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PubMed2004

FTY720 prevents anti-CD4 mAb-induced tolerance but cannot reverse established tolerance in a rat kidney transplantation model.

FTY720 is highly effective in various models of transplantation and autoimmunity. In order to find drugs that act synergistically with a tolerance-inducing nondepleting anti-CD4 mAb we studied this combination in a strong DA to LEW kidney transplantation model. Rats were treated with 0.3 mg/kg of FTY720 for 14 days and anti-CD4 mAb RIB5/2, alone or in combination. After kidney transplantation serum creatinine and blood lymphocyte counts were monitored. Immunohistology, ELISPOT and TaqMan trade mark -PCR analysis of biopsies were performed. Short-term application of RIB5/2 but not FTY720 induced long-term survival of kidney transplants. Moreover, the combination of FTY720 + RIB5/2 prevented tolerance induction. In the combination group serum creatinine levels increased 1 week after cessation of therapy and all rats died from uremia within 72 days. Intragraft immunohistology, ELISPOT and real-time RT-PCR analysis at day 21 demonstrated an enhanced T-cell infiltration and activation but a diminished up-regulation of protective genes in the grafts from recipients receiving the combination therapy. In contrast, delayed application of FTY720 to RIB5/2-treated rats did not interact with RIB5/2-induced tolerance. In summary, FTY720 is powerful in preventing intragraft infiltration by naive T cells but this might also affect the early development of graft-protecting regulatory T cells and tolerance induction.

Animals↗

PubMed1999

Comparison of the international immune tolerance registry and the North American immune tolerance registry.

Two immune tolerance registries--the International Immune Tolerance Study Group (ITSG) and North American Immune Tolerance Study (NAITS) - are compared and findings from combined data reported. The registries differed with respect to data collection tools, location, host and environmental factors, start date distribution and treatment products. The success and failure rates were similar in the two studies. There was a highly significant association between maximum historical titre and immune tolerance success; the success rate decreased as the historical titre increased. There was a significant association between inhibitor titre immediately prior to treatment and the probability for treatment success, and between outcome and time from diagnosis to treatment in the ITSG (of borderline significance in the NAITS). There was a significant association between outcome and dose, though the direction of the associations was not the same. In the ITSG, success was associated with doses greater than or equal to 200 IU/kg/day, while in the NAITS, greater success was observed with doses of less than 50 IU/kg/day. There was no association between outcome and treatment product. Data from the two registries were combined to produce a table for calculating the chance of successful treatment by historical titre, pretreatment titre, and dose.

Adult↗

PubMed1985

Chemotherapy of systemic murine infection due to beta-lactam antibiotic 'tolerant' and non-'tolerant' Staphylococcus aureus.

Two in vitro beta-lactam antibiotic (oxacillin, cefotaxime) 'tolerant' (MBC:MIC ratios = greater than 32) strains of Staphylococcus aureus served to intraperitoneally infect cyclophosphamide-pretreated (leukopenic) NMRI mice. With larger bacterial inocula (approximately 5 X 10(8) CFU) neither oxacillin nor gentamicin or netilmicin yielded optimal chemotherapeutic results. Only combination chemotherapy, in particular oxacillin combined with netilmicin, consistently reduced mouse mortality significantly (p less than 0.001). In contrast, moderate 'tolerant' staphylococcal inocula (approximately 2 X 10(8) CFU) were amenable to chemotherapy with either oxacillin or netilmicin, but not with cefotaxime or gentamicin. Oxacillin combined with either gentamicin or netilmicin resulted in significantly lowered murine mortality rates (p less than 0.001). Cefotaxime combined with either aminoglycoside antibiotic gave less satisfactory results. Systemic murine infections due to three non-'tolerant' strains of S. aureus were amenable to chemotherapy with oxacillin, cefotaxime or netilmicin alone and to combination chemotherapy. It is recommended that cases of life-threatening S. aureus infection, not complicated by acute endocarditis, initially be treated with oxacillin plus netilmicin until availability of laboratory results (antibiogram, documentation of 'tolerance').

Animals↗

PubMed1999

Improvement in exercise tolerance and symptoms of congestive heart failure during treatment with candesartan cilexetil. Symptom, Tolerability, Response to Exercise Trial of Candesartan Cilexetil in Heart Failure (STRETCH) Investigators.

BACKGROUND: The renin-angiotensin system plays an important part in the pathogenesis of congestive heart failure (CHF). This study evaluated the effect of an angiotensin II type 1 receptor antagonist on exercise tolerance and symptoms of CHF. METHODS AND RESULTS: In this multicenter, double-blind, parallel-group study, 844 patients with CHF were randomized to 12 weeks' treatment with placebo (n=211) or candesartan cilexetil 4 mg (n=208), 8 mg (n=212), or 16 mg (n=213) after a 4-week placebo run-in period. Changes in exercise time, Dyspnea Fatigue Index score, NYHA functional class, and cardiothoracic ratio were determined. Candesartan cilexetil produced a dose-related improvement in exercise time. For the intention-to-treat population, the increase produced by candesartan cilexetil 16 mg was significantly greater than that produced by placebo (47.2 versus 30.8 seconds, P=0.0463). All doses of candesartan cilexetil significantly improved the Dyspnea Fatigue Index score relative to placebo. NYHA class improved more frequently in the candesartan cilexetil groups; the differences relative to placebo were not significant. The decrease in cardiothoracic ratio with candesartan 4 to 16 mg was small but statistically significant compared with placebo (all P<0.05). In all candesartan cilexetil groups, plasma renin activity and angiotensin II levels increased from baseline and aldosterone levels decreased in the 8- and 16-mg treatment groups. Candesartan cilexetil was well tolerated at all doses. CONCLUSIONS: In summary, treatment with candesartan cilexetil demonstrated significant improvements in exercise tolerance, cardiothoracic ratio, and symptoms and signs of CHF and was well tolerated.

Adult↗

PubMed1989

Nitrate tolerance in epicardial arteries or in the venous system is not reversed by N-acetylcysteine in vivo, but tolerance-independent interactions exist.

N-acetylcysteine is assumed to reverse nitrate tolerance by replenishing depleted intracellular sulfhydryl groups, but data on interactions of N-acetylcysteine and nitrates in patients with stable angina are controversial and disappointing. Therefore, we studied the effect of N-acetylcysteine on nitrate responsiveness of epicardial arteries and of the venous system (assessed as changes in effective vascular compliance) in dogs (n = 12) during long-term nitroglycerin treatment (1.5 micrograms/kg/min i.v. for 5-6 days). In dogs with nitroglycerin-specific tolerance (shift of venous or epicardial artery dilation to 15-17-fold higher dosages), N-acetylcysteine (100 mg/kg i.v.) had no dilator effect and did not alter the dose-response relations of nitroglycerin. Yet, in nontolerant dogs (n = 17), N-acetylcysteine augmented (1.5-2.0-fold) the dilation of epicardial arteries and the reduction of peripheral vascular resistance induced by 0.5-1.5 micrograms/kg/min nitroglycerin. In vitro, the augmentation of purified guanylate cyclase activity by nitroglycerin (10-100 microM) was potentiated by N-acetylcysteine (0.01-1.0 mM) in saline or in canine plasma, but N-acetylcysteine alone was ineffective. We conclude that 1) N-acetylcysteine does not restore nitroglycerin responsiveness in tolerant epicardial arteries or veins in vivo, 2) a small, tolerance-independent augmentation of nitroglycerin-induced dilation may result from N-acetylcysteine-induced extracellular formation of a stimulant of guanylate cyclase from nitroglycerin.

Acetylcysteine↗

PubMed1990

Tolerance and cross-tolerance to stress-induced increases in plasma Met-enkephalin in rats with adaptively increased resting secretion.

Plasma concentrations of both native (pentapeptide plus its sulfoxide) and peptidase-derivable (trypsin followed by carboxypeptidase-B) Met-enkephalin showed brisk increases in response to the stresses of immobilization, hemorrhage, and electric footshock in conscious, freely moving, adult male rats. Daily exposure to 150-min periods of immobilization resulted in a maintained increase in baseline plasma concentrations of native Met-enkephalin 21.5 h after the sixth day and a further increase after 39 days. The plasma native Met-enkephalin response to acute immobilization was attenuated on day 7 and completely absent on day 40. Unstressed rats showed a plasma native Met-enkephalin response to hemorrhage of 15% blood volume and a further increase in response to 25% hemorrhage. Immediately after initial acute immobilization or 6 days of daily immobilization when plasma native Met-enkephalin was elevated but the response to acute immobilization was attenuated, plasma native Met-enkephalin responses to hemorrhage were also attenuated. Rats that had been immobilized daily for 40 days and showed no plasma native Met-enkephalin response to acute immobilization also showed no responses to hemorrhage. After 39 days of immobilization when there was no plasma native Met-enkephalin response to acute immobilization, there was also no response to footshock. Thus, development of tolerance or adaptive loss of plasma native Met-enkephalin response to immobilization with repeated exposure to this stressor is associated with cross-tolerance or adaptive loss of the responses to the stresses of hemorrhage or electric footshock. Development of tolerance and cross-tolerance of plasma responses of peptidase-derivable Met-enkephalin paralleled that of native Met-enkephalin. Thus, adaptation of plasma Met-enkephalin responses to repeated exposure to a stressor included both increased resting secretion and decreased acute responses to homotypic or novel stressors.

Adaptation, Physiological↗

PubMed1979

Study of glucose tolerance and the dynamic property of insulin secretion. Analysis of intravenous glucose tolerance test with the aid of a control theory.

The dynamic property of insulin secretion in relation to glucose tolerance was investigated quantitatively during iv glucose tolerance tests in 237 cases. The following results were obtained; 1) Glucose clearance constant (k-value) was not constant but variable with time and should be expressed as a function of time, K(t). In normal glucose tolerance, K(t) became greater with time. 2) Glucose-induced insulin secretion was expressed as the function of a proportional plus derivative response to glucose concentration. A weighting function of derivative response, reflecting the insulin secretion per unit of rate of change in blood glucose concentration, was calculated from blood glucose concentration (input) and insulin concentration (output) by the deconvolution method. It was clearly shown that the gain in weighting function was small and the response was slow even in the individual whose glucose tolerance was slightly impaired. 3) The greater the weighting function, the larger the change in K(t).

Blood Glucose↗

PubMed1985

Gestational diabetes mellitus and impaired glucose tolerance during pregnancy. Long-term effects on obesity and glucose tolerance in the offspring.

The effects of disturbances in carbohydrate metabolism during gestation were studied in the offspring of 1049 Pima Indian women who had no previous diagnosis of diabetes. Rates of fetal and maternal complications of pregnancy among women with diabetes first diagnosed during the pregnancy were similar to those among women in whom diabetes was recognized before gestation. Offspring, aged 5-19 yr, of women with abnormal glucose tolerance during pregnancy had a higher mean percent desirable weight and a higher mean postchallenge plasma glucose concentration than did offspring of women with normal glucose tolerance. Percent desirable weight and glucose concentration, however, were both lower than found in offspring of women with diabetes diagnosed before the pregnancy. Thus, metabolic events during pregnancy, as indicated by the detection of abnormal glucose tolerance during gestation, appear to have long-term effects on obesity and glucose tolerance in the offspring.

Adolescent↗

PubMed1987

Prevalence of complications among second-generation Japanese-American men with diabetes, impaired glucose tolerance, or normal glucose tolerance.

In a study sample of 229 second-generation Japanese-American (Nisei) men, 79 with normal glucose tolerance, 72 with impaired glucose tolerance (IGT), and 78 with non-insulin-dependent diabetes, we have determined prevalence rates for certain conditions (ischemic heart disease, peripheral vascular disease, hypertension, retinopathy, neuropathy, and nephropathy) associated with diabetes. All subjects participated in a 75-g oral glucose tolerance test. World Health Organization (WHO) diagnostic criteria and information from the subject's medical history and personal physician were used to classify the subjects. Retinopathy was observed only in diabetic men in the study sample (11.5% of diabetic men). Furthermore, it was observed only in men who were receiving drug treatment for diabetes--40.0% of insulin-treated and 17.2% of sulfonylurea-treated men. Electrophysiologic evidence of peripheral neuropathy was observed in 46.2% of diabetic men and in 4.0% of nondiabetic (normal and IGT) men. For diabetic men with fasting serum glucose greater than or equal to 140 mg/dl, 63.8% had peripheral neuropathy and 19.1% had retinopathy, whereas for diabetic men with fasting serum glucose less than 140 mg/dl, 19.4% had neuropathy and none had retinopathy. For diabetic men with a diabetes duration of greater than or equal to 10 yr, 72.7% had neuropathy and 31.8% had retinopathy; with a diabetes duration of 5-9 yr, 70.6% had neuropathy and 11.8% had retinopathy; and with a diabetes duration of less than 5 yr, 20.5% had neuropathy and none had retinopathy. Nephropathy was distinctly uncommon, and among the measurements of kidney function, only proteinuria was clearly abnormal with diabetes. Prevalence rates of hypertension, peripheral vascular disease, and ischemic heart disease were highest in Nisei men with diabetes, lowest in men with normal glucose tolerance, and intermediate in men with IGT.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Disease↗

PubMed2006

Prevalence of diabetes and impaired glucose tolerance in 64-year-old Swedish women: experiences of using repeated oral glucose tolerance tests.

OBJECTIVE: The purpose of this study was to describe the prevalence of diabetes and impaired glucose tolerance (IGT) in middle-aged women and to examine the variability and practical use of the oral glucose tolerance test (OGTT) in the screening for IGT and diabetes. RESEARCH DESIGN AND METHODS: All 64-year-old women living in Göteborg, Sweden, were invited to take part in a screening examination (n = 4,856). Of these, 82% (n = 3,998) responded and 53% (n = 2,595) participated and underwent anthropometric measurements and a 75-g standardized OGTT that was repeated within 2 weeks in those not showing normal glucose tolerance (NGT). RESULTS: The prevalences of known and new diabetes, IGT at both OGTTs, and impaired fasting glucose were 4.7, 4.8, 14.4, and 6.4%, respectively. Half of the women with diabetes were previously undiagnosed, and 37% of the diagnoses were based on OGTT and diabetes 2-h values at both or one of the two examinations. Women with IGT at both OGTTs, in comparison with those with one impaired and one normal OGTT, had higher BMI, waist girth, and blood pressure. More than 40% of the women showed impaired glucose metabolism. CONCLUSIONS: Among these women, the prevalence of undetected diabetes was high and repeated OGTTs were needed to identify and not misclassify a considerable proportion of patients. The degree of glucose tolerance impairment and the number of abnormal OGTTs were directly associated with occurrence of components of the metabolic syndrome.

Blood Pressure↗

PubMed2001

Determination of reference values for glucose tolerance, insulin tolerance, and insulin sensitivity tests in clinically normal cats.

OBJECTIVE: To determine reference values and test variability for glucose tolerance tests (GTT), insulin tolerance tests (ITT), and insulin sensitivity tests (IST) in cats. ANIMALS: 32 clinically normal cats. PROCEDURE: GTT, ITT, and IST were performed on consecutive days. Tolerance intervals (ie, reference values) were calculated as means +/- 2.397 SD for plasma glucose and insulin concentrations, half-life of glucose (T1/2 glucose), rate constants for glucose disappearance (Kglucose and Kitt), and insulin sensitivity index (Si). Tests were repeated after 6 weeks in 8 cats to determine test variability. RESULTS: Reference values for T1/2glucose, Kglucose, and fasting plasma glucose and insulin concentrations during GTT were 45 to 74 minutes, 0.93 to 1.54 %/min, 37 to 104 mg/dl, and 2.8 to 20.6 microU/ml, respectively. Mean values did not differ between the 2 tests. Coefficients of variation for T1/2glucose, Kglucose, and fasting plasma glucose and insulin concentrations were 20, 20, 11, and 23%, respectively. Reference values for Kitt were 1.14 to 7.3%/min, and for SI were 0.57 to 10.99 x 10(4) min/microU/ml. Mean values did not differ between the 2 tests performed 6 weeks apart. Coefficients of variation for Kitt and SI were 60 and 47%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: GTT, ITT, and IST can be performed in cats, using standard protocols. Knowledge of reference values and test variability will enable researchers to better interpret test results for assessment of glucose tolerance, pancreatic beta-cell function, and insulin sensitivity in cats.

Animals↗

PubMed1977

In vitro reactivity in allograft tolerance: persistence of mixed leukocyte culture reactivity in highly tolerant rats.

Mixed leukocyte culture reactivity was studied in adult W/Fu rats judged to be highly tolerant after the inoculation of (W/Fu X BN)F1 hybrid spleen and bone marrow cells at birth. Reactivity was observed in a majority of tolerant donors tested and documented by quantitative dose-response and kinetic studies. Allograft tolerance cannot be explained by a complete lack of specific immune reactivity to tolerated alloantigens.

Animals↗

PubMed1991

Recombinant human granulocyte colony-stimulating factor improves the compromised state of recipient mice without affecting the induction of specific tolerance in the cyclophosphamide-induced tolerance system.

The effects of recombinant human granulocyte CSF (rhG-CSF) on cyclophosphamide (CP)-induced tolerance was studied. In the recipient C57BL/10 Sn Slc (B10) mice given 1 x 10(8) B10.BR Sg Sn Slc (B10.BR) spleen cells (SC) on day -2 followed by 200 mg/kg CP on day 0, the number of leukocytes and neutrophils in the periphery declined to their minimum levels on day 4. When rhG-CSF in a dose of 200 micrograms/kg was given daily for 5 days to the B10 mice, which had been treated with B10.BR SC and CP, starting one day after the administration of CP, the leukocyte and neutrophil counts declined to the same levels as those in the B10 mice treated with B10.BR SC and CP alone on day 2. On day 4, however, the counts recovered to their normal levels. The nucleated cell count of the spleen in the B10 mice given B10.BR SC and CP followed by rhG-CSF decreased less and recovered faster than that in the B10 mice given B10.BR SC and CP. The case was found to be the same in bone marrow, and the difference did not reach statistical significance. When the recipient mice were inoculated i.p. with 4 x 10(4) Pseudomonas aeruginosa (GNB-139) on day 4, the survival of the B10 mice treated with B10.BR SC and CP was markedly improved by rhG-CSF administration. The administration of rhG-CSF did not affect either the prolongation or the specificity of skin allograft survival, as shown in an H-2 mis-matched combination of B10.BR----B10 and in an H-2 identical combination of AKR/J Sea(AKR)----C3H/HeN Crj (C3H). The tolerant state, which was demonstrated by various immune responses, such as CTL, delayed footpad reaction, and antibody, was also not affected by rhG-CSF. Furthermore, the basic mechanisms for inducing a long-lasting skin allograft tolerance in this system--namely, the specific destruction of Ag-stimulated and then proliferating mature T cells in the periphery, the establishment of mixed chimerism, and the intrathymic clonal deletion of immature T cells--were preserved even when rhG-CSF was given to C3H mice previously made tolerant of AKR.

Animals↗

PubMed1986

Studies on the induction of tolerance to alloantigens. II. The generation of serum factor(s) able to transfer alloantigen-specific tolerance for delayed-type hypersensitivity by portal venous inoculation with allogeneic cells.

The administration of C3H/He spleen cells into allogeneic BALB/c mice via portal venous (p.v.) route resulted in C3H/He alloantigen-specific tolerance for delayed-type hypersensitivity (DTH) responses. When serum from these tolerant BALB/c mice were transferred into naive syngeneic BALB/c mice, the recipient mice lost the capability of generating DTH responses as induced by s.c. immunization with C3H/He cells. Tolerance was transferred only by serum from BALB/c mice inoculated p.v. with C3H/He cells, but not by serum from C3H/He mice inoculated p.v. with C3H/He cells, or BALB/c mice inoculated i.v. with C3H/He cells. This tolerogenic activity in serum from p.v. inoculated BALB/c mice was C3H/He alloantigen specific, because the transfer of the serum did not interfere with the development of anti-C57BL/6 DTH responses in recipient BALB/c mice. Such a serum factor(s) was inducible as early as 1 wk after the inoculation of C3H/He cells into BALB/c mice and not associated with anti-C3H/He alloantibody activity. Moreover, anti-C3H/He or C57BL/6-specific tolerogenic factor(s) prepared in the respective BALB/c or C3H/He mice was successfully transferred into totally allogeneic recipient mice, indicating no requirement of H-2, as well as non-H-2 restriction for the function of serum tolerogenic factor(s). Thus this study demonstrates that p.v. inoculation of allogeneic cells generates serum factor(s) able to transfer in H-2 and non-H-2-unrestricted manners the in vivo tolerance of the alloreactivity specific for alloantigens used for p.v. inoculation.

Animals↗

PubMed1989

Differential cross-tolerance to opioid agonists in morphine-tolerant pigeons responding under a schedule of food presentation.

Effects of the opioid agonists morphine, l-methadone, ethylketazocine, U50,488 [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide methanesulfonate hydrate], cyclazocine and bremazocine, and the nonopioid chlorpromazine were determined in pigeons responding under a fixed-ratio 30 schedule of food presentation before, during and after chronic morphine administration. Before chronic morphine administration, all drugs produced dose-dependent decreases in response rates. After daily administration of up to 56 mg/kg of morphine for 7 weeks, dose-effect curves for the mu agonists morphine and l-methadone, as well as the mu/kappa agonist ethylketazocine shifted to the right approximately 1 1/4, 3/4 and 1/2 log units, respectively. In contrast, dose-effect curves for the mixed agonist/antagonists cyclazocine and bremazocine each shifted to the left approximately 3/4 log unit, whereas dose-effect curves for the kappa agonist U50,488 and the nonopioid chlorpromazine did not shift during chronic morphine administration. Dose-effect curves for all drugs except bremazocine returned to their prechronic positions within the period 3 to 8 weeks after termination of chronic morphine administration. The present study demonstrates that repeated administration of morphine produces tolerance to its rate-decreasing effects as well as cross-tolerance selective to other opioids possessing mu agonist properties. The cross-tolerance to ethylketazocine observed in morphine-tolerant pigeons corroborates studies of the discriminative stimulus effects of ethylketazocine in pigeons, suggesting that in this species ethylketazocine possesses predominantly mu agonist properties.

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

PubMed1988

Intrathecal morphine and clonidine: antinociceptive tolerance and cross-tolerance and effects on blood pressure.

The effects of acute and chronic intrathecal (i.t.) administration of the opioid receptor agonist, morphine, or the alpha-2 adrenoceptor agonist, clonidine, on nociception and blood pressure were examined in rats. In rats lightly anesthetized with pentobarbital, morphine produced dose-dependent inhibition of the nociceptive tail-flick reflex (ED50 = 10.0 micrograms) and small, non-dose-related pressor effects. These effects were antagonized by pretreatment with the opioid receptor antagonist naloxone (30.0 micrograms i.t.), whereas the alpha-2 adrenoceptor antagonist yohimbine (30.0 micrograms i.t.) potentiated the pressor effects and did not alter the antinociceptive effects of morphine. Chronic treatment with morphine (32.0 micrograms/day for 7 days) produced tolerance to the antinociceptive effects of morphine in conscious rats, and chronic morphine or chronic clonidine (32.0 micrograms/day for 7 days) reduced the antinociceptive potency of morphine in lightly anesthetized rats. The pressor effects of morphine were attenuated by chronic morphine and were converted to marked, dose-dependent depressor effects by chronic clonidine. Clonidine dose dependently inhibited the tail-flick reflex in lightly anesthetized rats (ED50 = 1.7 micrograms) and produced biphasic effects on blood pressure; lesser doses (0.1-3.2 micrograms) produced depressor effects whereas a greater dose (10.0 micrograms) produced a pressor response. Yohimbine, but not naloxone, antagonized the antinociceptive effects of clonidine, whereas both yohimbine and naloxone altered the dose-response function for the effects of clonidine on blood pressure. Tolerance developed to the antinociceptive effects of clonidine in the hot-plate, but not in the tail-flick, test in conscious rats. In lightly anesthetized rats, the antinociceptive potency of clonidine was reduced by chronic clonidine or chronic morphine, whereas chronic clonidine, but not chronic morphine, shifted the dose-response function for effects of clonidine on blood pressure to the right. These results indicate that the antinociceptive effects of acute i.t. morphine and clonidine are mediated by spinal opioid and alpha-2 adrenergic receptors, respectively. However, tolerance to and cross-tolerance between i.t. morphine and i.t. clonidine suggest that spinal opioid and alpha-2 adrenergic systems interact in producing antinociception. These systems also appear to interact in complex ways to exert effects on blood pressure.

Animals↗

PubMed1977

3H-etorphine levels in CNS of tolerant and non-tolerant rats.

Rats were rendered tolerant to etorphine by administering it daily for 5 days at doses of either 10 microgram/kg i.v. or 5 microgram/kg s.c..3H-etorphine was then injected to tolerant and non-tolerant rats; after 15 min their brain and spinal cord were removed for 3H-etorphine assay. Tolerant rats had lower 3H-etorphine levels in both tissues than control rats.

Animals↗

PubMed1980

Cellular events in tolerance. VIII. Analysis of the proliferative capacity of antigen-binding cells isolated from normal or tolerant spleens.

Previous studies in our laboratory have demonstrated that hapten-binding lymphocytes (ABC) can be isolated from the spleens of mice rendered tolerant to the hapten. These cells are reduced in PFC precursor frequency when stimulated with either specific antigen or mitogen (Reference 6). In the present studies, we have combined antigen-specific cell isolation and an analysis of thymidine uptake by purified B cells to determine whether hapten-binding B cells in tolerant mice can be stimulated to proliferate in response to specific antigen. Compared with normal ABC, "tolerant" ABC showed a significantly reduced thymidine incorporation responsiveness in vitro. This suggests that unresponsiveness in adult mice can result in an impairment of clonal proliferation. Hence, these "tolerant" ABC appear to be functionally though not physically, deleted.

Animals↗