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PubMed1994

No changes of insulin sensitivity in cystic fibrosis patients with different degrees of glucose tolerance: an epidemiological and longitudinal study.

Plasma glucose and insulin responses to oral glucose and insulin sensitivity by the euglycemic hyperinsulinemic clamp technique were investigated in 30 cystic fibrosis patients with normal fasting blood glucose levels and normal (N = 12), impaired (N = 12) or diabetic (N = 6) glucose tolerance, and in 12 control subjects. In a subgroup of 10 cystic fibrosis patients with non-diabetic glucose tolerance both oral glucose tolerance test and clamp were performed again 48-52 months later. Following oral glucose, glycemic responses were higher in cystic fibrosis patients than in controls, whereas insulin responses were reduced significantly only in the patients with diabetic glucose tolerance. Insulin sensitivity did not differ significantly in the patient subgroups with different degrees of glucose tolerance and in controls. In the 10 patients who underwent a 4-year follow-up, insulin responses to oral glucose decreased significantly, whilst insulin sensitivity did not change substantially. Insulin sensitivity persisted unmodified even in the patients with deteriorating glucose tolerance. No correlation were observed between metabolic data and clinical status of patients. In conclusion, in cystic fibrosis subjects with fasting euglycemia and different degrees of glucose tolerance: (i) insulin sensitivity is not impaired; (ii) eventually changes of glucose tolerance over time are not associated with modifications of insulin sensitivity; (iii) insulin secretion deteriorates over time even in the patients with stable glucose tolerance; (iv) eventual deterioration of both glucose tolerance and insulin secretion is not linked to a worsening of either nutritional or clinical parameters.

Administration, Oral↗
PubMed2004

Comparative mapping of a major aluminum tolerance gene in sorghum and other species in the poaceae.

In several crop species within the Triticeae tribe of the grass family Poaceae, single major aluminum (Al) tolerance genes have been identified that effectively mitigate Al toxicity, a major abiotic constraint to crop production on acidic soils. However, the trait is quantitatively inherited in species within other tribes, and the possible ancestral relationships between major Al tolerance genes and QTL in the grasses remain unresolved. To help establish these relationships, we conducted a molecular genetic analysis of Al tolerance in sorghum and integrated our findings with those from previous studies performed in crop species belonging to different grass tribes. A single locus, AltSB, was found to control Al tolerance in two highly Al tolerant sorghum cultivars. Significant macrosynteny between sorghum and the Triticeae was observed for molecular markers closely linked to putatively orthologous Al tolerance loci present in the group 4 chromosomes of wheat, barley, and rye. However, AltSB was not located within the homeologous region of sorghum but rather mapped near the end of sorghum chromosome 3. Thus, AltSB not only is the first major Al tolerance gene mapped in a grass species that does not belong to the Triticeae, but also appears to be different from the major Al tolerance locus in the Triticeae. Intertribe map comparisons suggest that a major Al tolerance QTL on rice chromosome 1 is likely to be orthologous to AltSB, whereas another rice QTL on chromosome 3 is likely to correspond to the Triticeae group 4 Al tolerance locus. Therefore, this study demonstrates a clear evolutionary link between genes and QTL encoding the same trait in distantly related species within a single plant family.

Aluminum↗
PubMed2004

Autoimmune diabetes and the circle of tolerance.

The concept of immunological tolerance is central to our understanding of type 1 diabetes and the development of strategies for its prediction, prevention, and cure. Tolerance simply refers to the absence of an immune response. Most of us are born with an immune system that develops tolerance to all the other systems of our bodies as well as to the things that we eat. It is the loss of immunological tolerance that leads to autoimmunity. And when that autoimmune response directly or indirectly targets the beta-cell, type 1 diabetes is the result. In the U.S., 1 in 600 of us loses tolerance to pancreatic beta-cells. Interference with T-cell function after the loss of tolerance, as can be achieved with immunosuppressive drugs like cyclosporin, arrests the disease, but the cost in side effects is high. Clearly, stopping the loss of tolerance would be preferable. If we can stop the loss of tolerance, we can prevent the disease. We and many others have investigated both approaches. But what of the people who already have diabetes? For them a separate but related strategy, tolerance induction, is required. Specifically, islet transplantation tolerance induction holds out the promise of being able to cure the disease. This has been the ultimate goal of our laboratory's work for the past two decades.

Animals↗
PubMed1997

Transient impaired glucose tolerance in South African Indians does not carry a risk for progression to NIDDM.

OBJECTIVE: To evaluate the significance of transient impaired glucose tolerance (IGT) in terms of the risk of progression to NIDDM and the serum insulin response during oral glucose tolerance test (OGTT) in a prospective study on the natural history of IGT in South African Indians. RESEARCH DESIGN AND METHODS: This is a report on 87 subjects who formed part of a 4-year prospective study in 128 subjects classified with IGT at baseline (year 0) using World Health Organization criteria for glucose tolerance. Subjects were reexamined at years 1 and 4. At year 1, based on OGTT results, the subjects were divided into three groups: transient IGT (normal glucose tolerance [trIGT], n = 40), persistent IGT (pIGT, n = 47), and diabetes (n = 41). Analysis was performed on the 87 subjects who were classified as IGT at year 0, but who had not progressed to NIDDM by year 1 of the study At baseline (year 0), a modified OGTT was performed; between years 1 and 4, the OGTT included timed midtest samples for plasma glucose and serum insulin. Analysis of predictive factors for progression to diabetes or reversion to normal glucose tolerance was undertaken using year 0 as baseline. RESULTS: By year 4, 72 subjects (82.8%) completed the study Of the 32 subjects in the trIGT group, none (0%) had progressed to NIDDM, 11 (34.4%) had reverted to IGT (N-IGT), and 21 (65.6%) had persisted with normal glucose tolerance (N-N); of the 40 subjects in the pIGT group, 16 (40%) had progressed to NIDDM (IGT-D), 17 (42.5%) had persisted with IGT (IGT-IGT), and 7 (17.5%) had reverted to normal glucose tolerance (IGT-N). Significant predictive factors for reversion to normal glucose tolerance included absence of obesity (P = 0.0131, odds ratio [OR] 4.2, 95% CI 1.4-13.1) and 2-h plasma glucose level (P = 0.027, OR 2.4, 95% CI 1.11-5.13) at baseline (year 0). Intergroup (cross-sectional) analysis showed that the serum insulin response was higher in the pIGT than in the trIGT subgroup (fasting serum insulin: IGT-N vs. N-IGT and N-N, 16.9 +/- 1.9 vs. 6.8 +/- 2.1 and 6.1 +/- 2.4 microU/ml, respectively, P < 0.001; 2-h postload serum insulin: IGT-IGT vs. N-IGT, 116.8 +/- 2.2 vs. 60.3 +/- 1.7 microU/ml, P < 0.05). By contrast, the insulinogenic index was higher in the trIGT subgroups both at year 1 (90-min: N-N vs. IGT-D, 48.9 +/- 3.9 vs. 14.1 +/- 2.5; P < 0.05) and at year 4 (N-N vs. remaining four subgroups, P < 0.01 at 60 min and 90 min). Intragroup (prospective) comparisons showed that in the N-IGT subgroup, the mean 2-h insulinogenic index was lower at year 4 than at year 1 (19.9 +/- 1.7 vs. 66.0 +/- 2.7; P < 0.05). CONCLUSIONS: In this 4-year prospective study in South African Indians, transient IGT carries no risk of progression to NIDDM. The significant predictive factors for reversion to normal glucose tolerance include lower baseline obesity prevalence and 2-h postload plasma glucose level. Moreover, in this group, beta-cell secretory function appeared to deteriorate with worsening of glucose tolerance.

Adult↗
PubMed1979

Dose-response studies on tolerance to multiple doses of secobarbital and methaqualone in a polydrug abuse population.

Patients from a polydrug abuse treatment program were titrated with either secobarbital or methaqualone, their primary drug of abuse, to a state of mild intoxication, consisting of lateral and vertical nystagmus, ataxia, slurred speech, and drownsiness. The mean dose required to produce each sign was compared to that determined in a similarly treated control group. Tolerance to secobarbital was more easily demonstrated than tolerance to methaqualone, and nystagmus was the least sensitive indicator of patient tolerance. The individual signs were also cumulated into a graded rating scale of central nervous system depression which would be related to the dose administered. Tolerence was easily demonstrated at the higher stages of toxicity for secobarbital in the overall patient population, but tolerance to methaqualone was only unequivocal in the subjects indicating a relatively high frequency of abuse. Tolerance to methaqualone occurred at the lower stages of toxicity, suggesting that there is a difference between tolerance to secobarbital and tolerance to methaqualone. There was no indication that patients who also abuse alcohol are more tolerant than their patient counterparts. The patients who also had a history of amphetamine abuse, however, were less tolerant than the nonusers of these drugs.

Adolescent↗
PubMed2003

Infectious nickel tolerance: a reciprocal interplay of tolerogenic APCs and T suppressor cells that is driven by immunization.

Previously, we reported that tolerance to nickel, induced by oral administration of Ni(2+) ions, can be adoptively transferred to naive mice with only 10(2) splenic T cells. Here we show that 10(2) T cell-depleted spleen cells (i.e., APCs) from orally tolerized donors can also transfer nickel tolerance. This cannot be explained by simple passive transfer of the tolerogen. The APCs from orally tolerized donors displayed a reduced allostimulatory capacity, a tolerogenic phenotype, and an increased expression of CD38 on B cells. In fact, it was B cells among the APCs that carried the thrust of tolerogenicity. Through serial adoptive transfers with Ly5.1(+) donors and two successive sets of Ly5.2(+) recipients, we demonstrated that nickel tolerance was infectiously spread from donor to host cells. After the transfer of either T cells or APCs from orally tolerized donors, the spread of tolerance to the opposite cell type of the recipients (i.e., APCs and T cells, respectively) required recipient immunization with NiCl(2)/H(2)O(2). For the spread of tolerance from a given donor cell type, T cell or APC, to the homologous host cell type, the respective opposite cell type in the host was required as intermediate. We conclude that T suppressor cells and tolerogenic APCs induced by oral administration of nickel are part of a positive feedback loop that can enhance and maintain tolerance when activated by Ag associated with a danger signal. Under these conditions, APCs and T suppressor effector cells infectiously spread the tolerance to naive T cells and APCs, respectively.

Administration, Oral↗
PubMed2004

Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants.

Transplantation tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This tolerance is donor Ag specific and depends on a population of CD4(+) regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2E(k), to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-beta. The nondepleting anti-CD4 mAb was also able to induce tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-beta. As in conventional mice, acquired tolerance was dominant, such that naive monospecific T cells were not able to override tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-gamma and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)(+) CD25(+) T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining transplantation tolerance after CD4 Ab blockade can be induced de novo through a TGF-beta-dependent mechanism, and come to accumulate in tolerated grafts.

Amino Acid Sequence↗
PubMed2005

Orally tolerized T cells can form conjugates with APCs but are defective in immunological synapse formation.

Oral tolerance is systemic immune hyporesponsiveness induced by the oral administration of soluble Ags. Hyporesponsiveness of Ag-specific CD4 T cells is responsible for this phenomenon. However, the molecular mechanisms underlying the hyporesponsive state of these T cells are not fully understood. In the present study, we investigated the ability of orally tolerized T cells to form conjugates with Ag-bearing APCs and to translocate TCR, protein kinase C-theta (PKC-theta), and lipid rafts into the interface between T cells and APCs. Orally tolerized T cells were prepared from the spleens of OVA-fed DO11.10 mice. Interestingly, the orally tolerized T cells did not show any impairment in the formation of conjugates with APCs. The conjugates were formed in a LFA-1-dependent manner. Upon antigenic stimulation, the tolerized T cells could indeed activate Rap1, which is critical for LFA-1 activation and thus cell adhesion. However, orally tolerized T cells showed defects in the translocation of TCR, PKC-theta, and lipid rafts into the interface between T cells and APCs. Translocation of TCR and PKC-theta to lipid raft fractions upon antigenic stimulation was also impaired in the tolerized T cells. Ag-induced activation of Vav, Rac1, and cdc42, which are essential for immunological synapse and raft aggregation, were down-regulated in orally tolerized T cells. These results demonstrate that orally tolerized T cells can respond to specific Ags in terms of conjugate formation but not with appropriate immunological synapse formation. This may account for the hyporesponsive state of orally tolerized T cells.

Administration, Oral↗
PubMed2006

Inhalation tolerance is induced selectively in thoracic lymph nodes but executed pervasively at distant mucosal and nonmucosal tissues.

Under immunogenic conditions, both the site of initial Ag exposure and consequent T cell priming in specific draining lymph nodes (LNs) imprint the ensuing immune response with lasting tissue-selective tropism. With respect to immune tolerance, whether the site of tolerance induction leads to compartmentalized or, alternatively, pervasive tolerance has not been formally investigated. Using a murine model of inhalation tolerance, we investigated whether the induction of respiratory mucosal tolerance precludes the development of de novo Th2 sensitization upon subsequent exposure to the same Ag at distant mucosal (gut) and nonmucosal (cutaneous) sites. By tracking the proliferation of CFSE-labeled OVA-TCR transgenic CD4(+) T cells upon OVA inhalation in vivo, we defined the site of tolerance induction to be restricted to the thoracic LNs. Expectedly, inhalation tolerance prevented de novo Th2 sensitization upon subsequent exposure to the same Ag at the same site. Importantly, although gut- and skin-draining LNs were not used during tolerance induction, de novo Ag-specific proliferation and Th2 differentiation in these LNs, as well as memory/effector Th2 responses in the gut (allergic diarrhea) and skin (late-phase cutaneous responses) were inhibited upon immunogenic challenge to the same Ag. Interestingly, this pervasive tolerogenic phenotype was not associated with the presence of suppressive activity throughout the lymphatics; indeed, potent suppressive activity was detected solely in the spleen. These data indicate that while inhalation tolerance is selectively induced in local thoracic LNs, its tolerogenic activity resides systemically and leads to pervasive immune tolerance in distant mucosal and nonmucosal sites.

Administration, Cutaneous↗
PubMed1999

Ontogeny of rapid tolerance to the hypnotic effects of ethanol.

BACKGROUND: Alcohol use typically begins during adolescence. Little is known regarding the antecedents and impact of this early alcohol use, although age-related changes in the neural systems modulating alcohol sensitivity could contribute to the propensity of adolescents to consume alcohol. We have previously observed a marked ontogenetic decline in acute tolerance to ethanol (EtOH), with preweanling pups exhibiting the most acute tolerance (Silveri and Spear, 1998). The objective of this study was to assess whether rapid tolerance shows a similar ontogenetic profile. METHODS: In Experiment I of the present study, female and male Sprague-Dawley preweanling rats at postnatal day (P) 16 or young adults at P56 were examined. On Day 1, preweanlings were pretreated with saline, 1.5, 3.5, or 5.0 g/kg EtOH and adults were pretreated with saline or 3.5 g/kg EtOH. This was followed by challenge with 3.5 g/kg EtOH and assessment of ethanol-induced sleep time on Day 2. In Experiment II, adolescents at P36 were pretreated with saline, 3.5, or 5.0 g/kg EtOH on Day 1 before Day 2 assessment of sleep time after 3.5 g/kg EtOH. Upon awakening, animals were killed and whole brains removed and analyzed for brain alcohol levels (BrALs). RESULTS: Rapid tolerance was observed in P36 and P56 animals, with EtOH-pretreated animals exhibiting significantly shorter sleep times than age-matched animals treated with saline. In contrast, no evidence for rapid tolerance was seen after any pretreatment dose at P16. Interestingly, although EtOH-pretreated adults woke at higher BrALs than saline-treated adults, this pattern was not evident in the adolescents, which suggests that at this age, metabolic tolerance may play a prominent role in the expression of rapid tolerance. Thus, it seems as though the ability to develop rapid tolerance to EtOH hypnosis emerges during adolescence and continues into adulthood. CONCLUSIONS: Together with previous findings that adolescent animals also display substantial acute tolerance to alcohol (Silveri and Spear, 1998), the propensity of adolescents for developing these two forms of tolerance may have important implications for the increased voluntary consumption of alcohol at this age relative to other ages.

Age Factors↗
PubMed2000

Endothelin receptor antagonism does not prevent the development of in vivo glyceryl trinitrate tolerance in the rat.

There is evidence that increased endothelial production of endothelin-1 (ET-1) may contribute to glyceryl trinitrate (GTN) tolerance. We used the competitive ET(A) receptor antagonist ZD2574 to determine whether chronic ET(A) receptor blockade affected the biochemical and functional responses to GTN during the development of GTN tolerance in vivo. Tolerance induced using transdermal GTN patches resulted in a 5.3 +/- 1.2-fold increase in the EC(50) value for GTN relaxation in isolated aorta from GTN-tolerant rats. Coadministration of ZD2574 (100 mg kg(-1) t.i.d. for 3 days) during tolerance induction had no effect on GTN-induced relaxation. This dose of ZD2574 markedly blunted the pressor response to ET-1, indicating effective blockade of ET(A) receptors, and also abolished the initial transient depressor response to ET-1, indicating that blockade of endothelial ET(B) receptors also occurred using this dosage regimen for ZD2574. Consistent with the relaxation data, coadministration of ZD2574 had no effect on the decrease in GTN-induced cGMP accumulation or on the decrease in GTN biotransformation that occurred in aortae from GTN-tolerant animals. Radioimmunoassay data indicated that the GTN tolerance induction protocol caused a 2.3 +/- 0.4-fold and a 2.2 +/- 0.5-fold increase in total tissue ET-1 levels in tolerant aorta and vena cava, respectively. These data suggest that chronic inhibition of ET receptors by ZD2574 was not sufficient to prevent or diminish the tolerance-inducing effects of GTN, and that the increase in ET-1 levels observed in tolerant tissues may occur as a consequence of the vascular changes that occur during chronic GTN exposure.

Animals↗
PubMed2000

[Induction of skin immune tolerance of mouse to rat xenogeneic transplantation].

OBJECTIVE: To explore a moderate and effective project which will be clinically suitable to induce donor-specific tolerance across xenogeneic barriers. METHODS: 4 x 10(7) Lewis rat bone marrow cells were infused to 300 rad total body irradiated (TBI) C57BL/6 (B6) mice, combined with intraperitoneal administration of cyclophosphamide (CTX) and intravenous injection of anti-mouse CD4 monoclonal antibody. Recipient B6 mice were characterized for the tolerance status with donor Lewis rat skin graft, mixed lymphocyte reaction (MLR), and delayed-type hypersensitivity (DTH) assays after 30 days. Adoptive transfer and the effect of IL-2 on MLR were detected to further explore the tolerance mechanism. RESULTS: Survival time of donor rat skin grafts was specifically prolonged in the tolerant B6 mice. The results of MLR and DTH assays showed donor-specific hyporeactivity, while the tolerant B6 mice were still immunocompetent to MHC-disparate third party BALB/c mouse or DA rat stimulator cells. CONCLUSIONS: A reliable xenogeneic transplantation tolerance of mouse to rat was achieved by this project of tolerance induction. The result of in vitro and in vivo adoptive transfer of spleen cells from tolerant B6 mice demonstrated that the suppressor cells were unlikely to exert effect in the tolerance. The inhibition of specific MLR could be reversed by adding IL-2, indicating that clonal anergy instead of clonal deletion is responsible for the tolerant maintenance.

Animals↗
PubMed2004

Opioid tolerance: is there a dialogue between glutamate and beta-arrestin?

Opioids are widely used as analgesics in clinical pain management for decades. However, opioid tolerance is a serious problem which limits their usefulness. The mechanisms of opioid tolerance are complex which involve many regulatory factors. Glutamate is an important extracellular neurotransmitter which activates glutamate receptor and induces a series of signal transduction to regulate the development of opioid tolerance. Previous studies have indicated an involvement of NMDA receptors in the development of beta-opioid tolerance and associated abnormal pain sensitivity. Many NMDA receptor antagonists had been demonstrated to regulate morphine tolerance development. In the NMDA-mediated intracellular mechanisms of opioid tolerance, protein kinase C (PKC) modulates beta-opioid receptor activation. Besides, the opioid receptor desensitization involves phosphorylation of receptors and subsequent binds to beta-arrestin. In knockout mice, lacking beta-arrestin-2, desensitization of beta-opioid receptor did not occur after chronic morphine treatment, and these animals also failed to develop antinociceptive tolerance. Moreover, morphine tolerance can be completely reversed with a low dose of the classical PKC inhibitor chelerythrine in the beta-arrestin-2 knock-out, but not wild-type mice. These findings indicate that, in the absence of beta-arrestin-2, contributions of PKC-dependent regulatory system would become apparent. In summary, PKC is regulated by NMDA receptors to affect the development of opioid tolerance, beta-arrestin-2 also influences PKC-induced opioid receptor desensitization. PKC may play an important role to coordinate these factors which regulate opioid tolerance.

Amino Acid Transport System X-AG↗
PubMed1991

Effect of cyclo(Leu-Gly) on cyclic GMP-phosphodiesterase activity changes associated with development of tolerance to morphine-induced antinociception, catalepsy, respiratory depression and mydriasis.

A biochemical basis for the development of tolerance to morphine has yet to be defined. Although a number of models have been proposed, none can account for complete tolerance to this drug. Previous studies in our laboratory indicated that the development of complete tolerance to certain morphine-induced behaviors (antinociception, catalepsy and respiratory depression) is associated with changes in the activity of some form(s) of phosphodiesterase with cyclic GMP as substrate (cGMP-PDE) activity in the brain areas that mediate these behaviors (periaqueductal gray, striatum and medulla). In the present study, experiments were performed in which Cyclo(Leu-Gly), a dipeptide that inhibits the development of tolerance to morphine, was administered daily (2 mg/kg) to morphine-naive rats, coadministered with morphine or coadministered with morphine to morphine-tolerant rats and the cGMP-PDE activity was measured. The development of tolerance to the effects was inhibited or reversed by administration of cyclo(Leu-Gly) and there were corresponding changes in cGMP-PDE activity in various brain regions. Differences in cGMP hydrolysis between brain regions from morphine-tolerant animals, tolerance-inhibited animals and tolerance-reversed animals strengthens the evidence for direct involvement of cGMP-PDE(s) in tolerance phenomena.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1990

The regulatory effects of cytokines on the induction of a peripheral immunologic tolerance in mice.

Previous reports have demonstrated that injection of rIL-1 alpha into mice abrogates the ability of deaggregated human gamma-globulin (HGG) to induce a state of antigen specific immunologic tolerance in vivo. Our results demonstrate that human rIL-1 beta and a bioactive nonapeptide of human IL-1 beta inhibit the induction of tolerance to HGG suggesting that IL-1 affects tolerance induction through a noninflammatory mechanism of action because the immunoactive nonapeptide possesses only immunomodulatory properties. Further, TNF-alpha but not IL-6, cytokines with many bioactivities in common with IL-1, was found to inhibit the induction of tolerance. Therefore, it appears unlikely that IL-6 plays a role in the pathway by which either IL-1 or TNF-alpha interferes with tolerance induction. Although IL-2, IL-4, and IFN-gamma were incapable of directly affecting the induction of tolerance to HGG, it was determined that IL-4 and IFN-gamma were capable of inhibiting the ability of IL-1 to abrogate tolerance induction. It has been suggested that IL-1 induces the generation of endogenous IL-1 in vivo. Further, it has been demonstrated that IFN-gamma as well as IL-4 inhibits the synthesis of IL-1. Inasmuch as IL-4 and IFN-gamma inhibit the ability of IL-1 to abrogate tolerance induction, it appears that it is the endogenously generated IL-1 that interferes with tolerance induction. It was also determined that neither IL-4 nor IFN-gamma inhibits the activity of IL-1 which is consistent with results reported by others. Thus, results presented here suggest that the inhibition of tolerance induction to HGG by IL-1 may involve the stimulation of endogenous IL-1 synthesis.

Amino Acid Sequence↗
PubMed1991

Genotype influences the development of tolerance to nicotine in the mouse.

Previous studies have demonstrated that chronic infusion of DBA/2 inbred mice with nicotine results in a dose- and time-dependent tolerance to many of the effects elicited by a challenge dose of nicotine. This tolerance was paralleled by increases in the number of brain nicotinic receptors measured with L-[3H]nicotine and alpha-[125I]bungarotoxin binding, suggesting that receptor up-regulation may underlie tolerance to nicotine. The studies reported here assessed the development of tolerance to nicotine in five inbred mouse strains that differ markedly in sensitivity to acute doses of nicotine. Mice were infused with nicotine doses ranging between 0 and 6 mg/kg/hr for 10 days and were tested for sensitivity to nicotine using several tests 2 hr after infusion was stopped. Some mouse strains, such as the C57BL/6, developed tolerance to nicotine, as measured by shifts to the right of dose-response curves, at the lowest infusion doses, whereas other strains, such as the C3H/2 and BUB, did not develop measurable tolerance until the highest infusion doses were used. A correlation between sensitivity to acute nicotine treatment and the threshold for tolerance development was observed, suggesting that tolerance develops only after a physiological effect is elicited. All of the mouse strains exhibited a dose-dependent increase in nicotine binding in all brain regions; no marked strain differences were seen in up-regulation of this binding site. Chronic nicotine infusion also evoked increases in alpha-bungarotoxin binding, but higher doses were required to elicit this effect. Changes in this binding site were observed after treatment with nicotine doses that elicited tolerance in those mouse strains that are more resistant to an acute dose of nicotine. These results indicate that the relationship between tolerance development and brain nicotinic receptor up-regulation may not be simple.

Animals↗
PubMed1987

Modulation of the induction and circumvention of immunological tolerance to human gamma-globulin by interleukin 1.

As with agents capable of causing the release of IL 1, IL 1 itself is capable of modulating certain tolerance-inducing events. Under the condition used in the present study, it previously has been firmly established that injection of A/J mice with DHGG induces a state of antigen-specific tolerance in both T helper (Th) and B cells. The tolerance in the B cell is of long duration, whereas that in the B cell is of shorter duration. Recombinant IL 1 (rIL 1) given shortly after the tolerogen DHGG results in the inhibition of the induction of tolerance resulting in antibody production. The induction of tolerance is inhibited at both its antigen-specific Th cell and B cell levels, although the latter may be caused by the former. The inhibition of the induction of tolerance by rIL 1 is not correlated to the generation of antigen-specific T suppressor cells. IL 1 mimics lipopolysaccharide and 8-bromoguanosine, which generate IL 1 production, in its ability to interfere with the in vivo induction of tolerance. However, in contrast to these latter mitogens which cause both terminal differentiation of B cells and IL 1 production, IL 1 itself does not cause in vivo circumvention of long-term tolerant Th cells in the presence of competent B cells and antigen. These latter findings suggest that a signal(s) in addition to those delivered by IL 1 is required for activation of the B cell compartment recovering from tolerance to antibody production. AHGG (immunogen) is a potent generator of IL 1 release, whereas DHGG has no effect on IL 1 release from macrophages and AHGG inhibits the induction of tolerance by DHGG. These latter results suggest that the lack of an IL 1 signal may be responsible for the deliverance of a tolerogenic rather than an immunogenic signal to the Th cell.

Animals↗
PubMed1988

Proinsulin, insulin, and C-peptide in cystic fibrosis after an oral glucose tolerance test.

The beta-cell response to an oral glucose load was studied in 22 patients with cystic fibrosis (CF) by means of insulin, C-peptide and proinsulin, and the results compared with those from 20 healthy sex and age matched controls. According to WHO criteria two had diabetes mellitus, eight had impaired glucose tolerance and twelve had normal glucose tolerance. All patients showed lower insulin and C-peptide levels than the controls at 30 minutes. However the insulin and C-peptide responses were sustained so that the areas under the curves were comparable between controls, CF patients with normal glucose tolerance, and CF patients with impaired glucose tolerance. By contrast, the area under the proinsulin curve was significantly higher in the CF patients with impaired glucose tolerance compared with both controls (p less than 0.05) and with the CF normal glucose tolerance group (p less than 0.02). In the CF patients with impaired glucose tolerance the proinsulin level was significantly elevated at 120 minutes (median 50 pmol/l) and at 180 minutes (29 pmol/l) as compared with the controls (24 and 19 pmol/l p less than 0.01) and with the CF patients with normal glucose tolerance (21 and 16 pmol/l p less than 0.01). These data confirm that impaired glucose tolerance and diabetes is frequent in cystic fibrosis. The elevated proinsulin immunoreactive material in CF patients with impaired glucose tolerance may partly compensate for the relative insufficient insulin response found in these patients.

Adolescent↗