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PubMed1998

The Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene contributes to the interindividual variation in serum C-peptide response during an oral glucose tolerance test: evidence from studies of 231 glucose-tolerant first degree relatives of type 2 diabetic probands.

The third form of maturity-onset diabetes of the young is caused by mutations in the hepatocyte nuclear factor-1alpha gene. Recently, we demonstrated an association between a prevalent polymorphism at codon 98, Ala/Val98, of this gene and a 20% decreased insulin release during an oral glucose tolerance test (OGTT) in middle-aged glucose-tolerant Danish Caucasian subjects. The major objective of the present study was to replicate this finding among glucose-tolerant first degree relatives of type 2 diabetic patients of the same ethnic origin. All participants, 231 glucose-tolerant offspring of 62 type 2 diabetic probands, underwent an OGTT with measurements of plasma glucose, serum insulin, and serum C peptide during the test. Thirty-three heterozygous carriers of the Ala/Val variant were identified, whereas no subjects had the variant in its homozygous form. Ala/Val carriers had a 20% reduction in serum C peptide at 30 min during the OGTT (1225+/-636 vs. 1507+/-624 pmol/L; P=0.02) compared to wild-type carriers. No significant differences in serum insulin levels during the OGTT were observed between carriers of the variant and Ala/Ala homozygotes. In conclusion, among Danish glucose-tolerant first degree relatives of type 2 diabetic patients the Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene is associated with a decreased serum C-peptide secretion during an OGTT. This finding confirms our previously reported observation of the functional importance of the variant to insulin secretion during an OGTT among middle-aged healthy subjects.

Adult↗
PubMed1994

Tolerance to nitroglycerin in vascular smooth muscle cells: recovery and cross-tolerance to sodium nitroprusside.

Treatment with nitric oxide (NO)-producing vasodilators such as nitroglycerin (NTG) and sodium nitroprusside (SNP) causes tolerance. Both NTG and SNP relax blood vessels by increasing guanosine 3',5'-cyclic monophosphate (cGMP) in vascular smooth muscle. We determined the effect of treatment with NTG on cGMP production in cultured pig coronary smooth muscle cells (CSM). Cells incubated for 1 h with 10 microM NTG were desensitized to the effect of NTG on cGMP, but 100 microM NTG was required to induce cross-tolerance to SNP. Acute concentration-response curves of cGMP to NTG and to SNP were determined in cells pretreated for 1 h with 100 microM NTG and compared to response curves in untreated cells. In untreated cells, both NTG and SNP increased cGMP concentration dependently. SNP (1 mM) increased cGMP to 575 +/- 22 pmol/mg vs 55 +/- 4 pmol/mg for 1 mM NTG (P < 0.01, n = 8). Pretreated cells were unresponsive to acutely applied NTG but remained responsive to SNP, although the concentration-response curve to SNP was significantly depressed by approximately 60%. After washout of the NTG pretreatment, the cGMP response to SNP returned to control within 48 h while response to NTG required 72 h. These results show that smooth muscle cells exposed to NTG become tolerant to the effect of NTG on cGMP, and that cross-tolerance to SNP required a 10-fold higher concentration of NTG. The cGMP concentration-response curves of these tolerant cells to rechallenge with NTG or SNP were different.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2007

Increasing the accuracy of oral glucose tolerance testing and extending its application to individuals with normal glucose tolerance for the prediction of type 1 diabetes: the Diabetes Prevention Trial-Type 1.

OBJECTIVE: We assessed the extent to which both standard and alternative indexes from 2-h oral glucose tolerance testing predict type 1 diabetes and whether oral glucose tolerance tests (OGTTs) predict type 1 diabetes in individuals with normal glucose tolerance. RESEARCH DESIGN AND METHODS: The prediction of type 1 diabetes from baseline OGTTs was studied in 704 Diabetes Prevention Trial-Type 1 participants (islet-cell autoantibody [ICA]-positive relatives of type 1 diabetic patients). The maximum follow-up was 7.4 years. Analyses utilized receiver-operator curves (ROCs), proportional hazards models, and survival curves. RESULTS: ROC areas under the curve (ROCAUCs) for both the AUC glucose (0.73 +/- 0.02) and an OGTT prediction index (0.78 +/- 0.02) were higher (P < 0.001) than those for the fasting (0.53 +/- 0.02) and 2-h glucose (0.66 +/- 0.02). ROCAUCs for the 60- and 90-min glucose (0.71 +/- 0.02 and 0.72 +/- 0.02, respectively) were also higher (P < 0.01) than those for the fasting and 2-h glucose. Among individuals with normal glucose tolerance, OGTTs were highly predictive, with 4th versus 1st quartile hazard ratios for the 2-h glucose, AUC glucose, and OGTT prediction index ranging from 3.77 to 5.30 (P < 0.001 for all). CONCLUSIONS: Certain alternative OGTT indexes appear to better predict type 1 diabetes than standard OGTT indexes in ICA-positive relatives of type 1 diabetic patients. Moreover, even among those with normal glucose tolerance, OGTTs are strongly predictive. This suggests that subtle metabolic abnormalities are present several years before the diagnosis of type 1 diabetes.

Area Under Curve↗
PubMed1998

Insulin secretion in normal glucose-tolerant relatives of type 2 diabetic subjects. Assessments using hyperglycemic glucose clamps and oral glucose tolerance tests.

OBJECTIVE: To assess insulin secretion in normal glucose-tolerant Caucasian first-degree relatives of type 2 diabetes subjects and in matched normal glucose-tolerant control subjects and to compare insulin secretion as assessed using a hyperglycemic glucose clamp with insulin secretion as assessed using an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: Twenty-one first-degree relatives of type 2 diabetic subjects and 21 control subjects without a family history of type 2 diabetes, who were matched for sex, age, BMI, waist-to-hip ratio, and aerobic capacity, underwent a hyperglycemic glucose clamp (10 mmol/l, 180 min). An OGTT (75 g glucose in 300 ml water) was also performed. RESULTS: First-phase insulin release (plasma insulin, 0-10 min) was not different (multiple analysis of variance [MANOVA]: F = 2.63, P = 0.11). Second-phase insulin release was lower (MANOVA: F = 4.18, P = 0.047). Separate analyses of variance showed decreased plasma insulin levels from 120 min onward (all P < 0.05), decreasing to geometric mean (95% CI) levels of 330 (270-402) and 462 (366-582) pmol/l at 180 min in relatives and control subjects, respectively. The insulin sensitivity index (ISI) as assessed using a hyperglycemic clamp was not different between the two groups. Mean +/- SE ISI during the 3rd hour was 27.5 +/- 2.2 and 30.5 +/- 3.0 micrograms.kg-1.min-1.pmol-1.l-1 in relatives and control subjects, respectively (P > 0.20). At 90 min after the OGTT, log plasma insulin levels correlated significantly with second-phase insulin release as assessed using the hyperglycemic glucose clamp. CONCLUSIONS: Normal glucose-tolerant first-degree relatives of type 2 diabetic subjects have a decreased second-phase insulin release, compared with matched control subjects. After an OGTT, 90-min values of log plasma insulin and 90-min values of the ratio of log plasma insulin to blood glucose may be good indicators of insulin secretory properties in normal glucose-tolerant family members of type 2 diabetic subjects.

Adult↗
PubMed2000

An intra-Peyer's patch gene transfer model for studying mucosal tolerance: distinct roles of B7 and IL-12 in mucosal T cell tolerance.

Development of mucosal immunity and tolerance requires coordinated expression of a number of genes within the mucosa-associated lymphoid tissue (MALT). To study the roles of these genes in the MALT, we have established a MALT-specific gene transfer model using replication-defective adenovirus as vector. In this model, the target gene of interest is directly delivered into the Peyer's patch by intra-Peyer's patch injection of the recombinant virus. Using this gene transfer model, we investigated the roles of B7-1 and IL-12 in the development of mucosal tolerance. We found that intra-Peyer's patch injection of OVA induced Ag-specific T cell hyporesponsiveness, as manifested by decreased T cell proliferation and IL-2/IFN-gamma production upon subsequent immune challenge. Intra-Peyer's patch B7-1 gene transfer at the time of OVA administration partially reversed the inhibition of T cell proliferation and IL-2 secretion, but had no effect on IFN-gamma production. By contrast, intra-Peyer's patch IL-12 gene transfer completely restored T cell proliferation and IFN-gamma secretion and partially reversed IL-2 inhibition. Using an adoptive TCR transgenic model, we further demonstrated that B7 and IL-12 played distinct roles during the inductive phase of mucosal tolerance. B7 selectively increased T cell proliferation and IL-2 secretion without affecting IFN-gamma production, whereas IL-12 increased both IL-2 and IFN-gamma production. These results indicate that B7 alone may not be sufficient to abrogate mucosal tolerance, and that cytokines such as IL-12 may also be required. Based on these findings, we propose a new model to explain the paradoxical roles of B7 in mucosal immunity and tolerance.

Adenoviruses, Human↗
PubMed2003

Tolerance through indifference: autoreactive B cells to the nuclear antigen La show no evidence of tolerance in a transgenic model.

Systemic autoimmune diseases are characterized by the production of high titer autoantibodies specific for ubiquitous nuclear self-Ags such as DNA, Sm, and La (SS-B), so the normal mechanisms of B cell tolerance to disease-associated nuclear Ags have been of great interest. Mechanisms of B cell tolerance include deletion, anergy, developmental arrest, receptor editing, and B cell differentiation to the B-1 subtype. However, recent studies in our laboratory have suggested that B cell tolerance to the nuclear autoantigen La is limited in normal mice, and tolerance may reside primarily in the T cell compartment. To test this hypothesis, we created Ig transgenic mice expressing the IgM H chain from an mAb specific for a xenogeneic epitope within human La (hLa). These mice were bred with hLa-transgenic mice that constitutively express hLa in a manner comparable to endogenous mouse La. Between 5-15% of transgenic B cells developing in the absence of hLa were specific for hLa, and these cells were neither depleted nor developmentally arrested in the presence of endogenous hLa expression. Instead, these autoreactive B cells matured normally and differentiated into Ab-forming cells, capable of secreting high titer autoantibody. Additionally, the life span of autoreactive hLa-specific B cells was not reduced, and they were phenotypically and functionally indistinguishable from naive nonautoreactive hLa-specific B cells developing in the absence of hLa. Together these data suggest a lack of intrinsic B cell tolerance involving any known mechanisms indicating that these autoreactive B cells are indifferent to their autoantigen.

Animals↗
PubMed2005

Mechanisms of gene therapy for tolerance: B7 signaling is required for peptide-IgG gene-transferred tolerance induction.

LPS-activated B cells, transduced with IgG fusion proteins, are highly tolerogenic APCs. To analyze the mechanisms for this B cell-delivered gene therapy, we first followed the fate of CFSE-labeled B cell blasts. These cells primarily localized to the spleen, where a small population persisted for at least 1 mo after injection. By day 7 after injection, approximately 95% of the transduced cells had divided at least once, presumably an effect of the in vitro LPS activation into the cycle, because resting cells did not divide. B cells from gld donors were not tolerogenic, initially suggesting a role for Fas ligand (FasL) in tolerance. Because transduced normal B cells expressed only low levels of FasL and did not kill Fas-expressing Jurkat or A20 B lymphoma cells in vitro, these data suggest that gld B cells are not tolerogenic due to unique characteristics of these B cells rather than the lack of functional FasL expression. The transduced B cell blasts displayed significant up-regulation of both B7 costimulatory molecules, and B7.2 up-regulation was maintained through day 7 in vivo. When B cells from B7 knockout donors were transduced to express Ig fusion proteins, they were not tolerogenic in two different mouse strains and Ag models. Moreover, anti-B7 Ab blocked tolerance induction in this model, a result consistent with a role for B7 in tolerance induction. We propose that tolerance may be induced in this model by B7-driven negative regulatory signaling, but tolerance is maintained by a lack of signal 2, because expression of B7 is eventually lost in vivo.

Animals↗
PubMed2006

Oral nickel tolerance: Fas ligand-expressing invariant NK T cells promote tolerance induction by eliciting apoptotic death of antigen-carrying, effete B cells.

Whereas oral nickel administration to C57BL/6 mice (Ni(high) mice) renders the animals tolerant to immunization with NiCl2 combined with H2O2 as adjuvant, as determined by ear-swelling assay, it fails to tolerize Jalpha18-/- mice, which lack invariant NKT (iNKT) cells. Our previous work also showed that Ni(high) splenic B cells can adoptively transfer the nickel tolerance to untreated (Ni(low)) recipients, but not to Jalpha18-/- recipients. In this study, we report that oral nickel administration increased the nickel content of splenic Ni(high) B cells and up-regulated their Fas expression while down-regulating expression of bcl-2 and Bcl-xL, thus giving rise to an Ag-carrying, apoptosis-prone B cell phenotype. Although oral nickel up-regulated Fas expression on B cells of both wild-type Ni(high) and Jalpha18-/- Ni(high) mice, only the former showed a reduced number of total B cells in spleen when compared with untreated, syngeneic mice, indicating that iNKT cells are involved in B cell homeostasis by eliciting apoptosis of effete B cells. Upon transfer of Ni(high) B cells, an infectious spread of nickel tolerance ensues, provided the recipients are immunized with NiCl2/H2O2. As a consequence of immunization, Fas ligand-positive (FasL+) iNKT cells appeared in the spleen and apparently elicited apoptosis of Ni(high) B cells. The apoptotic Ni(high) B cells were taken up by splenic dendritic cells, which thereby became tolerogenic for nickel-reactive Ni(low) T cells. In conclusion, FasL+ iNKT cells may act as ready-to-kill sentinels of innate immunity, but at the same time assist in tolerance induction by eliciting Fas/FasL-mediated apoptosis of effete, Ag-containing B cells.

Administration, Oral↗
PubMed1976

Tolerance and limited cross-tolerance to the effects of N, N-dimethyltryptamine (DMT) and lysergic acid diethylamide-25 (LSD) on food-rewarded bar pressing in the rat.

Lysergic acid diethylamide=25 (LSD) and N,N-dimethyltryptamine (DMT) abolish food-rewarded, fixed-ratio bar pressing by rats in a dose-related fashion. Adult male Holtzman rats trained to press a bar (respond) for milk reward on a 4-response fixed-ratio schedule were given i.p. injections of 3.2 or 10 mg/kg of DMT every 2 hours for 21 days. Every 24 hours the animals were placed in operant chambers for 30 minutes before a scheduled injection and were left in the chambers for 30 to 80 minutes after. During the first week of chronic treatment, daily bar pressing worsened progressively until the 6th day of the series, at which time rats in the 10 mg/kg group did not bar press at all. As the chronic injections continued, rates of bar pressing gradually increased until responding was not disrupted at all by an injection of DMT. Rats in the 3.2 mg/kg group showed cross-tolerance to an injection of LSD (0.1 mg/kg). Another group of rats was made partially tolerant to the disruptive effects of LSD (0.1 mg/kg i.p.) on bar pressing with a series of injections given once per day for 21 days and then three times per day for the next 4 days. Cross tolerance was not demonstrated to a challenge injection of 10 mg/kg of DMT. The LSD injections were continued for another 3 to 5 days until the animals were completely tolerant to the LSD. They then displayed cross-tolerance to 3.2 mg/kg of DMT.

Animals↗
PubMed2000

Peripheral tolerance to human papillomavirus E7 oncoprotein occurs by cross-tolerization, is largely Th-2-independent, and is broken by dendritic cell immunization.

The E7 oncoprotein of human papillomavirus 16 functions as a tumor-specific antigen in transformed epithelial cells of the uterine cervix to which immunotherapeutic strategies aimed at CTL induction may be directed. We previously have shown in mice transgenic for the E7 gene driven off an epithelial specific (keratin-14) promoter, that expression of E7 protein in peripheral epithelium is sufficient to tolerize E7-directed CTL precursors (pCTL; Doan et al, J. Virol., 73: 6166-1670, 1999). Here we show that E7 is presented to T cells for tolerization by cells of bone marrow origin ("cross-tolerization"). We demonstrate that tolerization of E7-directed pCTLs occurs within 2 weeks of exposure to E7 in epithelium. It is maintained in the near absence of CD4+ cells and in the absence of the thymus, and is independent of a coexisting E7-directed Th2-type antibody response. Tolerance was broken by immunization with E7 CTL epitope-pulsed dendritic cells. These findings have implications for immunotherapy of patients with human papillomavirus 16-associated cervical carcinoma, whose immune systems may have experienced long-term exposure to E7-expressing epithelial cells.

Adoptive Transfer↗
PubMed1976

Transplantation tolerance at the T-lymphocyte receptor level. I. Spontaneous release of T-cell receptors by lymphocytes from tolerant mice.

Spleen and lymph node T cells from CBA mice when cultivated in vitro almost immediately started to shed receptors for A alloantigens. In contrast, cultivated T lymphocytes from CBA mice tolerant of A alloantigens for 657 or 692 days began releasing receptors for the formerly tolerated A alloantigen after a delay of 8 h. This delay in receptor shedding coincided with that observed when nontolerant lymphocytes were treated with antisera to T-cell receptors. The results suggested a close similarity of mechanisms and indicated that transplantation tolerance may be maintained by active suppression of otherwise reactive T cells mediated by anti-receptor antibody. Lymphocytes from untreated tolerant mice and those treated with a nonspecific anti-receptor serum showed normal responses, as measured in terms of receptor release, to third-party alloantigens, as did cells from untreated normal mice. Precultivated normal lymphocytes treated with anti-receptor antibody and complement failed to release the appropriate receptor specificity but similarly treated tolerant lymphocytes were almost resistant, presumably because they expressed only few receptors at the time of treatments.

Animals↗
PubMed1992

Neonatal tolerance induction in the thymus to MHC-class-II-associated antigens. V. Thymus medulla and the site for deletional signaling achievement in Mls tolerance.

Intravenous (i.v.) injection of Mls-1a peritoneal cavity (PerC) cells from (BALB/c x AKR)F1 (Mls-1b/a, H-2d/k) mice into newborn BALB/c (Mls-1b, H-2d) mice induced thymus cell tolerance by one week of age, accompanied by V beta 6+ cell elimination. The tolerant state is associated with intrathymic chimerism with MHC-class II(IA+) cells, confluent in the medulla and scattered in the cortex. To clarify the anatomical site for the deletional signaling, we injected Mls-1a PerC cells directly into the thymus lobe of BALB/c mice on the day of birth. Thus induced tolerant state was limited to the injected lobe and there was no penetration to the contralateral lobe. The tolerant state lasted less than 2 weeks, by which time donor-derived Ia+ cell had disappeared from the thymus. Thus, PerC cells seem to have little self-renewing ability. One week after the intrathymic injection of a small amount (0.3 microliter) of PerC cell suspension in several different sites, the thymus lobes were removed without killing the mice and serial cryostat sections were cut and stained immuno-histochemically for analysis of the donor cell distribution. Four weeks later, the functional activities of peripheral T cells in the spleens of the treated mice were tested. These experiments revealed that inoculated cells lodging in the medulla, but not in the cortex, induced tolerance to the Mls determinants. Target thymocytes for negative signaling are probably located in the medulla/juxta-medullary area in the thymus. Data are discussed in relation to Mls-bearing stroma cells in the thymus.

Animals↗
PubMed2003

Is it possible to detect Echinochloa spp. tolerance to ACCase-inhibiting herbicides using a simple quick tolerance test?

The objective of this work was to evaluate the reliability of one quick tolerance test that would enable us, in only six days, to quantify tolerance levels of one biotype to one or more herbicides. For this purpose, we evaluated tolerance levels to cyhalofop-butyl of five Echinochloa spp. biotypes: muricata, crus-galli, crus-pavonis, oryzicola and utilis, with unknown records of herbicide treatment. Moreover, two biotypes of Echinochloa phyllopogon were tested, one of them resistant (R) to fenoxaprop-P-ethyl and the other one susceptible (S). The Oryza sativa Puntal var. and Oryza sativa var. (wild rice) were also checked in order to demonstrate cyhalofop-butyl selectivity profiles. The assays were conducted with petri-dishes where, over the following increasing doses, fifty seeds per biotype and dose, were placed in each one: 0, 3, 6, 12, 18, 24, 48 and 60 ppm of cyhalofop-butyl and codacide oil adjuvant. Six days later, the following parameters were evaluated: plumule length, root length, germination (%) and fresh weight reduction (%). E. muricata germination was reduced by 50% with a 6 ppm dose. A non linear relation dose-germination was observed in the rest of the biotypes. The plumule length permitted the ranking of the biotypes into three groups: (1) resistant (E. phyllopogon R) or very tolerant (Oryza sativa Puntal var. and wild rice), those with a reduction of less than 30%, (2) tolerant, between 30 and 60% (E. oryzicola), and (3) susceptible, with a reduction of over 80% (E. muricata, E. crus-galli, E. crus-pavonis, E. utilis and E. phyllopogon S). Only Oryzo sativa and E. phyllopogon R had a minimal reduction of fresh weight (less than 15%). The assays were repeated with whole plants and we checked the accuracy of this test that indicated the resistance level of one biotype in a quick, reliable and economic way.

Drug Tolerance↗
PubMed1977

Mechanisms of B cell tolerance. I. Tolerance to dextran B1355 induced with the oxidized dextran.

The bacterial dextran B1355, which is normally a potent thymus-independent immunogen, was made tolerogenic by oxidation. The injection of the oxidized dextran into BALB/c mice before, at the same time, or up to 4 days after the injection of the immunogenic form of the dextran resulted in a marked immunologically specific suppression of the number of anti-dextran antibody-forming cells found in the spleen. This suppression resulted from a direct inactivation of antibody-forming cell precursors rather than from either inhibition of antibody secretion or the exhaustive utilization of precursor B cells that have been observed in other tolerance systems. A substantial degree of tolerance was achieved after only a 1-hr in vivo exposure of the spleen cells to the tolerogen. At a dose of 1 mg of oxidized dextran per mouse, tolerance persised for at least 3 weeks. A complete recovery was apparent by 10 weeks. The stability of the tolerance was demonstrated by transferring tolerant spleen cells to irradiated recipients. The response in the recipient animals to an immunogenic dextran challenge remained suppressed. It appears that the tolerogenicity of the oxidized dextran is due to its ability to couple covalently with free amino groups in or near the receptor site of the cell membrane via the reactive dialdehyde groups of the dextran.

Animals↗
PubMed1985

A preliminary study on the mechanism of neonatal allotransplantation tolerance. Participation of suppressor cells in the mediation of neonatal allotransplantation tolerance.

Using a method from Billingham, an animal model of the neonatal allotransplantation tolerance of SWI to C57BL inbred mice was established and the mechanism of neonatal tolerance established by us was preliminarily studied. Our experiment indicates that the clonal deletion theory is not the unique explanation for the neonatal tolerance and a peripheral active inhibitory mechanism including suppressor cells may participate in mediating and maintaining the neonatal tolerance. The suppressor cells in the neonatal tolerance are radioresistant, but rather sensitive to mitomycin C treatment. These results suggest that suppressor cell population may be nonhomogenous. Further studies about this problem are needed.

Animals↗
PubMed1984

Insulin-specific tolerance induction. II. Tolerant helper T cells can be rescued by insulin complexed to Brucella abortus.

Murine antibody responses to heterologous insulins are under H-2-linked immune response (Ir) gene control. We previously demonstrated that the immune response to insulin in Freund's complete adjuvant (CFA) can be specifically inhibited by prior injection of soluble insulin i.v. Unresponsiveness requires at least 4 days after i.v. injection to develop, and once induced, it lasts 4 wk or more. Unresponsiveness is caused by T cell, but not B cell, tolerance; furthermore, we have been unable to demonstrate any role for suppressor T cells in this unresponsiveness. The following experiments examine the nature of the T cell tolerance induced by i.v. injection of insulin, and the data suggest that helper T cells were not clonally deleted by this procedure. The functional activity of the tolerized T cells can be rescued by stimulation with insulin covalently complexed to the type 1 T-independent (TI-1) antigen, Brucella abortus. This observation suggests that tolerance induced by soluble insulin is due to clonal anergy rather than clonal deletion of helper T cells; thus, this system could provide a model for determining the cellular events involved in tolerance induction and reversal in helper T cells.

Animals↗
PubMed1978

Studies of contact hypersensitivity and tolerance in vivo and in vitro. I. Basic characteristics of the reactions and confirmation of an immune response in tolerant mice.

Contact hypersensitivity to dinitrochlorobenzene (DNCB), picryl chloride (PCl) or oxazolone was induced in mice by skin painting with these agents, and was measured by skin testing in vivo using the ear swelling method. Prior administration of dinitrobenzene sulfonate (DNBS) or picryl sulfonic acid prevented sensitization to DNCB and PCl, respectively. Both this tolerization and the original sensitization were specific for the hapten used. Cyclophosphamide given before sensitization enhanced skin reactions, but when given before tolerization it interfered with establishment of tolerance. Cells from both sensitized and tolerized mice were shown to be reactive with the corresponding haptens in vitro in the leukocyte adherence inhibition (LAI) reaction. LAI specificity was similar to that found for cutaneous reactivity. The reaction of DNCB-sensitized cells with DNBS led to the production of a soluble mediator which induced LAI in normal cells. The demonstration of potentially reactive cells in mice judged to be tolerant by skin testing indicates the concomitant existence of suppressor factors.

Animals↗
PubMed1983

Tolerance to phencyclidine in pigeons: cross-tolerance to ketamine.

In order to determine whether tolerance developed to the behavioral effects of phencyclidine, pigeons were trained to respond under a multiple fixed-ratio 30, fixed-interval 600-sec schedule of food presentation. When rates and patterns of responding reached stability, dose-response curves for phencyclidine (0.1-10 mumol/kg i.m.), ketamine (3-56 mumol/kg i.m.) and pentobarbital (1-75 mumol/kg i.m.) were determined. Phencyclidine, ketamine and pentobarbital all decreased fixed-ratio 30 responding in a dose-related manner and increased fixed-internal 600-sec. responding at immediate doses. At higher doses, pentobarbital decreased responding. High doses of phencyclidine and ketamine suppressed responding in the early portions of the session, but when responding returned, it returned at a high rate. After 35 daily injections of phencyclidine (3 mumol/kg/day i.m.), dose-response curves were redetermined for all three drugs. A tolerance was observed for moderate doses of phencyclidine, and a moderate cross-tolerance was observed to ketamine. No tolerance was observed for the total suppression of responding produced by high doses of phencyclidine and ketamine early in the test sessions. No cross-tolerance to pentobarbital was observed. After 215 days of daily phencyclidine administration, no withdrawal signs were observed upon the discontinuation of daily injections.

Animals↗