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PubMed1984

Manipulation and pain tolerance. A controlled study of the effect of spinal manipulation on paraspinal cutaneous pain tolerance levels.

The response of paraspinal cutaneous pain tolerance levels to spinal manipulation has not been studied in an experimental model. This paper proposes such a model of pain tolerance measurement and describes the results of a controlled study of 50 assymptomatic subjects. The group receiving a spinal manipulation demonstrated a 140% increase in local cutaneous pain tolerance levels which was statistically significant (p less than 0.05). This is consistent with previous hypotheses regarding the mode of action of manipulation in the relief of spinal pain.

Adult↗
PubMed1983

Penicillin (cloxacillin)-tolerant Staphylococcus aureus from bovine mastitis: identification and lack of correlation between tolerance in vitro and response to therapy in vivo.

Twenty-four isolates of Staphylococcus aureus from naturally occurring cases of bovine mastitis were examined in vitro for resistance to cloxacillin. All strains produced penicillinase and none showed intrinsic resistance (methicillin resistance) to cloxacillin. The minimum inhibitory concentration of cloxacillin for all these strains was normal (low) but differences were found between them in their sensitivities to the bactericidal action. Three were considered to be tolerant to cloxacillin and a further five possibly so. In a mouse model of mastitis there was no difference in the response to intramammary therapy with cloxacillin between cloxacillin-sensitive or tolerant strains of S aureus and a known methicillin-resistant strain was similarly sensitive to cloxacillin therapy in vivo. It is concluded that cloxacillin tolerance may have little clinical significance in mastitis therapy.

Acute Disease↗
PubMed1995

Mixed xenogeneic chimerism and tolerance III. A nonlethal approach to induce donor-specific transplantation tolerance to simultaneous islet xenografts.

Previously, we reported that transplantation of rat bone marrow into lethally irradiated (950 rads) mouse recipients results in stable xenogeneic (rat-->mouse) chimerism and confers donor-specific transplantation tolerance for subsequent or simultaneous islet xenografts. For potential clinical application of chimerism to induce tolerance, it would be important to avoid the morbidity and mortality associated with lethal conditioning. Recently, we established a model to achieve durable multilineage xenogeneic chimerism using a nonlethal cytoreductive approach. We report here for the first time that donor-specific rat islet xenografts placed coincident with the bone marrow transplant are permanently accepted by nonlethally conditioned recipients. All recipients conditioned with 700 cGy of total body irradiation and transplanted with 40 x 10(6) F344 rat bone marrow cells repopulated as mixed donor/host chimeras. The chimeras exhibited permanent acceptance of donor islet xenografts, since donor-specific F344 (Rt1A1) rat islet xenografts were significantly prolonged (median survival time > 110 days), while MHC-disparate third-party WF (Rt1Au) rat islets were prolonged but rejected (median survival time = 33.2 days). The islets were functional to maintain normoglycemia and regulated in function to respond to an intraperitoneal glucose challenge. These data suggest that tolerance to donor-specific islet xenografts placed coincident with bone marrow transplantation can be achieved after nonlethal conditioning.

Animals↗
PubMedDate not supplied

[Relationship between manifestation of hyporeactivity (tolerance) in interferon production and the presence of a viral interferon inductor in the cells of the tolerant animal].

Experiments revealed parallelism between the duration of the main manifestations of the hyporeactivity phenomenon (tolerance) in interferon induction and the duration of detection of a masked infection with the inducer virus (Newcastle disease virus) in peritoneal exudate cells of tolerant mice. It was also shown that after contact of chick fibroblasts with a dose of interferon which completely inhibited replication of vesicular stomatitis virus infecting the cells this virus was found in the cells in the masked form. Persistence of a virus interferon inducer in the masked form appears to play a significant role in the mechanism of tolerance as well as creation in the interferon-treated cells of conditions for masking viruses infecting these cells.

Animals↗
PubMed2001

Motor stimulant effects of the adenosine A(2A) receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats.

Several evidences indicate that the selective blockade of adenosine A(2A) receptors counteracts the motor activity impairment in experimental models of Parkinson's disease. In the present study, the effects of the adenosine A(2A) receptor antagonist, SCH 58261 (5-amino-7-(beta-phenylethyl)-2-(8-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine, were assessed following a repeated treatment schedule in the contralateral turning behavior rat model of Parkinson's disease. Unilateral lesions of the nigrostriatal pathway were induced by injecting 6-hydroxydopamine (6-OHDA) in medial forebrain bundle. Repeated administration of SCH 58261 was performed either alone (7 and 14 days repeated SCH 58261) or together with L-dopa (19 days repeated SCH 58261 plus L-dopa or L-dopa alone). After a 7- and 14-day repeated administration schedule, SCH 58261 (5 mg/kg) maintained its ability to potentiate the contralateral turning behavior induced by a subthreshold dose of L-dopa (2 mg/kg i.p.), showing no tolerance to its stimulant effects. SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) or L-dopa (6 mg/kg) alone induced, at these dosages, the same number of contralateral turnings after the first administration. While chronic intermittent SCH 58261 plus L-dopa did not lead to a modified turning behavior during treatment, L-dopa alone produced a progressive increase in turning behavior intensity and duration. These results provide evidence that SCH 58261 retains its ability to potentiate L-dopa effects in a validated rat model of Parkinson's disease even after repeated treatments. Moreover, these results suggest that adenosine A(2A) blockade prevents the appearance of motor response alterations in L-dopa-treated rats, supporting the concept that A(2A) receptor antagonists have a therapeutic potential for the treatment of Parkinson's disease. Copyright 2001 Wiley-Liss, Inc.

Journal Article↗
PubMed2001

The immune tolerance network and rheumatic disease: immune tolerance comes to the clinic.

The development of effective, new, biologically based therapies for RA has created real excitement and justifiable optimism in recent years among rheumatologists and among patients with rheumatic diseases. Recent advances in our understanding of the mechanisms of immune activation and immune tolerance provide further cause for optimism. Against this background, the establishment of the ITN is an important step. However, significant hurdles remain to be cleared. First, despite dramatic scientific progress, restoration of immune tolerance in the face of an established autoimmune response is still an elusive goal, even in the laboratory. Not only does the ITN face this fundamental scientific challenge, but it also faces daunting practical and political challenges. For example, can the ITN influence the research agenda of the pharmaceutical and biotechnology industries? This question and other important questions will only be answered as the ITN matures. Autoimmune disease, although individually uncommon, affects more than 2% of Americans. The rheumatologist is especially aware of the devastating potential of autoimmune diseases. If the ITN succeeds in linking basic research into the mechanisms of autoimmunity with clinical trials of promising new therapies, it can be expected to play a critical role in advancing the practice of clinical rheumatology.

Animals↗
PubMed1996

Evidence that induction of tolerance in vivo involves active signaling via a B7 ligand-dependent mechanism: CTLA4-Ig protects V beta 8+ T cells from tolerance induction by the superantigen staphylococcal enterotoxin B.

Co-stimulation through CD28 is thought to be necessary for the activation of unprimed CD4+ T cells, which are otherwise rendered tolerant. However, we previously found that CD4+ T cell priming was normal or augmented in mice which overexpressed a soluble form of CTLA4 where co-stimulation through CD28 was abrogated. To investigate this CD4+ T cell response, we exploited the capacity of the superantigen staphylococcal enterotoxin B to stimulate T lymphocytes bearing V beta 8+, which represent approximately 30% of all CD4+ T cells. In litter-mate controls of CTLA4-Ig transgenic mice, immunization with staphylococcal enterotoxin B leads to expansion, followed by deletion of V beta 8+ T cells, and the remaining cells are tolerant when stimulated in vitro. Comparable expansion and deletion of V beta 8 T cells occurs in CTLA4-Ig transgenic mice. However, in contrast to normal mice, the remaining V beta 8+ T cells from CTLA4-Ig transgenic mice are not anergic and remain responsive to superantigen in vitro.

Abatacept↗
PubMed1980

Reversal of ethanol tolerance and cross-tolerance to pentobarbital in the rat.

Adult male Wistar rats were fed nutritionally adequate liquid diets providing 35% of the total calories as ethanol, while pair-fed controls received the corresponding diet with ethanol replaced by an equicaloric concentration of sucrose. After 2, 4, 6, 8, 10 and 14 weeks of chronic ethanol treatment, separate groups of rats were injected with a test dose of either ethanol (3 g/kg) or pentobarbital (40 mg/kg). Rectal temperatures were determined prior to and at 30, 60, 90 and 120 min after injection. The fall in rectal temperature after a test dose of ethanol or pentobarbital was significantly lower at 2 and 4 weeks in ethanol-treated rats than in pair-fed controls. After 6 and 8 weeks of chronic ethanol treatment, the fall in temperature after the same test doses was still less in ethanol-treated rats than in controls. However, at 10 and 14 weeks the fall in temperature was virtually identical in the two groups. A similar pattern of results was obtained when ethanol-induced sleep was compared in ethanol-treated rats and control rats. These intriguing results challenge the generally believed concept that tolerance and cross-tolerance, once produced, are sustained with chronic treatment, and may raise the possibility that such processes are reversible even during chronic treatment, at least under certain regimens.

Animals↗
PubMed1978

Development of tolerance to the analgesic effect of clonidine in rats. Cross-tolerance to morphine.

The influence of chronic treatment with clonidine on analgesia produced by clonidine and morphine was studied in rats. Electrical stimuli were applied to the tail, and analgesia was measured as increase in the threshold voltage that elicited vocalisation. Twenty-two hours after the last of 14 injections of increasing doses of clonidine over 7 days, the acute analgesic effects of both clonidine and morphine were reduced, i.e. tolerance had developed. Pretest vocalisation thresholds (voltage) were unchanged by long-term treatment with clonidine, or, respectively, saline. Contrarywise, acute administration of clonidine enhanced the effect of morphine. The tolerance developed after long-term treatment with clonidine might be associated with changes in brain noradrenaline mechanisms.

Analgesics↗
PubMed1984

Lack of tolerance to cyclopropane and cross-tolerance to halothane in rats.

Cyclopropane requirement (MAC) in rats was determined before, during, and after repeated exposure to anaesthetic concentrations of cyclopropane and halothane for one hour every day for 20 and 30 days, respectively. MAC values during and after exposure ranged from 93 to 103 per cent (mean = 99 per cent) of control values, which indicates a lack of significant tolerance to cyclopropane or a cross-tolerance between cyclopropane and halothane.

Anesthetics↗
PubMed1976

The periaqueductal gray: site of morphine analgesia and tolerance as shown by 2-way cross tolerance between systemic and intracerebral injections.

The periaqueductal gray was shown to be an important component of morphine analgesia and tolerance. Two-way analgesic cross tolerance was obtained between systemic and intracerebral morphine administrations when the intracerebral site was the periaqueductal gray. Rats were pretreated with intraperitoneal morphine and tested with intracerebral morphine in the periaqueductal gray. A dose-dependent reduction in analgesia as a function of morphine pretreatment level was obtained. Conversely, when rats were pretreated with intracerebral morphine in the periaqueductal gray and tested with intraperitoneal morphine, significant reductions in analgesia were obtained.

Analgesia↗
PubMed1985

Induction of hapten-specific immunological tolerance and immunity in B lymphocytes. VII. Correlation between trinitrobenzenesulfonic acid administration, serum trinitrophenyl content, and level of tolerance.

The induction of immunological tolerance with trinitrobenzenesulfonic acid (TNBS) was studied by a comparison of the concentration of trinitrophenyl (TNP) in the serum of tolerant mice (TolS) and the degree of unresponsiveness induced as the dose and time of tolerogen injection were varied. The concentration of TNP in TolS was greater with a larger dose of TNBS, as expected, and decreased with time after tolerogen injection in a biphasic manner. The rapid initial decline followed on Day 10 by a more gradual decrease in TNP concentration suggests that there were two classes of TNP conjugates produced by TNBS injection. The serum TNP concentration appeared to correlate to the in vivo response of TNBS-treated mice to thymic-dependent and thymic-independent antigenic challenge while little correlation was evident with the in vitro response.

Animals↗
PubMed1988

Role of self carriers in the immune response and tolerance. XII. Effect of epitope density and antigen-presenting cell phenotype on the presentation of hapten-modified self for the induction of immunity or tolerance in vitro.

The data presented in the accompanying paper (J. P. Cogswell, R. P. Phipps, and D. W. Scott, Cell. Immunol. 114, 55-70, 1988) indicate that certain macrophage-like and lymphoid dendritic-like (P388AD.2) tumor lines which express major histocompatibility encoded class II (Ia) antigens and produce interleukin 1 (IL-1) are uniquely able to present hapten-modified self (HMS) in an immunogenic fashion in vivo. In the current study, the relationship between phenotype and function has been confirmed utilizing a completely in vitro system. This investigation revealed that B-cell priming required T cells restricted to P388AD.2's I-A antigens. In addition, exogenous IL-1 reconstituted the response of an IL-1-deficient tumor (P388AD.2-ILd), although it had no effect on the other nonimmunogenic Ia+ tumor lines. Unlike the in vivo system, effective B-cell tolerance was induced when P388AD.2 was modified with high concentrations (10 mM) of hapten or when highly haptenated tumor was added to 0.1 mM TNBS-modified P388AD.2. These results suggest that positive regulation of in vitro immune responses to HMS is dependent upon the phenotype of the accessory cell carrier (with lymphoid dendritic-like cells being unusually potent), while negative regulation is associated with high epitope density. This system now allows the dissection of the properties of different accessory cells and the signals required for B-cell priming or tolerance induction.

Animals↗
PubMed1984

Analgesic activity of substance P in rats: tolerance and cross-tolerance with enkephalin.

In rats, tolerance to the analgesic effect of intraventricular substance P (SP) develops quickly. In rats made tolerant to [D-Ala2, D-Leu5]enkephalin the analgesic efficacy of SP is reduced significantly. The latter result suggests some overlap in the sites of action of SP and [D-Ala2,D-Leu5] enkephalin. Since SP seems to lack any direct effect on opiate receptors of the brain, the present data suggest that the analgesic effect of SP is mediated by enkephalin release at supraspinal levels which are related to pain control.

Analgesics↗
PubMed1982

Development of clonidine-tolerance in the rat vas deferens: cross tolerance to other presynaptic inhibitory agents.

Possibility of the development of clonidine-tolerance in the peripheral nervous tissue was examined using vas deferens isolated from rats chronically treated with clonidine. Rats were treated with clonidine for 10 days by adding the drug to drinking water (10 microgram/ml). For the control rats, drug-free tap water was provided. Electrically evoked twitch response of vas deferens was suppressed by adenosine, beta-endorphine and alpha 2-adrenergic agonists, such as clonidine and B-HT 933, both in control and clonidine-treated groups. Vas deferens isolated from clonidine-treated rats showed significantly lower responsiveness to the inhibitory effects of clonidine and B-HT 933 compared to those from control rats. Vas deferens from clonidine-treated rats also was less responsive to adenosine and beta-endorphin, both of which interact with presynaptic inhibitory receptors other than alpha 2-adrenoceptors. On the other hand, responsiveness of the postsynaptic smooth muscle to both alpha-adrenergic and muscarinic cholinergic stimulation did not change after 10 days of treatment with clonidine. These results suggest that clonidinetolerance can be induced in the peripheral nervous system by chronic treatment of this drug and that the tolerance is not specific to alpha 2-adrenergic agonists. Some common pathway in the inhibitory mechanisms of various agents or possible interactions between the different types of presynaptic inhibitory receptors may be involved in this phenomenon.

Adenosine↗
PubMed1987

Discriminative stimulus effects of caffeine: tolerance and cross-tolerance with methylphenidate.

Twice daily injection of caffeine (30 mg/kg) for 3-1/2 days shifted the caffeine stimulus generalization curve to the right by 3-fold in rats trained to discriminate saline from 30 mg/kg of caffeine, and by 4-fold in rats trained to discriminate saline from 10 mg/kg of caffeine. The latter group was also tested for cross-tolerance with methylphenidate, a drug that generalizes completely with caffeine. Twice daily injection of caffeine (30 mg/kg) for 3-1/2 days increased the ED50 of methylphenidate for caffeine-appropriate responding from 1.5 to 5.5 mg/kg. Conversely, injections of methylphenidate (3.0 mg/kg) increased the ED50 of caffeine from 5.2 to 15 mg/kg. The development of symmetrical cross-tolerance to the discriminative effects of caffeine and to the caffeine-like discriminative effects of methylphenidate supports previous observations suggesting commonalities in the cellular bases of the stimulus properties of these drugs.

Animals↗
PubMed1985

Tolerance to some behavioural effects of lisuride, a dopamine receptor agonist, and reverse tolerance to others, after repeated administration.

To investigate whether prolonged pretreatment with the dopamine (DA) agonist lisuride would result in modification of some of its behavioural effects, food intake, locomotor activity, body temperature or stereotyped and mounting behaviour were evaluated after acute injections of different doses of lisuride into rats, pretreated daily for four weeks with either saline or lisuride. Rats pretreated with lisuride developed tolerance to its anorexigenic and hypothermic effects, and reverse tolerance to its effects on locomotor activity, stereotyped and mounting behaviour. Pretreatment with lisuride did not modify the activity of drug-metabolizing enzymes in the liver. These results, in addition to revealing the pattern of the changes in the behavioural effects of a DA agonist drug, after repeated administration, may be taken as evidence for the existence of different DA receptor systems in different areas of the brain, that mediate different behavioural effects, and that differ markedly in their reactions to prolonged stimulation with an agonist drug.

Animals↗
PubMed1985

Acquired immunological tolerance in aged mice III. The contribution of lymphoid cells and their environments to the age related resistance to tolerance induction.

Whether lymphoid cells or their environment are responsible for the decreased tolerogen sensitivity of aged mice was examined using an adoptive transfer system. Bone marrow cells from old (24 months), middle aged (12 months) and young adult mice (2 months) were equally sensitive to tolerance induction with deaggregated human immunoglobulin (DHGG) when they were transplanted into young lethally irradiated syngeneic hosts. Adoptively transferred splenocytes also showed no age related difference in tolerogen sensitivity. Thus, the age related difference seen in the intact animal is due largely to environmental factors acting on lymphoid cells in the aged animal. The role of lipopolysaccharide (LPS) as one such environmental factor affecting tolerance induction was investigated. LPS administered to aged mice produced greater polyclonal B cell activation and autoantibody formation than it did in young animals. When LPS was administered shortly after DHGG injection it converted the tolerogen to an immunogen with greater efficiency in aged animals.

Aging↗