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PubMed1987

Drug-induced tolerance to allografts in mice. XII. The relationships between tolerance, chimerism, and graft-versus-host disease.

When AKR/J Sea (AKR, H-2k) mice were primed i.v. with 1 X 10(8) viable spleen cells from naive C3H/He Slc (C3H, H-2k) mice and treated i.p. with 200 mg/kg cyclophosphamide (CP) 2 days later, a minimal degree of mixed chimerism associated with tolerance to C3H skin was established without graft-versus-host disease (GVHD) and maintained for at least one month. When AKR mice were primed i.v. with 1 X 10(8) viable spleen cells from C3H mice preimmunized i.v. 7 days earlier with 5 X 10(7) viable AKR spleen cells, and treated with 200 mg/kg CP, chimerism became exclusive, but lethal GVHD occurred in the AKR mice. Moreover, most of normal AKR mice primed with the preimmunized C3H spleen cells without CP died of GVHD. In contrast, in a major histocompatibility complex (MHC)-incompatible combination of AKR (H-2k)-C57BL/6 Cr Slc (B6, H-2b), mixed chimerism, tolerance to skin allografts, and GVHD were not observed, whether or not the mice had been treated with naive or preimmunized B6 spleen cells with or without CP.

Animals↗

PubMed1994

Tolerance induction to cultured islet allografts. I. Characterization of the tolerant state.

The immunogenicity of murine pancreatic islets can be reduced by culture in 95% O2 prior to transplantation. Such cultured tissue can reverse diabetes indefinitely in nonimmunosuppressed, allogeneic recipients. Although the cultured graft does not trigger a rejection response, the graft retains recognizable alloantigens in that the graft is acutely rejected when the host is immunized with donor-type antigen-presenting cells. However, over time the recipients bearing cultured islet allografts become increasingly resistant to rejecting the established graft following APC challenge. Data show that this process of graft "stabilization" is a function of time postgrafting and initial graft mass. Graft stabilization is not due to a change in the vulnerability of the graft to immune recognition--that is, stabilization cannot be accounted for by the spontaneous adaptation of the long-term graft. Rather, graft stabilization is associated with a change in host reactivity (tolerance induction). This conclusion is based on the findings that (1) recipients of long-term established grafts (> 120 days) resist rejection of both the primary and secondary donor-type grafts, and (2) donor-specific tolerance can be transferred to severe-combined-immune-deficient (scid) recipient mice.

Animals↗

PubMedDate not supplied

Should we consider performing oral glucose tolerance tests more frequently in postmenopausal women for optimal screening of impaired glucose tolerance?

OBJECTIVE: To investigate an optimal screening protocol for impaired glucose tolerance (IGT) and type II or non-insulin-dependent diabetes mellitus (DM) by using fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT) in postmenopausal women. DESIGN: One hundred consecutive postmenopausal women were screened with FPG determination, and then all underwent an OGTT. Basal serum lipid and insulin levels of these women were also determined. Insulin sensitivity was determined by using the homeostasis model assessment. Receiver operating characteristic analysis was performed to determine the efficacy of these variables in detecting women with IGT and DM, and optimal cutoff values were determined. RESULTS: FPG with a cutoff value of 98 mg/dL had the best combination of sensitivity (71%) and specificity (76%) for the detection of IGT and DM. Combined FPG and body mass index screening (with the optimal cutoff value of 26.5 kg/m2) improved the sensitivity to 96% but decreased the specificity to 47%. This combined screening protocol detected 94% of the women with IGT and all diabetic women. CONCLUSIONS: Given that IGT and DM are common among postmenopausal women and DM can be prevented by nonpharmacologic interventions in women with IGT, OGTT may be used more frequently among these women. Our data indicate that for optimal screening of non-insulin-dependent DM and IGT, OGTT should be considered in postmenopausal women, especially when risk factors in addition to age are present. This model may detect most of the women with IGT and almost all diabetic women.

Aged↗

PubMed1980

Neonatal tolerance of H-2 alloantigens. I. I region modulation of tolerance potential of K and D antigens.

By utilizing H-2 congenic strains of mice and appropriate recombinants, it has been possible to determine that Class I alloantigens (of K and D region genes) function poorly as tolerogens when inoculated into neonatal recipients. Alternatively, Class II alloantigens (encoded by I region genes) are excellent tolerogens. Moreover, Class I alloantigens are converted to good tolerogens when conjoined in the tolerizing inoculum with Class II alloantigens. The I subregions in which genes reside that mediate this tolerance-promoting effect are IJ and/or IE. It is suggested that elicitation of a suppressor mechanism, perhaps related to IJ region alloantigens, is responsible.

Animals↗

PubMed1982

Coupling between dietary changes, reduced body weight, muscle fibre size and improved glucose tolerance in middle-aged men with impaired glucose tolerance.

Fourteen middle-aged med with impaired glucose tolerance were studied prior to and 6 months after exchange of simple carbohydrates for complex carbohydrates rich in fibers and saturated for polyunsaturated fats in their diet when exchangeable. Body weight was reduced by 6.4 kg (p less than 0.001). Physical work capacity was unchanged. Fasting blood glucose and insulin were lowered (p less than 0.001) at 6 months and so were the values during an OGTT at 120 min. Both serum triglyceride and cholesterol concentrations were reduced (p less than 0.01) by the changes diet, the most marked reduction being found in the VLDL fraction. HDL levels increased by 21% (p less than 0.01). Enzyme activities in gastrocnemius muscle specimens were subnormal and uninfluenced by changed dietary habits. The number of capillaries per fiber was normal throughout, but as muscle fiber size was reduced in relation to the decreased body weight, the number of capillaries/mm2 increased during the dieting period. It is suggested that the observed improvement in insulin sensitivity and glucose tolerance after a dietary period with weight reduction is related to and partly explained by shorter diffusing distances in weight-bearing muscles.

Age Factors↗

PubMed2006

Long-term beneficial effects of glipizide treatment on glucose tolerance in subjects with impaired glucose tolerance.

AIMS: To assess the efficacy and long-term effects of glipizide treatment on glucose and insulin metabolism in individuals with impaired glucose tolerance (IGT). METHODS: Thirty-seven first-degree relatives of patients with type 2 diabetes fulfilling WHO criteria for IGT were randomized to treatment with either glipizide 2.5 mg once daily or matching placebo for 6 months. A 75 g, 2-h oral (OGTT) and 60 min intravenous glucose tolerance test (IVGTT) were performed at baseline and after 6 months. The subjects were followed up for another 12 months after discontinuation of treatment and a repeat OGTT was performed at 18 months. RESULTS: Thirty-three subjects fulfilled the study. Markers of insulin sensitivity - i.e. fasting insulin and HOMA(IR)-index - improved in the glipizide group (P = 0.04 and 0.02 respectively) as well as HDL cholesterol (P = 0.05) compared with placebo group after 6 months. At 18 months, both fasting and 2 h glucose concentrations were significantly lower in the glipizide group compared with the placebo group (P = 0.04 and 0.03 respectively). The prevalence of type 2 diabetes was 29.4% in the placebo group and 5.9% in the glipizide group at 18 months. This equals an 80% relative risk reduction in the active treatment group. CONCLUSIONS: Short-term treatment with glipizide improves glucose and insulin metabolism in subjects with IGT primarily by improving insulin sensitivity mediated by lowering glucose toxicity, thereby providing the beta cells rest. Larger studies are needed to establish whether these effects are sufficient to prevent progression to manifest type 2 diabetes and associated cardiovascular morbidity in subjects at increased risk of developing type 2 diabetes.

Adult↗

PubMed1996

Comparison of the 50 g capillary plasma glucose tolerance test with the 75 g venous plasma glucose tolerance test in pregnancy.

OBJECTIVE: To compare the 50 g oral glucose tolerance test with capillary sampling used in the Mercy Hospital for Women, Melbourne with the 75 g test with venous sampling advocated by the Australasian Diabetes in Pregnancy Society. METHODS: Both the 50 g and 75 g glucose tolerance tests were performed on 60 women. Criteria for diagnosing gestational diabetes were the combination of a 1-hour capillary plasma glucose > or = 9 mmol/l and a 2-hour glucose > or = 7 mmol/l for the 50 g test and a fasting glucose > or = 5.5 mmol/l and/or a 2-hour venous plasma glucose > or = 8.0 mmol/l for the 75 g test. RESULTS: Twenty-eight of 60 women had gestational diabetes diagnosed with the 50 g test; 24 of these, and an additional 5 had gestational diabetes diagnosed on the 75 g test. Twenty-seven women had normal results on both tests. The kappa statistic was 0.70. The 1-hour glucose value was similar for both tests, but the 2-hour value was significantly higher for the 75 g test (mean difference 0.65 mmol/l, 95% confidence limits 0.24-1.01 mmol/l, p = 0.003). The area under the curve was similar for the 2 tests. CONCLUSIONS: The 2 tests diagnose similar women as having gestational diabetes. The combination of a 75 g load and venous sampling gives similar 1-hour but higher 2-hour values than a 50 g load and capillary sampling.

Diabetes, Gestational↗

PubMed1988

Tolerance to ethanol and cross-tolerance to pentobarbital by isolated hearts from chronic alcoholic rats.

The effects of ethanol and pentobarbital on the function of isolated working hearts from control and ethanol-fed male Long-Evans rats were studied. Hearts from ethanol-fed animals (38% of calories; 10-12 months) exhibited functional tolerance to the cardiodepressive effects of 18-71 mM ethanol in the perfusing medium. Left ventricular systolic pressure, peak relaxation rate, isovolumic pressure indexes, peak aortic flow rate, cardiac output, and stroke work of the control hearts were depressed to a greater extent than were those indexes of the alcoholic rat hearts during exposure to ethanol in vitro. Differences in the functional responses of controls and alcoholics were not the result of differences in energetics; myocardial O2 consumption, O2 supply-to-utilization ratio, and external work efficiency changed similarly in both groups of hearts during perfusion with ethanol. Cross-tolerance of the alcoholic rat hearts to the in vitro cardiodepressive effects of pentobarbital was also apparent. Peak rate of left ventricular pressure development, peak aortic flow rate, isovolumic pressure indexes, and cardiac output of the control rat hearts were significantly lower than those indexes of the alcoholic rat hearts during perfusion with 0.5 mM pentobarbital. In addition, four of the seven control hearts could not be paced during pentobarbital perfusion using 3V electrical pulses; the pacing voltage had to be raised and right ventricular pacing used to maintain stable function of those hearts at a 321 beats/min pacing rate. Myocardial O2 consumption and O2 supply-to-utilization ratios of control and alcoholic rat hearts were similar, but external work efficiency was slightly higher in the alcoholics than in controls during pentobarbital perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism↗

PubMed1981

Tolerance and cross-tolerance in chronic alcoholics: reduced membrane binding of ethanol and other drugs.

Membrane binding of ethanol, anesthetics, and hydrophobic molecules in brain synaptosomes and liver mitochondria from rats is conspicuously reduced after long-term consumption of ethanol. The membranes are resistant to structural disordering by both ethanol and halothane. Tolerance, cross-tolerance, and dependence in chronic alcoholics may in part result from membrane alterations that inhibit the binding of ethanol and other drugs.

Alcoholism↗

PubMedDate not supplied

The glucose tolerance test, but not HbA(1c), remains the gold standard in identifying unrecognized diabetes mellitus and impaired glucose tolerance in hypertensive subjects.

The objective of this study was to compare the value of the oral glucose tolerance test (GTT), glycated hemoglobin concentration (HbA(1c)), and fasting plasma glucose (FPG) for identifying unrecognized diabetes mellitus (DM) and impaired glucose tolerance (IGT) in hypertensive subjects. One hundred forty-four consecutive subjects who were not known to have DM and who were attending the Hypertension Clinic underwent 24-hour ambulatory blood pressure (BP) monitoring. A GTT and an HbA(1c) measurement were also carried out. Abnormal results from GTT were found in 94 patients (65%). Results from FPG were not different between those with DM and IGT but were significantly higher than in the euglycemic subjects. The FPG was between 110-125 mg/dL (6.1-6.9 mmol/L) in 31% (n = 20) of patients with IGT and in 53% (n = 16) of those with DM. With use of the previously published criteria to diagnose DM of FPG > or = 103 mg/dL (5.7 mmol/L) and HbA(1c) > or = 5.9%, 33% of our diabetic subjects and 75% of those with IGT would have been misclassified as euglycemic. The previously reported cut-off point for HbA(1c) of >6.1% to diagnose DM was present in 77% of our patients with DM and in 14% (n = 9) of the patients with IGT. Multiple regression analysis showed that an abnormal result from GTT was independent of the level of clinical or ambulatory BP, nocturnal BP dip, cholesterol level, smoking history, race, or class of antihypertensive medication taken. FPG levels or HbA(1c), or their combination, are not accurate enough to identify DM or IGT in patients attending a hospital Hypertension Clinic. A GTT may be required in these patients to reliably identify those with DM or IGT.

Adult↗

PubMedDate not supplied

Comparison of estimates of insulin sensitivity in pre- and postmenopausal women using the insulin tolerance test and the frequently sampled intravenous glucose tolerance test.

OBJECTIVE: We assessed insulin sensitivity in women comparing the insulin tolerance test (ITT) with the intravenous glucose tolerance test with frequent sampling and computer modeling (FSIVGTT) and evaluated the effects of hormonal therapy in postmenopausal women using both methods. METHODS: This prospective study tested 18 premenopausal women and ten postmenopausal women randomized to receive either estrogen alone or estrogen with a sequential progestin for 6 months at a menopause research clinic. All subjects received an ITT and an FSIVGTT within 48-72 hours of each other in random sequence. Postmenopausal women were then randomized to receive either 0.625 mg conjugated equine estrogen for 6 months or 0.625 mg conjugated equine estrogen with medroxyprogesterone acetate, 10 mg, for 10 days each month for 6 months. Both the ITT and the FSIVGTT were repeated following hormonal therapy at 2 and 6 months. Plasma insulin and glucose were measured; insulin sensitivity was calculated after the ITT (Kitt) and the FSIVGTT (Si) at each visit in each group. RESULTS: A close correlation was found between Kitt and Si values at initial testing in both pre- and postmenopausal women and following both types of hormonal therapy (r = 0.76 for all tests, P < .001). A reduction in insulin sensitivity was observed in postmenopausal compared to premenopausal women; this occurred in five of ten postmenopausal women using the Kitt measurement and in four of ten women using Si. Estrogen replacement had a beneficial effect on insulin sensitivity. While Kitt increased by 24.2 +/- 9.6% (P < .05), the increase in Si (6.7 +/- 18%) was not significant because of the variability with this measurement. An attenuation in insulin sensitivity was seen with added progestin. Kitt values decreased by 17.7 +/- 7.7% and Si values by 31.9 +/- 12%. Similar findings were noted at 2 and 6 months. CONCLUSIONS: The ITT and FSIVGTT provide quantitatively similar information regarding insulin sensitivity in healthy women. A mild degree of insulin resistance appears to be present in some healthy postmenopausal women. Estrogen appears to improve insulin sensitivity, while added progestin may attenuate this beneficial effect.

Adult↗

PubMed2006

Effect of repaglinide on endothelial dysfunction during a glucose tolerance test in subjects with impaired glucose tolerance.

BACKGROUND: Impaired glucose tolerance (IGT) is associated with increased cardiovascular risk. The pathophysiological mechanisms linking post-challenge hyperglycemia to accelerated atherosclerosis, however remain to be elucidated. METHODS: A prospective, open, randomised, cross-over study was performed to investigate the effect of 2 mg repaglinide on hyperglycemia and endothelial function during an oral glucose tolerance test (75 g glucose) in 12 subjects with diagnosed IGT. Blood samples for determination of plasma glucose were drawn fasting, 1 and 2 hours after glucose ingestion. Endothelial function was assessed by measuring flow-mediated dilatation (FMD) of the brachial artery with high-resolution ultrasound. RESULTS: Administration of repaglinide resulted in a significant reduction of plasma glucose at 2 hours (172.8+/-48.4 vs. 138.3+/-41.2 mg/dl; p < 0.001). The flow-mediated dilatation (FMD) 2 hours after the glucose-load was significantly reduced in comparison to fasting in the control group (6.21+/-2.69 vs. 7.98+/-2.24 %; p = 0.028), whereas after theadministration of repaglinide the FMD was not significantly different to fasting values (7.24+/-2.57 vs. 8.18+/-2.93 %; p = n.s.). Linear and logistic regression analysis revealed that only the change of glucose was significantly correlated to the change of FMD observed (p < 0.001). Regression analysis after grouping for treatment and time confirmed the strong negative association of the changes of plasma glucose and FMD and indicate that the effect of repaglinide observed is based on the reduction glycemia. CONCLUSION: In subjects with IGT, the endothelial dysfunction observed after a glucose challenge is related to the extent of hyperglycemia. Reduction of hyperglycemia by repaglinide reduces endothelial dysfunction in a glucose dependent manner.

Aged↗

PubMed1992

[The effects of indigestible dextrin on sugar tolerance: I. Studies on digestion-absorption and sugar tolerance].

It is widely acknowledged that high viscosity water-soluble dietary fibers such as pectin and guar gum affect a lowering of blood glucose levels and a reducing of insulin secretion following a sugar load. However, as dietary fibers vary in origin and in chemical properties, their physiological functions differ as well. In this study the effects of Indigestible Dextrin (PF-C), a low viscosity, water-soluble dietary fiber obtained through acid and heat-treatment of potato starch, on various aspects of sugar tolerance were examined. First, the influence of PF-C on sucrose hydrolysis was examined in rat intestinal mucosa cell homogenate confirming that PF-C did not inhibit sucrase activity. Then, in order to investigate the influence of PF-C on sugar digestion-absorption, an experiment was performed by using the everted intestinal sac of the rat in vitro. PF-C did not have an effect on glucose-transport into the serosal medium, whereas PF-C did inhibit the transport of hydrolyzed-glucose from sucrose, with no change in the hydrolysis of sucrose. Recently, Crane et al. reported that there is a specific route for hydrolyzed glucose from sucrose in glucose-absorption on the enteric surface (disaccharidase related transport system). The possibility exists that PF-C specifically affects this pathway. Further, total glucagon released into the serosal medium stimulated by both glucose and sucrose were reduced by PF-C. On the basis of these results, an oral sugar tolerance test was conducted in both rats and healthy human subjects. In male Sprague-Dawley rats (8 weeks old, 250-280g) concurrent administration of PF-C (0.6g/kg body weight) reduced an increase in plasma insulin levels with no change in glucose levels following a glucose (1.5g/kg body weight) load. Further noted were reductions in increases in both plasma glucose and insulin levels following a sucrose (1.5g/kg body weight) plus PF-C (0.6g/kg body weight) load to that of the sucrose (1.5g/kg body weight) single load. These findings reflect the above mentioned in vitro results. Moreover, in healthy male subjects the increase in both plasma insulin and glucagon-like immunoreactivity (Gut GLI) levels following a Trelan-G75 load were significantly reduced by concurrent administration of PF-C. From these observations it would appear that the effectiveness of reducing insulin secretion by PF-C results due to the decrease in sugar absorption by inhibiting the disaccharidase-related transport system.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed2001

Insulin sensitivity in women: a comparison among values derived from intravenous glucose tolerance tests with different sampling frequency, oral glucose tolerance test or fasting.

OBJECTIVE: To determine the correlation between insulin sensitivity (S(I)) obtained by the minimal model method applied to a frequently sampled (n=33) intravenous glucose tolerance test (FSIGT(33)), and values obtained by reduced FSIGTs, oral glucose tolerance test (OGTT), or fasting. DESIGN: Retrospective analysis on tests performed in prospective studies. METHODS: A total of 78 FSIGT(33), and 59 OGTT were performed in non-diabetic women of which 10 were young cyclic females in the early follicular menstrual phase, 10 were young non-obese subjects with polycystic ovary syndrome (PCOS) and 30 were in post-menopause. Some of these individuals were investigated both prior to and during specified treatments. FSIGT(33) was transformed into FSIGT(22) and FSIGT(12) by removing samples from the analysis. Values of SI derived from reduced FSIGTs or calculations performed on glucose and insulin values observed in fasting conditions and/or during OGTT were related to those of FSIGT(33). RESULTS: S(I) values derived from FSIGT(33) were highly correlated with those derived from FSIGT(22) (r=0.965) or FSIGT(12) (r=0.955), but were only weakly correlated with those derived from fasting or OGTT calculations (r below 0.5). Between-group (PCOS vs normal) or within-group (prior to and during treatment) comparisons showed that reduced FSIGTs were only slightly less powerful than FSIGT(33) in detecting differences in S(I). CONCLUSIONS: In non-diabetic women, reduced FSIGTs but not calculations based on fasting or OGTT values may be used in place of FSIGT(33) to document S(I) and its variation.

Administration, Oral↗

PubMed1998

Differential glucose tolerance in dipper and nondipper essential hypertension: the implications of circadian blood pressure regulation on glucose tolerance in hypertension.

OBJECTIVE: The goals of this study were to compare glucose tolerance in dipper and nondipper hypertensive patients and to explore the cause of glucose intolerance in essential hypertension. RESEARCH DESIGN AND METHODS: A total of 50 patients <45 years old who had essential hypertension were recruited and studied by 24-h blood pressure monitoring and an oral glucose tolerance test (OGTT). Autonomic function was assessed with spectral analysis of heart rate variability RESULTS: Dipper hypertensive patients (n=25) had lower nocturnal blood pressure than nondipper (n=25) patients. During OGTT, postprandial glucose levels were higher in the nondippers at 0, 90, and 120 min (all P < 0.05). Nondippers had a higher fasting insulin/glucose ratio than was apparent in normal control subjects. Despite higher postprandial glucose levels, nondippers had lower postprandial insulin levels. These results suggest that nondippers were insulin resistant and that their pancreatic beta-cell function was impaired. For all patients, nocturnal reduction of blood pressure was inversely related to total glucose levels under the OGTT curve and was positively related to postprandial insulin levels. Daytime heart rate did not differ between the dippers and nondippers, but nocturnal heart rate was higher in the nondippers, suggesting that nocturnal sympathetic activities were higher among the nondippers. Spectral analysis of heart rate variability suggests that the nondippers had lower parasympathetic activities and unbalanced sympathetic/parasympathetic outflow. CONCLUSIONS: These findings indicate that nondipper hypertensive patients are more glucose intolerant than are dipper patients. The abnormalities of glucose metabolism in nondippers could be explained by insulin resistance and beta-cell dysfunction. The results of spectral analysis suggest that abnormal autonomic outflow may represent a possible link between hypertension and associated metabolic dysfunction.

Adult↗

PubMed2005

Use of the diabetes risk score for opportunistic screening of undiagnosed diabetes and impaired glucose tolerance: the IGLOO (Impaired Glucose Tolerance and Long-Term Outcomes Observational) study.

OBJECTIVE: To evaluate an opportunistic screening strategy addressed to individuals with one or more cardiovascular risk factor, based on the Diabetes Risk Score (DRS) as the initial instrument, for the identification of individuals with type 2 diabetes or impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: The DRS, a simple self-administered questionnaire, was completed by individuals identified by general practitioners and presenting with one or more cardiovascular risk factor. All patients underwent a 2-h oral glucose tolerance test (OGTT). The optimal DRS cutoff was calculated by applying the receiver-operating characteristic curve. RESULTS: Overall, 1,377 individuals aged between 55 and 75 years received an OGTT and completed the DRS. Mean DRS values showed a marked variation according to glucose metabolism categories, as follows: 8.7 +/- 3.0 in normoglycemic individuals, 9.5 +/- 3.1 in individuals with impaired fasting glucose, 9.9 +/- 3.3 in individuals with IGT, and 12.0 +/- 3.5 in individuals with type 2 diabetes. The receiver-operating characteristic curve showed that, with a cutoff of 9, the sensitivity of DRS in detecting individuals with glucose abnormalities (type 2 diabetes or IGT) was 77% and the specificity 45%. The use of the DRS as an initial screening instrument, followed by the measurement of fasting blood glucose in individuals with a score > or =9 and by the OGTT in individuals with a fasting blood glucose between 5.6 and 6.9 mmol/l, would lead to the identification of 83% of the case subjects with type 2 diabetes and 57% of the case subjects with IGT, at a cost of an OGTT in 38% of the sample and a fasting blood glucose in 64%. CONCLUSIONS: The DRS can represent a valid inexpensive instrument for opportunistic screening and a useful alternative to indiscriminate fasting blood glucose measurement, not readily available in general practice.

Aged↗

PubMed2001

Oral tolerance revisited: prior oral tolerization abrogates cholera toxin-induced mucosal IgA responses.

Oral delivery of a large dose or prolonged feeding of protein Ags induce systemic unresponsiveness most often characterized as reduced IgG and IgE Ab- and Ag-specific CD4(+) T cell responses. It remains controversial whether oral tolerance extends to diminished mucosal IgA responses in the gastrointestinal tract. To address this issue, mice were given a high oral dose of OVA or PBS and then orally immunized with OVA and cholera toxin as mucosal adjuvant, and both systemic and mucosal immune responses were assessed. OVA-specific serum IgG and IgA and mucosal IgA Ab levels were markedly reduced in mice given OVA orally compared with mice fed PBS. Furthermore, when OVA-specific Ab-forming cells (AFCs) in both systemic and mucosa-associated tissues were examined, IgG AFCs in the spleen and IgA AFCs in the gastrointestinal tract lamina propria of mice given OVA orally were dramatically decreased. Furthermore, marked reductions in OVA-specific CD4(+) T cell proliferative and cytokine responses in spleen and Peyer's patches were seen in mice given oral OVA but were unaffected in PBS-fed mice. We conclude that high oral doses of protein induce both mucosal and systemic unresponsiveness and that use of mucosal adjuvants that induce both parenteral and mucosal immunity may be a better way to assess oral tolerance.

Adjuvants, Immunologic↗

PubMed2000

Chronic l-alpha-acetylmethadol (LAAM) in rhesus monkeys: tolerance and cross-tolerance to the antinociceptive, ventilatory, and rate-decreasing effects of opioids.

Although l-alpha-acetylmethadol (LAAM) is a maintenance treatment for opioid dependence, few studies have systematically assessed the behavioral effects of LAAM and other drugs in LAAM-treated subjects. In the current study, we assessed the ventilatory, antinociceptive, and rate-decreasing effects of drugs (s.c. except dynorphin, which was administered i.v.) in rhesus monkeys (n = 3 or 4) before and during chronic treatment with 1.0 mg/kg/12 h LAAM (s.c.). Minute volume (V(E)) was reduced to 62% of baseline during LAAM treatment and remained depressed after more than 10 months of LAAM treatment. A cumulative dose of 10.0 mg/kg morphine decreased V(E) to similar values under baseline (53%) and LAAM-treated (52%) conditions; however, larger doses of morphine (up to 56.0 mg/kg) could be administered safely to LAAM-treated monkeys. LAAM treatment produced dependence as evidenced by a 220% increase in V(E) after a dose of naltrexone (0.032 mg/kg) that did not modify ventilation under baseline conditions. Compared with baseline, LAAM treatment increased the ED(50) values for the rate-decreasing effects of nalbuphine, morphine, and alfentanil by 7-, 7-, and 2-fold, respectively, in monkeys responding under a fixed ratio 10 schedule of food presentation. Similarly, LAAM treatment increased ED(50) values for the antinociceptive effects of morphine and alfentanil by 5- and 3-fold, respectively. LAAM treatment also increased the ED(50) values for the antinociceptive effects of the kappa-agonist enadoline by 5-fold and not those of U-50,488. That tolerance developed differentially to the ventilatory, rate, and antinociceptive effects of mu-agonists in LAAM-treated monkeys suggests that cross-tolerance might not be a safe therapeutic approach for the treatment of some opioid abusers.

Analgesics, Opioid↗