Cross-tolerance' was observed between systemic and supraspinal morphine but not between intrathecal and supraspinal morphine. The data indicate that tolerance to chronic intracerebral morphine produces the same behavioral consequences as tolerance to systemic morphine.

Animals↗

PubMed1985

Primed lymphoid cell tolerance. II. In vivo tolerization of highly tolerogen-sensitive hapten-primed, potentially IgG-producing B cells.

The relative ease of tolerizing IgM-bearing versus IgG-bearing B cells was investigated. Previous work had shown that IgG-bearing trinitrophenyl (TNP)-specific B cells from mice primed and boosted with TNP-keyhole limpet hemocyanin (TNP-KLH) are highly susceptible to tolerization in vitro by TNP presented on an unrelated carrier. TNP-OVA was used as tolerogen, as it may represent a more general class of tolerogens than those which are nonmetabolizable or immunoglobulin containing. This study showed that highly primed B cells are tolerizable in vivo using TNP-OVA, with the IgG response to TNP-KLH easier to tolerize than the IgM response. To determine if the ease of tolerization of the IgG response in vivo was due to intrinsic differences in B-cell precursors of the IgM and IgG responses, tolerance was performed in vitro with B cells of defined surface isotypes. A T-independent antigen, TNP-endotoxin, was employed to minimize T-cell effects. At least 10 times as much TNP-OVA was required to tolerize B cells bearing the IgM surface isotype than those with the IgG surface isotype. Thus, the ease of inhibition of the IgG response as compared to the IgM response in vivo by preexposure to TNP-OVA may be at least partially explained by inherent differences in IgM and IgG B-cell precursors.

Animals↗

PubMed1982

Cross tolerance to etorphine in rats tolerant to morphine-induced antidiuresis.

Previously in the analgesic tail flick assay, mice and rats implanted with morphine pellets were shown to be highly tolerant to subcutaneously administered morphine but not to etorphine. The present purpose was to see whether the same differential response would be found to the antidiuretic response of morphine and etorphine in water-loaded rats because the presence of such a differential response would be value in studying mechanisms of tolerance. Etorphine injected subcutaneously was about 1000x more potent than morphine in producing an antidiuretic response. Following chronic administration of morphine by pellet implantation, where the pellets remained in place during the drug challenge, profound tolerance developed to the antidiuretic effect of both morphine and etorphine. The dose-response curves for both were shifted to the right in non-parallel fashion with decreased slopes and antidiuretic efficacies. The large degree of tolerance developed to the antidiuretic effect of etorphine in morphine pellet implanted rats in contrast to the lack of development of tolerance to etorphine in the tail flick assay indicated that different mechanisms of development of tolerance exist for the two responses.

Animals↗

PubMed1983

Dissociations between the behavioral effects of LSD and tolerance development during ontogeny in cats: a novel approach to the study of tolerance mechanisms.

The characteristic behavioral effects of d-lysergic acid diethylamide (LSD) in cats first appeared at approximately 25 days of age and increased rapidly in magnitude over the next 10 days. However, 25 day old kittens showed no tolerance to the repeated administration of the drug. While the behavioral response to the initial dose of LSD remained relatively constant between 35 and 112 days of age, the tolerance gradually became more pronounced throughout this time period, reaching an adult level of virtually complete tolerance at 112 days. These findings provide new insight into the nature of the relationship between the primary drug action and the development of tolerance, and suggest a new strategy for investigating the neural bases of tolerance, i.e., examining the neurochemical effects of repeated LSD administration in kittens during various stages of tolerance development.

Animals↗

PubMed1989

Behavioral effects of benzodiazepine antagonists in chlordiazepoxide tolerant and non-tolerant rats.

Rats were trained to respond under 3-min fixed-interval schedules of food presentation, and effects of the benzodiazepine-receptor ligands, flumazenil, 2-(4-methoxy-phenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one (CGS 9895), 3-carbo-t-butoxy-beta-carboline (beta-CCtB), and beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) were assessed before and after the induction of tolerance to chlordiazepoxide. Before daily administration of chlordiazepoxide, none of the antagonists produced appreciable effects on rates of responding up to doses of 32.0 mg/kg i.p. beta-CCE was the only antagonist studied at a higher dose (100.0 mg/kg i.p.), which decreased response rates. After 23 days of daily chlordiazepoxide administration (oral doses started at 10 and increased to 100 mg/kg/day by the 17th day), dose-effect curves for chlordiazepoxide were shifted to the right by about one-half log unit. Subjects were also more sensitive to the flumazenil, CGS 9895, and beta-CCtB, however, since these drugs produced only small effects in non-tolerant subjects, precise estimates of the degree of the shift in dose-effect curves could not be estimated. However, there were differences in the changes in the dose-effect curves induced by chlordiazepoxide tolerance. These results suggest differences in mechanism of action of antagonists in tolerant and non-tolerant subjects, and further that the sensitivity that is induced to antagonists in tolerant subjects is not conferred equally to all drugs having benzodiazepine antagonist activity.

Animals↗

PubMed1981

Chronic amphetamine: is dopamine a link in or a mediator of the development of tolerance and reverse tolerance?

Rats were administered chronic multiple injections of amphetamine (AMPH) using dosage regimens which produce tolerance to the AMPH facilitation of self-stimulation responding, or reverse tolerance (sensitization) to the locomotor stimulant and stereotypy-producing effects of the drug. Subsequently rats were challenged with AMPH at behaviorally relevant doses and times and striatal and mesolimbic dopamine (DA) dynamics were assessed using the conversion of 3H-tyrosine to 3H-DA, and endogenous levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) as indices of dopaminergic function. Acute administration of AMPH produced dose and time related changes in all indices of DA function in both the striatal and mesolimbic brain regions. Co-administration of haloperidol during chronic AMPH pretreatment prevented the appearance of most of the behavioral changes induced by chronic AMPH, suggesting an important role for DA systems. However, following chronic AMPH treatment, no additional biochemical changes in striatal or mesolimbic DA metabolism could be detected which would parallel the development of tolerance to AMPH facilitation of self-stimulation behavior or reverse tolerance to AMPH as reflected in enhanced post-stereotypy locomotor activity or a suggested increased intensity of stereotypy. Challenge with AMPH after chronic AMPH pretreatment did accelerate the changes in striatal but not mesolimbic DA metabolism, correlating with the more rapid onset of stereotypy induced by chronic AMPH. Thus, while DA systems appear to be a critical link, not only in the acute effects of AMPH, but also in the development of tolerance and reverse tolerance, most of the behavioral differences between acutely and chronically treated animals are not reflected by comparable differences in DA synthesis and metabolism.

Amphetamine↗

PubMed1988

Tolerance to and cross tolerance between ethanol and nicotine.

Female DBA mice were subjected to one of four treatments: ethanol-containing or control diets, nicotine (0.2, 1.0, 5.0 mg/kg/hr) infusion or saline infusion. After removal from the liquid diets or cessation of infusion, the animals were challenged with an acute dose of ethanol or nicotine. Chronic ethanol-fed mice were tolerant to the effects of ethanol on body temperature and open field activity and were cross tolerant to the effects of nicotine on body temperature and heart rate. Nicotine infused animals were tolerant to the effects of nicotine on body temperature and rotarod performance and were cross tolerant to the effects of ethanol on body temperature. Ethanol-induced sleep time was decreased in chronic ethanol- but not chronic nicotine-treated mice. Chronic drug treatment did not alter the elimination rate of either drug. Chronic ethanol treatment did not alter the number or affinity of brain nicotinic receptors whereas chronic nicotine treatment elicited an increase in the number of [3H]-nicotine binding sites. Tolerance and cross tolerance between ethanol and nicotine is discussed in terms of potential effects on desensitization of brain nicotinic receptors.

Alcoholism↗

PubMed1992

Tolerance to the anticonvulsant effects of phenobarbital, trimethadione, and clonazepam in kindled rats: cross tolerance to carbamazepine.

The kindled-convulsion model was used to assess the development of tolerance and cross tolerance to the anticonvulsant effects of antiepileptic drugs. In Experiment 1, tolerance developed to the anticonvulsant effects of bidaily (one every 48 h) IP injections of phenobarbital, trimethadione, and clonazepam on convulsions elicited 1 h after each injection in kindled rats by amygdala stimulation. In Experiment 2, kindled rats that were tolerant to the anticonvulsant effects of phenobarbital, trimethadione, or clonazepam received bidaily IP injections of carbamazepine, each followed 1 h later by a convulsive amygdala stimulation. There was a statistically significant transfer of tolerance from phenobarbital to carbamazepine, but not from either trimethadione or clonazepam to carbamazepine. Apparently, tolerance to anticonvulsant drugs is most likely to transfer between drugs that are effective against similar kinds of clinical and experimental seizures and have similar putative mechanisms of action.

Amygdala↗