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PubMed2004

Quantitative trait loci mapping for ethanol sensitivity and neurotensin receptor density in an F2 intercross derived from inbred high and low alcohol sensitivity selectively bred rat lines.

BACKGROUND: Genetic variance in initial sensitivity to ethanol has been implicated as a risk factor for the development of alcoholism. Identification of the genes that confer differential initial sensitivity is an important goal for the development of new treatment strategies and for a comprehensive understanding of the mechanism of ethanol's action. Quantitative trait loci (QTL) mapping for initial sensitivity and other ethanol-related behavioral traits in model organisms has become an important first step for the ultimate identification of genes that contribute to variation in ethanol responses. METHODS: An F(2) intercross was made from the Inbred High and Low Alcohol Sensitivity rat lines (IHAS and ILAS). The F(2) rats were tested for duration of the loss of righting reflex test (LORR); blood ethanol concentration at regain of righting reflex (BECrrr); BEC at the first time to reach criterion on the rotarod after 1.6 g/kg of ethanol (BEC1); acute functional tolerance on the rotarod (AFT); and high-affinity neurotensin receptor (NTR1) density in the nucleus accumbens (NAc), caudate putamen (CP), and ventral midbrain (VMB). A full genome scan with an average marker spacing of 16.8 cM for interval QTL mapping was conducted on the F(2) rats (N = 363). RESULTS: Seven significant or suggestive QTL were detected for LORR, one for BECrrr, three for BEC1, two for NTR1 binding in the CP, and one for binding in the NAc, but none were mapped for AFT or NTR1 binding density in the VMB. Effect size of the seven LORR QTL, the trait for which the parental strains were selected, ranged from 3 to 4%, with all accounting for approximately 22% of the total phenotypic variation. One of the LORR QTL on chromosome 2 (approximately 87 cM) was significant, and a second QTL on chromosome 5 (approximately 37 cM) was suggestive for both LORR and BECrrr. CONCLUSIONS: The results indicate that segregating populations derived from the IHAS and ILAS strains can be used for mapping ethanol sensitivity QTL. The chromosome 2 LORR QTL may confer variation in ethanol metabolism, whereas the chromosome 5 LORR/BECrrr QTL likely mediates central nervous system ethanol sensitivity. The small number or absence of QTL for BEC1, AFT, and NTR1 receptor density suggests that genetic variation for these traits is minimal in the IHAS/ILAS strains and/or the effect size of QTL for these traits is too small to be mapped efficiently in this sample of F(2) rats. The ultimate identification of genes underlying these alcohol sensitivity QTL will contribute to our understanding of the actions of alcohol in the central nervous system if not to a deeper understanding of the genetic risk factors for alcoholism.

Alcohol Drinking↗
PubMed2005

Genetic dissociation between ethanol sensitivity and rapid tolerance in mouse and rat strains selectively bred for differential ethanol sensitivity.

BACKGROUND: The Inbred Long- and Short-Sleep mice (ILS and ISS) and the Inbred High- and Low-Alcohol-Sensitive rats (IHAS and ILAS) were selectively bred for differential alcohol sensitivity with use of the duration of loss-of-righting-reflex test (LORR), with the IHAS and ILS animals being much more sensitive than the ILAS and ISS animals, respectively. The current study was undertaken to determine whether acute sensitivity in these strains is genetically correlated to a rapid tolerance to alcohol, a form of tolerance that is evident 24 hr after a single alcohol dose. METHODS: Separate groups of animals were administered a single pretreatment dose of alcohol (0-6 g/kg for the mice; 0-4 g/kg for the rats). Alcohol sensitivity was tested 24 hr later with the LORR test, and blood ethanol concentration was tested at regain of righting (BECRR). Alcohol-induced hypothermia also was determined in the mice. Independently derived replicate rat strains were used for all experiments (IHAS1, ILAS1; IHAS2, ILAS2); no such replicates exist for the ILS and ISS strains. RESULTS: Alcohol pretreatment caused a dose-dependent decrease in LORR duration accompanied by an increase in BECRR in the ILS strain, but LORR increased in the ISS strain with no effect on BECRR. Both strains became hypothermic during the LORR test on day two, but the only significant effect of alcohol pretreatment was in the ISS strain, in which alcohol-induced hypothermia was enhanced. Alcohol pretreatment caused a significant dose-dependent decrease in LORR duration accompanied by an increase in BECRR in the IHAS1 but not in the IHAS2 strain. In contrast, ILAS1 and ILAS2 strains both showed a significant increase in LORR duration and also a significant increase in BECRR. CONCLUSIONS: Alcohol pretreatment caused a dose-dependent decrease in LORR duration and an increase in BECRR in the IHAS1 and ILS strain, suggesting the development of functional rapid tolerance. In contrast, LORR duration increased in the ILAS1, ILAS2, and ISS groups, but BECRR either increased (ILAS1, ILAS2) or did not change (ISS). These observations suggest that central nervous system sensitivity was decreased in the ILAS1 and ILAS2 groups (i.e., rapid functional tolerance) or unchanged in the ISS strain, but that some pharmacokinetic property also was altered in these strains. Overall, the results do not support a genetic relation between alcohol sensitivity and the development of rapid tolerance.

Alcoholism↗
PubMed1981

Suppression of contact sensitivity by IgG1 antihapten antibody in contact-sensitized guinea pigs.

The guinea pig sera obtained 2 weeks after 1-fluoro-2,4-dinitrobenzene sensitization had ability to suppress elicitation of contact sensitivity when transferred intravenously into contact sensitized guinea pigs. The activity was found only in the sera obtained 2 weeks after the sensitization, whereas the sera obtained 1 and 3 weeks after the sensitization had no effect on contact sensitivity. Pretreatment of cyclophosphamide abolished the generation of the suppressive factor. The suppressive factor was hapten-specific. It was eluted from a Sephadex G-150 column into 7S gamma-globulin fraction and from DEAE ion exchange cellulose column into IgG1 fraction. The suppressive activity was absorbed on a dinitrophenylated bovine gamma globulin Sepharose 4B column and was eluted by either acidic buffered solution or dinitrophenol from the affinity column. It was absorbed by antiguinea pig IgG1-Sepharose and not by antiguinea pig IgG2-Sepharose, Therefore, the suppressive activity found in the sera of 1-fluoro-2, 4-dinitrobenzene sensitized guinea pigs was attributed to IgG1 antihapten antibody.

Animals↗
PubMed2005

Fecal microbiota in sensitized wheezy and non-sensitized non-wheezy children: a nested case-control study.

BACKGROUND: It has been suggested that intestinal microbiota of allergic and non-allergic children differs in composition, and that microbiota-immune system interactions may predispose children to develop sensitization. Previous studies have examined fecal microbiota of allergic children with atopic dermatitis, but little is known about that of atopic wheezy children. OBJECTIVE: To investigate the composition of the fecal microbiota of young sensitized wheezy and non-sensitized non-wheezy children, using molecular methods. METHODS: Within the context of a prospective birth cohort, we carried out a nested case-control study of sensitized wheezy children (cases) and non-sensitized non-wheezy controls. Cases and controls were matched for age, sex, parental atopy, allergen exposure, and pet ownership. We evaluated the composition of fecal microbiota by nucleic acid-based methods (PCR combined with denaturing gradient gel electrophoresis and quantification of bifidobacteria by fluorescent in situ hybridization). RESULTS: Thirty-three case-control pairs (mean age 4.4 years) provided stool samples. Comparison of total bacterial community profiles showed that each child had a unique fecal microbiota (mean Dice's similarity coefficient 22%, range 3.3-60.8%). There was no difference between the groups in prevalence of Lactic Acid bacteria (12/33 vs. 11/33, P=0.8) or bifidobacteria (30/33 vs. 31/33, P=1.00, cases vs. controls). The bifidobacterial species detected were similar in both groups. The percentage of bifidobacteria in total fecal microflora was no different between cases (median 1.7%, range 0-20.8%) and controls (1.9%, 0-18.2%, P=0.7). However, cases with eczema had significantly fewer bifidobacteria (median 1.6%, range 0-4.8%) than their controls (4.0%, 1.9-18.2%, P=0.05). CONCLUSION: We found no differences in fecal microbiota composition between sensitized wheezy and non-sensitized, non-wheezy children aged 3-5 years using nucleic acid-based methods. Differences appear to be isolated to those allergic children with eczema.

Bifidobacterium↗
PubMed2005

Reactivity to euro coins and sensitization thresholds in nickel-sensitive subjects.

BACKGROUND: The 1- and the 2-euro coins consist of nickel alloys, which release nickel. The nickel released by far exceeds the amount allowed by the European Union Nickel Directive referring to products intended to come into direct and prolonged contact with the skin. As there is only temporary contact with the skin, the clinical relevance of nickel-containing coins with regard to nickel dermatitis is a matter of debate, although there is evidence that the nickel released from the coins affects some nickel-sensitive subjects through occupational exposure. OBJECTIVES: Our aim was to study skin reactivity to euro coins, and to correlate the frequency and intensity of coin patch test responses to sensitization thresholds to nickel. PATIENTS AND METHODS: Sixty-four nickel-sensitized and 30 non-nickel-sensitized subjects were patch tested with serial dilutions of nickel sulfate (5, 1, 0.5, 0.1, 0.05, 0.01 and 0.005% in distilled water) and with coins. Italian coins (500, 200, 100 and 50 lira) and euro coins (2 and 1 euros, 20 and 5 euro cents) were used for patch testing and compared. RESULTS: The application of 1- and 2-euro coins to the skin induced eczematous reactions, being more frequent and intense in comparison with those provoked by other coins. A correlation between intensity of responses to coin patch tests and sensitization threshold to nickel was observed. Patients with the strongest reactions to 1- and 2-euro coins showed positive responses to the lowest nickel concentrations. CONCLUSIONS: The nickel content in euro coins represents a possible health hazard, especially for highly nickel-sensitive subjects. We recommend that nickel sulfate patch tests should be performed at different concentrations to determine sensitization thresholds at least in individuals with occupational exposure to coins.

Adult↗
PubMed1983

Direct skin test in highly sensitized guinea pigs for rapid and sensitive determination of staphylococcal enterotoxin B.

The direct skin test in highly sensitized guinea pigs was developed as a rapid and extremely sensitive assay for detection of staphylococcal enterotoxin B (SEB) in foods. This report details the experimental conditions required to elicit optimal sensitization of guinea pigs to SEB. An intense and persistent immunoglobulin E (IgE) anti-SEB response was established in strain 13 guinea pigs pretreated with cyclophosphamide followed by four sensitizing doses of 10 micrograms of SEB 1 month apart. The conditions, however, optimal for eliciting IgE responses led to a sustained failure to produce antibody of the IgG1 subclass. With the use of highly sensitized guinea pigs, one can achieve a sensitivity ranging from 0.1 to 1.0 pg of purified SEB by the direct skin test for at least 7 months after the last challenge. For analysis of SEB in food extracts, the entire assay can be accomplished within 20 min with a sensitivity of 10 to 100 pg SEB per ml of prepared food samples, and the recovery of enterotoxin from spiked food products ranged between 75 and 89% of the amount added.

Biological Assay↗
PubMed1997

Characterization of an NaCl-sensitive Staphylococcus aureus mutant and rescue of the NaCl-sensitive phenotype by glycine betaine but not by other compatible solutes.

To further study mechanisms of coping with osmotic stress-low water activity, mutants of Staphylococcus aureus with transposon Tn917-lacZ-induced NaCl sensitivity were selected for impaired ability to grow on solid defined medium containing 2 M NaCl. Southern hybridization experiments showed that NaCl-sensitive mutants had a single copy of the transposon inserted into a DNA fragment of the same size in each mutant. These NaCl-sensitive mutants had an extremely long lag phase (60 to 70 h) in defined medium containing 2.5 M NaCl. The osmoprotectants glycine betaine and choline (which is oxidized to glycine betaine) dramatically shortened the lag phase, whereas L-proline and proline betaine, which are effective osmoprotectants for the wild type, were ineffective. Electron microscopic observations of the NaCl-sensitive mutant under NaCl stress conditions revealed large, pseudomulticellular cells similar to those observed previously in the wild type under the same conditions. Glycine betaine, but not L-proline, corrected the morphological abnormalities. Studies of the uptake of L-[14C]proline and [14C]glycine betaine upon osmotic upshock revealed that the mutant was not defective in the uptake of either osmoprotectant. Comparison of pool K+, amino acid, and glycine betaine levels under NaCl stress conditions in the mutant and the wild type revealed no striking differences. Glycine betaine appears to have additional beneficial effects on NaCl-stressed cells beyond those of other osmoprotectants. The NaCl stress protein responses of the wild type and the NaCl-sensitive mutant were characterized and compared by labeling with L-[35 S]methionine and two-dimensional gel electrophoresis. The synthesis of 10 proteins increased in the wild type in response to NaCl stress, whereas the synthesis of these 10 proteins plus 2 others increased in response to NaCl stress in the NaCl-sensitive mutant. Five proteins, three of which were NaCl stress proteins, were produced in elevated amounts in the NaCl-sensitive mutant under unstressed conditions compared to the wild type. The presence of glycine betaine during NaCl stress decreased the production of three NaCl stress proteins in the mutant versus one in the wild type.

Amino Acids↗
PubMed1977

Herpes simplex virus DNA polymerase as the site of phosphonoacetate sensitivity: temperature-sensitive mutants.

Temperature-sensitive (ts) mutants in a number of complementation groups of herpes simplex virus type 1 (HSV-1) are deficient in DNA polymerase induction at the restrictive temperature. Twenty-two mutants in 15 complementation groups were tested for sensitivity to phosphonoacetate (PAA), a compound that inhibits HSV replication in vivo and the DNA polymerase in vitro. One mutant, tsD9, was resistant to PAA (Pr), whereas all others were sensitive. Revertants of tsD9 to the ts+ phenotype simultaneously lost PAA resistance. Additional Pr mutants were isolated from ts mutants belonging to several complementation groups of HSV-1. Double mutants (ts Pr phenotype) were used in three-factor recombination analyses to locate the PAA locus on the genetic map at a position indistinguishable from the ts lesion in tsD9. In all cases, resistance or sensitivity to PAA in vivo was correlated with resistance or sensitivity of DNA polymerase in vitro. These data are compatible with the temperature-sensitive lesion of tsD9 and the determinant of PAA sensitivity both residing in the structural gene for DNA polymerase.

DNA-Directed DNA Polymerase↗
PubMed2000

Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.

Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The "gold standard" glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 nonobese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SI(Clamp)) and minimal model analysis (SI(MM)) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I(0)) and glucose (G(0))] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I(0)) + log(G(0))]) that has substantially better correlation with SI(Clamp) (r = 0.78) than the correlation we observed between SI(MM) and SI(Clamp). Moreover, we observed a comparable overall correlation between QUICKI and SI(Clamp) in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research.

Adult↗
PubMed1984

Relationship of arachidonic acid metabolism to indomethacin-sensitive immunoregulatory function and lymphocyte PGE sensitivity in peripheral blood mononuclear cells of disseminated solid tumor cancer patients.

The relationship between the conversion of arachidonic acid (AA) to E series prostaglandins (PGE), indomethacin-sensitive immunoregulation and lymphocyte PGE sensitivity was investigated in the peripheral blood mononuclear cells (PBMC) of normal subjects and disseminated solid tumor patients. Production of PGE was assessed by thin layer chromatography of ether-extracted glass adherent cells following a 24-hour pulse with 3H-AA. Immunoregulatory cell function was assessed in PHA-stimulated PBMC cultured in the presence of the prostaglandin synthetase inhibitor, indomethacin. Lymphocyte PGE sensitivity was assessed in PHA stimulated glass nonadherent cells cultured in the presence of 10(-8) M PGE. The cells from cancer patients demonstrated greater AA conversion to PGE and greater indomethacin sensitive immunoregulatory cell function than the cells of normal subjects. However, lymphocyte PGE sensitivity was comparable for both groups. When levels of arachidonic acid conversion to PGE were correlated to levels of indomethacin-sensitive immunoregulatory cell function by linear regression analysis, a significant correlation was found. These data suggest that the increased indomethacin-sensitive immunoregulatory cell function seen in PBMC from cancer patients can be directly correlated with increased production of E series prostaglandins by cancer patient peripheral blood monocytes.

Adult↗
PubMed2000

Phenotypic and genotypic relationships between ethanol tolerance and sensitivity in mice selectively bred for initial sensitivity to ethanol (SS and LS) or development of acute tolerance (HAFT and LAFT).

BACKGROUND: Genetically based risk for development of alcoholism in humans seems to be related to initial sensitivity and/or acute tolerance to ethanol. The genetic basis for the development of tolerance has received less attention than other ethanol-related behaviors. We have selected lines of mice, according to genetics, which are differentially sensitive to the initial hypnotic effect of ethanol (Short Sleep and Long Sleep, SS and LS) and other lines that differentially develop acute functional tolerance to ethanol (High and Low Acute Functional Tolerance, HAFT and LAFT). We review reports of the relationship between initial sensitivity and two forms of tolerance as measured using different behavioral measures and different time scales. The goal of the study was to investigate alcohol tolerance as measured by different behavioral tests conducted over different time periods and relate these variables to hypnotic sensitivity. METHODS: We investigated the phenotypic and genotypic relationships between different measures of tolerance to ethanol in the SS and LS mice. We used two measures of tolerance: (a) The time an animal can remain on a stationary dowel or roto-rod at 5-min intervals up to 30 minutes after a single low dose of ethanol (Acute Single Dose Tolerance, ASDT-dowel or ASDT-roto-rod); and (b) The difference in blood ethanol levels taken when a mouse could repeatedly regain balance on a stationary dowel or roto-rod after successive doses of ethanol (Acute Functional tolerance, AFT-dowel or AFT-roto-rod). The time course in AFT was much longer, up to 2 hours. We carried out the same studies on the High and Low Acute Functional Tolerance (HAFT and LAFT) mice. RESULTS: SS and LS mice differ in hypnotic sensitivity as measured by sleep time, and they differ in all forms of acute tolerance that were measured except in AFT-dowel. Although there were phenotypic correlations between AFT-dowel and ASDT-roto-rod in the Heterogeneous Stock (HS) of mice, provisional Quantitative Trait Loci (determined with Recombinant Inbred mice from a SS X LS cross) for the two phenotypes did not overlap, which indicated that there was little or no genetic correlation between the measures. HAFT and LAFT mice do not differ in hypnotic sensitivity as measured by sleep time measurements nor in ataxic sensitivity as measured on the dowel. The HAFT and LAFT mice both developed tolerance when tested in the 30-minute time frame, but the differences between the lines was largely in the rate of development of tolerance and not the amount developed. On the other hand, when tolerance was measured over 2 hr on the dowel or roto-rod, the HAFT and LAFT animals developed different levels of tolerance. CONCLUSIONS: We concluded that measures of tolerance depended on both the time of ethanol's action and the behavioral task used. It seemed that the measures of tolerance used in this study had different genetic bases in mice. Presumably, tolerance will also vary in humans depending on the behavioral measure, and tolerance will also have different genetic bases for the different behavioral measures in humans.

Alleles↗
PubMed2000

[Sensitized photomodification of DNA with binary sysytems of oligonucleotide conjugates. VI. Effect of substituents in the anthracene residue of the sensitizer].

Photomodification of ssDNA by binary systems of oligonucleotide conjugates complementary to the adjacent sequences of the target DNA was studied. One of the conjugates comprised a substituted anthracene as a sensitizer; the other, p-azidotetrafluorobenzaldehyde 3-aminopropionylhydrazone as a photoreagent. The sensitized photomodification is initiated by the 365-580-nm light through an efficient energy transfer from the photoexcitated sensitizer onto the photoreagent in a complementary complex of the binary system with the DNA target where the sensitizer and the photoreagent are sterically converged. Influence of substituents in the anthracene residue on the efficiency of the DNA sensitized photomodification was considered. The oligonucleotide conjugate of anthracene-9-al 3-aminopropionylhydrazone allows highly specific initiation of the sensitized photomodification upon irradiation with visible light at > 460 nm in conditions generating no photoreaction in the sensitizer's absence.

Anthracenes↗
PubMed2002

Impact of moderate aerobic exercise training on insulin sensitivity in type 2 diabetic men treated with oral hypoglycemic agents: is insulin sensitivity enhanced only in nonobese subjects?

BACKGROUND: Few studies have evaluated the effect of aerobic physical training on insulin sensitivity in subjects with type 2 diabetes treated with oral hypoglycemic agents. Most studies that involved nonobese subjects showed enhanced insulin sensitivity whereas studies involving obese subjects with type 2 diabetes are inconsistent because of concomitant fat loss. MATERIAL/METHODS: Thirteen men with type 2 diabetes (6 nonobese and 7 obese) treated with oral hypoglycemic agents carried out a 12-week ergocycle program at 60% VO2 peak, one hour thrice a week. Diet and medications were maintained throughout the study. Insulin sensitivity was assessed with the euglycemic hyperinsulinemic clamp technique. RESULTS: VO2 peak (ml/kg/min) increased with exercise training. There were no significant changes in fat mass, percent body fat, fasting plasma glucose and insulin levels, glycated hemoglobin levels, or insulin sensitivity. However, when the subjects were separated into two groups, they showed different insulin sensitivity adaptation to training. In fact, nonobese subjects with type 2 diabetes showed an increase in insulin sensitivity, whereas no change was observed in the obese subjects. CONCLUSIONS: These findings suggest that moderate aerobic exercise training of 3 months duration enhanced insulin sensitivity only in nonobese men with type 2 diabetes. Obese men with type 2 diabetes showed no benefit. Thus, adiposity per se may be a determining factor in the exercise-induced metabolic benefit of exercise training in subjects with type 2 diabetes.

Blood Glucose↗
PubMed1986

Effect of altered membrane structure on NK cell-mediated cytotoxicity. II. Conversion of NK-resistant tumor cells into NK-sensitive targets upon fusion with liposomes containing NK-sensitive membranes.

There is a large body of evidence that supports the notion that NK cells exert important immune surveillance functions in vivo, against a variety of virus-infected and neoplastic cells. However, certain targets are not susceptible to lysis by NK cells. The exact mechanism by which resistance or sensitivity is conferred on target cells is not known. We investigated whether the selectivity to NK lysis is a property of the membrane of the target cell. This was examined by the application of a recently developed method which is aimed at changing the membrane structure of the target cell by cell-liposome fusion. Our studies demonstrate that NK-resistant tumor cells acquired sensitivity to lysis by NK cells after fusion with reconstituted vesicles which contained membrane components derived from NK-sensitive target cells. The fusion required the presence of Sendai virus envelope glycoproteins and exogenous lipids (soybean lecithin and cholesterol) for maximal efficiency. This finding was demonstrated in both the human system (with U937 and Raji as NK-sensitive and -resistant cell lines, respectively) and the rat/murine system (with YAC-1 as NK-sensitive target and P815 and YAC-asc as NK-resistant targets). Both the 51Cr-release assay and the single cell assay showed lysis of the modified target cells in a 3-hr incubation period. The magnitude of the cytotoxic activity was found to depend on the concentration of reconstituted vesicles used in the fusion step. The effect seen was specific because target cells were not lysed when fused with vesicles which contained membrane constituents derived from either NK-resistant targets or NK-sensitive targets from another species (human vs mouse). The resistance of modified target cells to lysis by xenogeneic NK cells was not due to failure of membrane fusion, as detected by immunofluorescence, or to failure to form conjugates. These results demonstrate the feasibility of converting a resistant NK target to a sensitive target by cell-liposome fusion. Furthermore, the data indicate that susceptibility to lysis by NK cells is a property of the membrane composition of the target cell. The significance of these findings is discussed.

Animals↗
PubMed1994

Inhibition of IgE production and normalization of airways responsiveness by sensitized CD8 T cells in a mouse model of allergen-induced sensitization.

The functional role of CD8 T cells in in vivo IgE production, immediate cutaneous reactivity, and altered airways responsiveness (AR) was examined in a murine model of allergen-induced sensitization. Exposure of BALB/c mice to nebulized OVA triggered an IgE anti-OVA response in the serum, immediate-type skin test responses to OVA, and the development of increased AR (as measured by nonspecific reactivity to electrical field stimulation). In spleens of sensitized mice, analysis of the distribution of CD4/CD8 T cell subpopulations revealed an increase in total numbers of CD8 T cells. Transfer of purified spleen CD8 T cells from OVA-sensitized mice (CD8OVA) to sensitized recipients reduced serum IgE anti-OVA production by roughly 50%. Furthermore, studies of in vitro Ig production indicated that mononuclear cells from recipients of CD8 cells (CD8OVA > CD8PBS) produced less IgE and IgG1 antibodies, whereas in vitro IgG2a production was enhanced. The suppression of IgE production in recipients of CD8OVA T cells was associated with the failure to respond to intradermal challenge with OVA. The increase in AR found in sensitized mice was prevented after transfer of CD8OVA cells. When CD8 T cells from nonimmunized animals (CD8PBS) were used for the transfer into sensitized recipients, serum anti-OVA IgE was decreased by only 20%, whereas skin test reactivity and AR were not significantly affected. The ex vivo analysis of the pattern of cytokine-producing lymphocytes by immunofluorescence microscopy indicated that the sensitization procedure increased the fraction of IFN-gamma- and IL-4-positive cells in the spleen. Further in vitro analysis demonstrated that a high percentage of CD8 T cells were positive for IFN-gamma, whereas IL-4 was produced mainly by CD4 T cells. These data suggest that CD8 T cells may play an important role in the negative regulation of IgE production and AR and that IFN-gamma may be a relevant mediator of the functions of CD8 T cells in this model.

Animals↗
PubMed1996

In vitro primary sensitization of hapten-specific T cells by cultured human epidermal Langerhans cells--a screening predictive assay for contact sensitizers.

BACKGROUND: The need to develop predictive tests which could identify potential allergens has been recognized for many years. There is as yet no accepted in vitro method for the assessment of contact sensitizers. OBJECTIVE: We have tested the ability of a range of contact allergens to induce in vitro primary sensitization of autologous T cells. METHOD: T-cell proliferation induced by haptens using 2-day cultured human Langerhans cells as antigen-presenting cell was assessed by 3H thymidine incorporation. Antigen specific stimulation was calculated as stimulation indexes. RESULTS: Strong allergens induced in vitro a primary T-cell response in all (trinitrophenyl, TNP: 13/13) or in the majority (fluorescein isothiocyanate, FITC: 7/10) of experiments. An irritant, sodium dodecyl sulfate (SDS), failed to generate a significant T-cell proliferation in any of the experiments (0/10). We obtained a significant lymphoproliferative response to weak sensitizers only in a limited number of experiments: (coumarin: 1/12, citronellal: 0/10, hydroxycitronellal: 2/8). p-Phenylenediamine (PPDA), a prohapten and highly sensitizing chemical in vivo, generated primary sensitization in vitro in only one of six experiments, while Bandrowski's base (BB), a metabolization product of PPDA induced a significant T-cell response in all six experiments. CONCLUSION: The present in vitro model allows discrimination between two groups of substances: strong contact sensitizers (TNP, FITC, BB) on the one hand and weak sensitizers (coumarin, citronellal and hydroxycitronellal) and irritants (SDS) on the other hand. It could be used as a screening in vitro assay to eliminate strong contact allergens before further predictive animal tests have to be performed.

Coumarins↗
PubMed1988

Dual-function radiation sensitizers and bioreductive drugs: factors affecting cellular uptake and sensitizing efficiency in analogues of RSU 1069.

Alkyl aziridine analogues of the hypoxic cell radiosensitizer RSU 1069 have been synthesized and one of these, RB 7040, containing the tetramethyl substituted aziridine, is a more efficient sensitizer in vitro than RSU 1069 (Ahmed et al., 1986). The extent to which variation in drug uptake can influence the sensitizing efficiency of RSU 1069 and its analogues has been investigated by determining the cellular uptake of these weakly basic sensitizers as a function of the pH of the extracellular medium (pHe) over the range 5.4-8.4. Following exposure of V79 cells to these agents for 1 h at room temperature, the ratio of intra- to extracellular concentration (Ci/Ce) was near unity at pH 5.4. Increasing pHe to 8.4 resulted in no change in the ratio Ci/Ce for RSU 1069 (pKa = 6.04). In contrast, the values of Ci/Ce increased three-fold for RSU 1165 (pKa = 7.38) and eleven-fold for RB 7040 (pKa = 8.45). Radiosensitization by RSU 1069 showed little dependence on pHe over the range studied, whereas increasing pH caused an apparent increase in sensitizing efficiency of both RSU 1165 and RB 7040. However, when the enhancement ratios for sensitization were normalized to take account of the effect of extracellular pH on drug uptake, efficiency of sensitization was independent of pHe. This study suggests that changes in basicity (pKa) may have wider potential for therapeutic exploitation on the basis of selective tumour uptake for this type of agent.

Animals↗
PubMed1993

Dopamine antagonists can inhibit methamphetamine sensitization, but not cocaine sensitization, when assessed by ambulatory activity in mice.

The repeated subcutaneous administration of methamphetamine (2 mg kg-1) and cocaine (10 mg kg-1) at 3-4 day intervals induced sensitization to their ambulation-increasing effects in mice. Subcutaneous administration of SCH 23390 (R-(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.003-0.03 mg kg-1) and YM-09151-2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide; 0.003-0.03 mg kg-1), the selective dopamine D1 and D2 antagonists, respectively, reduced dose-dependently the acute ambulation-increasing effect of methamphetamine. The development of methamphetamine sensitization was inhibited when it was administered in combination with either SCH 23390 or YM-09151-2 in the repeated administration schedule. Although SCH 23390 (0.01-0.1 mg kg-1) and YM-09151-2 (0.01-0.1 mg kg-1) also reduced the ambulation-increasing effect of cocaine (10 mg kg-1), neither drug inhibited the cocaine sensitization. Mice given cocaine with SCH 23390 (0.03 mg kg-1) or YM-09151-2 (0.03 and 0.1 mg kg-1) showed higher sensitivity than those given cocaine alone. The present results suggest that, although both the dopamine D1 and D2 antagonists reduce the acute stimulant effects of both methamphetamine and cocaine, they are only effective for inhibition of the methamphetamine sensitization. Mechanisms other than the dopaminergic system appear to be involved in the cocaine sensitization.

Animals↗