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PubMed2001

A role for TGFbeta and B cells in immunologic tolerance after intravenous injection of soluble antigen.

BACKGROUND: Intravenous injection of soluble antigen has been reported to induce immunologic tolerance through a variety of mechanisms including T-cell deletion, anergy, and suppression. To clarify the reported discrepancies, we studied mechanisms of intravenous tolerance to a defined transgenic minor transplantation antigen in mice. METHODS: Wild-type C57BL/6 (B6) mice or congenic B6 B-cell knockout mice were made tolerant to beta-galactosidase (beta-gal). Clinical tolerance was assessed by placement of B6 beta-gal transgenic (tg) and third-party skin grafts. In vitro analysis of T- and B-cell immunity and in vivo treatment with anti-TGFbeta antibodies were used to define mechanisms of induced tolerance. RESULTS: Intravenous injection of beta-gal induced true immunologic tolerance to beta-gal tg skin in wild-type but not in B-cell-deficient recipients, suggesting that antigen presentation by B cells was required for the effect. The tolerogenic manipulation primed a population of CD4+, beta-gal-specific, TGFbeta-producing T cells. Although evidence for both anergy and suppression were observed, subsequent data demonstrated that TGFbeta was a critical immunoregulatory mediator of the tolerant state: neutralizing anti-TGFbeta antibodies fully prevented the induction of tolerance to B6 beta-gal tg skin grafts. Second male beta-gal tg grafts placed onto female recipients that were previously made tolerant to female beta-gal tg skin were rapidly rejected, however, suggesting that this TGFbeta-induced tolerance could not be linked to additional antigenic determinants. CONCLUSIONS: The studies demonstrate a critical role for TGFbeta in mediating tolerance after intravenous injection of antigen but additionally raise concerns about the stability of this tolerant state.

Animals↗
PubMed2000

Suppression of Cox-2 and TNF-alpha mRNA in endotoxin tolerance: effect of cycloheximide, antinomycin D, and okadaic acid.

Lipopolysaccharide (LPS)-tolerant human promonocytic THP-1 cells produce decreased levels of inflammatory mediators such as eicosanoids and tumor necrosis factor alpha (TNFalpha) in response to LPS. We hypothesized that transcriptional repression by newly synthesized proteins may be a mechanism for the reduced cellular response to a secondary challenge with LPS. THP-1 cells were desensitized after a 3.5 h or 20 h pre-exposure to LPS (1 microg/mL) and subsequently challenged with LPS (10 microg/mL). In cells rendered tolerant by exposure to LPS for 20 h, LPS-induced expression of cyclooxygenase (Cox)-2 and TNFalpha mRNA was suppressed. Cycloheximide (10 microM) prevented the transcriptional down-regulation of Cox-2 mRNA and to a lesser extent, TNFalpha mRNA, in LPS-tolerant cells. Transcriptional arrest with actinomycin D stabilized steady-state expression of Cox-2 mRNA in naive and tolerant cells but destabilized TNFalpha mRNA expression in LPS-tolerant cells. The observation that in naive cells Cox-2 and TNFalpha mRNA levels subside at 3 to 4 h after LPS (10 microg/mL or 1 microg/mL) suggested that LPS tolerance may occur earlier. Therefore, in subsequent experiments, the effect of LPS pretreatment for only 3.5 h was examined. This abbreviated tolerance regimen diminished secondary LPS-induced Cox-2 mRNA expression but had a lesser effect on TNFalpha mRNA expression. However, cycloheximide augmented both Cox-2 and TNFalpha mRNA expression in this group. Also, the serine/threonine phosphatase inhibitor okadaic acid augmented Cox-2 and TNFalpha mRNA expression in the LPS-tolerant cells. Although LPS-induced TNFalpha production in LPS-tolerant cells was suppressed relative to the naive cells, okadaic acid induced comparable levels of TNFalpha in tolerant and naive cells. These findings support the concept that LPS tolerance is associated with induction of proteins that alter expression of certain genes. Expression of Cox-2 mRNA appears to be particularly sensitive to down-regulation and, to a lesser extent, TNFalpha mRNA. However, this seems to vary depending on the LPS pretreatment regimen. The ability of a phosphatase inhibitor to induce TNFalpha and expression of Cox-2 and TNFalpha mRNA in LPS tolerance suggests that there may be alterations in phosphorylation status of signaling pathways, transcriptional mechanisms, or post-transcriptional mRNA stability.

Cycloheximide↗
PubMed2004

The effects of NMDA and GABAA pharmacological manipulations on acute and rapid tolerance to ethanol during ontogeny.

BACKGROUND: Sensitivity to several ethanol effects increases during ontogeny, perhaps in part because of a notable decline in acute tolerance. In contrast, rapid tolerance to ethanol-induced sedation emerges slowly during ontogeny. This study tested the hypothesis that ontogenetic differences in glutamate and/or gamma-aminobutyric acid systems influence tolerance expression. METHODS: Sprague-Dawley rats at postnatal day (P)26 or P70 received (+)MK-801, muscimol, or saline before ethanol (3.5 or 4.5 g/kg) or saline on day 1 and ethanol only on day 2. Loss of and time to regain the righting reflex and blood alcohol levels at recovery were recorded. The presence of acute tolerance was indicated as a positive slope of the linear regression of blood alcohol levels at recovery versus ethanol dose. Rapid tolerance was estimated on day 2 by comparing animals given ethanol only on day 2 with those given ethanol on both days. RESULTS: Acute tolerance on day 1 only was observed at P26; this was disrupted by (+)MK-801 but not muscimol. Evidence for acute tolerance also emerged in adults on day 2. Whereas both drugs increased ethanol sedation at both ages, they did not facilitate ontogenetic expression of rapid tolerance: rapid tolerance was not evident at P26 regardless of pretreatment when indexed in terms of recovery time. CONCLUSIONS: These data provide further evidence for an ontogenetic dissociation in the expression of acute and rapid tolerance to ethanol-induced sedation. Pharmacological attenuation of the expression of acute tolerance was sufficient but not necessary to delay recovery of righting after ethanol. The greater propensity of young animals to develop acute tolerance, seemingly modulated in part by NMDA receptors, may contribute to their relative resistance to ethanol, although other factors, including pharmacokinetic factors, also contribute to their more rapid recovery from ethanol sedation.

Aging↗
PubMed1980

Suppressor cells and their precursors in A/J mice, tolerant to heterologous gamma globulin.

The role of suppressor cells and of their precursors was examined in A/J mice, immunized or tolerized-immunized with rabbit gamma globulin. Antibody response and tolerance were assessed by antigen elimination, followed by an indirect plaque-forming assay. Reconstitution experiments were performed to estimate loss of cooperative capacity in thymus and spleen cells. Infectious tolerance was examined by reconstitution with mixtures of spleen or thymus cells of normal and tolerant donors. Infectious tolerance could not be detected after neonatally induced tolerance. It could be detected when tolerance was induced 11-16 days after birth. Under these circumstances, loss of cooperative capacity and increased capacity for infectious tolerance occurred rapidly over the first 2 days and reached completion by the 10th-20th day after administration of tolerogen. Thymectomy, after tolerance induction, resulted in relative recovery of responsiveness of spleen cells and loss of capacity for infectious tolerance. Pretreatment with cyclophosphamide resulted in a less profound state of unresponsiveness and in the disappearance of the capacity for infectious tolerance. Simultaneous treatment with tolerogen and colchicine also resulted in a less profound state of tolerance. This effect of colchicine was more profound when a low dose of tolerogen was used or when animals were thymectomized before administration of tolerogen and colchicine.

Animals↗
PubMed2005

Suppression extends to major histocompatibility antigens linked to tolerizing minor histocompatibility antigens, but not the other way round.

'Active suppression', a mechanism of transplantation tolerance, can spread to newly introduced minor antigens once these antigens are linked to tolerizing antigens. We explored whether this suppression can extend to major histocompatibility (MHC) antigens and whether this phenomenon can be demonstrated once tolerance is induced to a MHC antigen. Mice were tolerized using donor bone marrow plus CD4 and CD8 monoclonal antibodies. The following strain combinations were used: AKR (H-2k) into CBA (H-2k), a multiple minor difference and B6 (H-2b) into B6(bm12) (H-2b), a MHC class II difference. Tolerance was tested by a donorskingraft. CBA mice tolerant to AKR received a second skin carrying either AKR antigens plus additional multiple minor antigens [F1(AKRxBalb.K)] or carrying additional minors and a MHC class I antigen (B10.AKM-H2M). B6(bm12) (H-2b) tolerant to B6 (H-2b) were grafted with skin from a Balb.B donor (Balb minors linked to the tolerizing class II antigen) or from a B10.A(3R) strain (a MHC class I antigen linked to the tolerizing class II antigen). CBA mice tolerant to AKR accepted F1(AKRxBalb.K) skin, whereas F1(CBAxBalb.K) were rejected. Rejection of B10.AKM/H2M skin by tolerant mice was delayed as compared with nontolerant mice. Tolerant and nontolerant B6(bm12) mice rejected Balb.B skin and B10.A(3R) skin within the same time. Thus, in this model, suppression was linked to minors. Alloreactivity against minors and majors could be suppressed. Suppression linked to a class II antigen could not be demonstrated.

Animals↗
PubMed2005

Induction of immune tolerance across major histocompatibility complex barrier by transfusion of ultraviolet B-irradiated immature dendritic cells.

BACKGROUND: Transfusion of ultraviolet B (UVB)-irradiated peripheral blood mononuclear cells (PBMNCs) induces immunologic tolerance across the major histocompatibility complex (MHC) barrier in a murine model. It is necessary, however, to reduce contaminating platelets (PLTs) to a minimum. Ex vivo preparation of dendritic cells (DCs) offers an opportunity to rid the contaminating PLTs. The use of immature and mature DCs (iDCs and mDCs) with and without UVB irradiation for tolerance induction was therefore investigated. STUDY DESIGN AND METHODS: iDCs and mDCs were prepared by culture of Balb/c (H-2d) mouse marrow cells in the presence of granulocyte-macrophage-colony-stimulating factor and interleukin-4. Different dose schedules of iDCs were tested for tolerance induction in CBA (H-2k) mice. Tolerance induction by UVB-irradiated iDCs and mDCs was compared. Tolerance induction in two additional strains of mice (C3H and C57BL/6) was also studied. The induction of tolerance was tested by challenging transfusions of treated mice with PBMNCs from the donor strain. The induction of negative regulatory CD4+ T cells in tolerized mice was examined. RESULTS: Four weekly transfusions of 5 x 10(4) UVB-irradiated iDCs from Balb/c mice efficiently induced immune tolerance in CBA and C3H mice. iDCs and mDCs without UVB irradiation could not induce immune tolerance. Tolerance induced by transfusions of UVB-irradiated iDCs was associated with the development of CD4+-regulatory T cells as demonstrated by an adoptive transfer study. CONCLUSION: Transfusion of UVB-iDCs induces immune tolerance across the MHC barrier in certain combinations of mouse strains. The results support the idea that iDCs irradiated with UVB may be applied to induce immune tolerance across the MHC barrier.

Animals↗
PubMed2006

Increasing donor chimerism and inducing tolerance to islet allografts by post-transplant donor lymphocyte infusion.

Inducing donor chimerism is the most consistently successful approach to achieve transplant tolerance. We found that a low level of donor chimerism, which was induced by a relatively non-toxic approach, induced donor-specific tolerance to islet allografts in chemically induced diabetic mice. However, a similar level of donor chimerism could not protect donor islet allografts in non-obese diabetic (NOD) mice that spontaneously developed autoimmune diabetes. Rejection of donor islet allografts in diabetic NOD mice with a low level of donor chimerism was mediated by recurrent autoimmunity. We used post-transplant donor lymphocyte infusion (DLI) to increase donor chimerism and to induce tolerance to islet allografts. DLI significantly increased donor chimerism and promoted donor-specific tolerance to islet allografts in diabetic NOD mice. Self-tolerance to islet autoantigens was restored and restoring self-tolerance is mediated by immunoregulation. Thus, our data showed that adoptive immunotherapy with post-transplant DLI after establishing a low level of donor chimerism as a platform enhances donor chimerism, induces donor-specific tolerance to islet allografts and restores self-tolerance in the setting of autoimmune diabetes. Our data also showed that central tolerance is not sufficient to induce tolerance and peripheral tolerance through immunoregulation for restoring self-tolerance is required in the setting of autoimmune diabetes.

Adoptive Transfer↗
PubMed1975

Laeve-[1-3H]Methadone disposition in tolerant dogs.

1. Following a subcutaneous dose (4mg/kg) of [3H]methadone, peak levels of drug occurred in plasma, tissues and selected areas of the central nervous system (CNS) 2h after injection in both non-tolerant and tolerant dogs. Highest concentrations of methadone were attained in bile and lung compared to other tissues. 2. Levels of methadone in plasma, tissue and CNS of tolerant and non-tolerant animals were not markedly different up to 8h after injection, but a much faster rate of egression of free drug (lower t1/2) was observed subsequently in tolerant dogs. 3. Peak levels of methadone in various areas of the CNS ranged between 2-7 (spinal cord) to 3-6 (thalamus) mug/g in non-tolerant and 3-0 -rebellum) to 4-1 (thalamus) mug/g in tolerant dogs 2h after injection. No marked accumulation of methadone occurred in selected areas of the CNS in spite of the persistence of drug in these areas. 4. The plasma protein electrophoretic profiles did not differ between control, non-tolerant and tolerant dogs. 5. Similar qualitative patterns of metabolites were observed in non-tolerant and tolerant dogs and the development of tolerance did not appear to modify the metabolic pathways of methadone.

Animals↗
PubMed2003

Tolerance and immunity following in utero transplantation of allogeneic fetal liver cells: the cytokine shift.

Although in utero transplantation (IUT) has resulted in donor-specific tolerance to posnatal solid organ transplantation, the mechanisms of this tolerance remain poorly understood. Our recent findings demonstrate that under specific conditions prenatal injection of allogeneic cells may lead to allosensitization instead of tolerance. These laboratory observations were supported by clinical findings as well, and therefore suggested that, depending on the conditions of prenatal transplantation, tolerance or immunity may develop. The present study explored the role of CD4 cells, cytokines, and I-E superantigen in developing tolerance vs. immunity after in utero transplantation. Sixteen animals survived IUT (40-60% survival rate) and were free from any signs of graft-versus-host disease (GVHD). Mice were considered tolerant when their antidonor and antihost CTL responses were similar, sensitized when antidonor responses were significantly higher than antihost and anti-third-party responses, and nontolerant when antidonor responses in transplanted and control mice were similar. The TH1 --> TH2 shift was associated with tolerance and TH2 --> TH1 shift with allosensitization. Our results showed that tolerant BALB/c (H-2d, I-E+) --> CS7BL/6 (H-2b, I-E-) (2/7) mice showed higher IL-4 (p < 0.05) in antidonor MLR, and partial deletion of recipient I-E-reactive T cells (CD3Vbeta11) (p < 0.045). On the other hand, nontolerant animals (5/7) demonstrated high production of IFN-gamma (p < 0.05) without deletion of CD3Vbeta11 T cells. In C57CBL/6 (H-2b, I-E-) --> C3H (H-2k, I-E+) mice CD3Vbeta11 T cells do not play any role in tolerance induction because they are deleted in the C3H background. Tolerant mice (4/9) showed an overproduction of IL-4 (p < 0.05) in antidonor MLR whereas allosensitized animals (5/9) demonstrated high level of IFN-gamma (p < 0.05). Suppressor cells seem to play no role in tolerant C57BL/6 --> C3H as demonstrated by suppressor assay. Hence, a shift from TH1 --> TH2 or TH2 --> TH1 cytokines may determine whether tolerance or immunity develops.

Animals↗
PubMed2002

Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells.

Prior exposure to LPS induces a transient state of cell refractoriness to subsequent LPS restimulation, known as endotoxin tolerance. Induction of LPS tolerance has been reported to correlate with decreased cell surface expression of the LPS receptor complex, Toll-like receptor 4 (TLR4)/MD-2. However, other results have underscored the existence of mechanisms of LPS tolerance that operate downstream of TLR4/MD-2. In the present study we sought to delineate further the molecular basis of LPS tolerance by examining the TLR4 signaling pathway in endotoxin-tolerant cells. Pretreatment of human monocytes with LPS decreased LPS-mediated NF-kappaB activation, p38 mitogen-activated protein kinase phosphorylation, and TNF-alpha gene expression, documenting the induction of endotoxin tolerance. FACS and Western blot analyses of LPS-tolerant monocytes showed increased TLR2 expression, whereas TLR4 expression levels were not affected. Comparable levels of mRNA and protein for myeloid differentiation factor 88 (MyD88), IL-1R-associated kinase 1 (IRAK-1), and TNFR-associated factor-6 were found in normal and LPS-tolerant monocytes, while MD-2 mRNA expression was slightly increased in LPS-tolerant cells. LPS induced the association of MyD88 with TLR4 and increased IRAK-1 activity in medium-pretreated cells. In LPS-tolerant monocytes, however, MyD88 failed to be recruited to TLR4, and IRAK-1 was not activated in response to LPS stimulation. Moreover, endotoxin-tolerant CHO cells that overexpress human TLR4 and MD-2 also showed decreased IRAK-1 kinase activity in response to LPS despite the failure of LPS to inhibit cell surface expression of transfected TLR4 and MD-2 proteins. Thus, decreased TLR4-MyD88 complex formation with subsequent impairment of IRAK-1 activity may underlie the LPS-tolerant phenotype.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Regulatory CD8+ T cells control neonatal tolerance to a Th2-mediated autoimmunity.

Exposure of newborn animals to a foreign Ag may result in immunological tolerance to that specific Ag, a phenomenon called neonatal tolerance. We have previously reported that neonatal administration to Brown-Norway rats of mercury, a heavy metal toxicant, induces a dominant tolerance, specific for the chemical otherwise responsible for Th2 cell-mediated autoimmune responses in this susceptible strain of rats. Neonatal exposure to Ags can prime immunity, rather than inactivate or delete responses, and sustain regulatory functions effective against autoreactive T cells. Here, we address whether such a tolerant response is due to the generation of regulatory cells. The results suggest that the CD8(+) T cell subset is involved in neonatal tolerance to mercuric salt-induced Th2 autoimmune disease. Thus, we demonstrate that in vivo CD8 depletion breaks tolerance following mercury recall in animals under a neonatal tolerance protocol. Furthermore, adoptive cotransfer of splenocytes from naive and tolerant rats as well as transfer of CD8(+) T cells from tolerant animals prevent naive syngeneic rats from developing pathologic Th2 immune responses. These observations indicate that CD8(+) T cells are endowed with regulatory functions in neonatal tolerance and mediate active suppression. Moreover, neonatal tolerance induced the expansion of CD8(+)CD45RC(high) T cells and the emergence of a high percentage of IFN-gamma-synthesizing CD8(+) T cells, which probably reflects the implication of regulatory Tc1 cells. Thus, in vivo induction of neonatal tolerance suppresses Th2 autoimmune responses via generation of a CD8(+) cell-mediated regulatory response.

Adoptive Transfer↗
PubMed1975

Permanent hapten-specific tolerance in B lymphocytes.

Tolerance to the hapten TNP was induced in mice congenic with CBA but bearing the Ig-b allotype (Ig-b mice). To induce a high degree of tolerance it was necessary to give five injections of TNP-sulphonate followed by an immunogenic challenge (alum precipitate of TNP-BSA with pertussis adjuvant). Lymph node or spleen cells from these mice were transferred, with or without an equal number of non-tolerant CBA spleen cells, to irradiated CBA recipients and these were challenged with a different TNP-protein conjugate. Anti-TNP antibody bearing the Ig-b allotype was then assayed separately from total anti-TNP, as a measure of the contributions made by tolerant and non-tolerant B-cell populations respectively. Tolerant lymph node cell did not depress the response of normal cells, nor did the normal cells 'break' the tolerance of the Ig-b population even when the latter had been treated with anti-T-cell serum and complement. No response was obtained from tolerant lymph node cells when the recipients were challenged at different time up to 12 weeks after transfer. By this time the control non-tolerant lymph node cells had also lost the capacity to respond. It is concluded that: (1) effectively permanent tolerance, which is not maintained by afferent mechanisms, can be induced in lymph node B cells; (2) B-cell tolerance can be greatly enhanced by immunogenic challenge; (3) spleen may contain a distinct population of B cells which is less susceptible to tolerance; and (4) the life-span of virgin lymph node B cells is probably less than 12 weeks.

Animals↗
PubMed2006

[Impaired glucose tolerance in patients with acute myocardial infarction].

BACKGROUND: Diabetes and impaired glucose tolerance are associated with increased mortality in patients with acute myocardial infarction. We have used standardised oral glucose tolerance tests shortly after a myocardial infarction. METHODS: 109 patients admitted with acute myocardial infarction were prospectively enrolled in the study. An oral glucose tolerance test was performed the first morning the patients were stable, without pain, nausea or hyperglycaemia. The patients were classified into normal glucose tolerance, impaired glucose tolerance or diabetes, according to the results of the oral glucose tolerance test and fasting plasma glucose levels. RESULTS: 109 patients (25 women) were included. Eight patients were previously diagnosed with diabetes type 2. Oral glucose tolerance was tested for 90 patients, usually the day after admission. The test was positive in 47 patients; 32 of them had 2-h plasma glucose levels between 7.8 and 11.0 mmol/L and were classified as having impaired glucose tolerance, and 15 had 2-h plasma glucose > or = 11.1 mmol/L and were classified as newly diagnosed diabetes patients. Similar body mass indexes and lipid values were found in patients with different glycometabolic states. Smoking was associated with a positive oral glucose tolerance test. INTERPRETATION: More than half of the patients with acute myocardial infarction had undiagnosed impaired glucose tolerance or diabetes type 2, as determined by an oral glucose tolerance test. The test could easily be performed shortly after a myocardial infarction in most of the patients. Oral glucose tolerance testing should be considered in all patients with coronary heart disease without a history of diagnosed diabetes.

Adult↗
PubMed1986

Differential susceptibility of cytotoxic and helper T cell precursors to neonatal tolerization to histocompatibility antigens.

The ability of various (C57BL/6J X CBA/HT6T6)F1 spleen cell subpopulations to induce tolerance to allogeneic histocompatibility antigens after injection into neonatal CBA/HT6T6 mice was examined. The requirements for tolerization of cytotoxic T lymphocyte precursors (CTLp) and IL 2-producing helper T cell precursors (IL 2Tp) appear to be coordinated but not identical. CTLp frequencies measured in limiting dilution analysis (LDA) were found to be decreased by 90 to 99% in mice injected neonatally with unseparated or a variety of semiallogeneic spleen cell fractions, including T cells, T cell-depleted spleen, the Ig+ and Ig- fractions of nylon-adherent, T-depleted spleen cells, Sephadex-G10 (G10)-nonadherent spleen cells, and T-depleted allogeneic C57BL/6J spleen cells. In contrast, IL 2Tp showed tolerization only after neonatal injection of unseparated or T cell-depleted F1 spleen cells, and not after injection of T or B cells or of G10-nonadherent or T-depleted allogeneic spleen cells. These studies show that the CTLp and IL 2Tp compartments have different requirements for neonatal tolerization, which appear to correlate with the presence of cells expressing class I or class II alloantigens in the inoculum: all spleen cell types tested were capable of tolerizing the CTLp compartment, whereas only whole spleen and T-depleted spleen cells could tolerize IL 2Tp; donor T cells, although capable of inducing CTLp tolerance, are not necessary for either CTLp or IL 2Tp tolerance induction; Ig+ B cells alone are marginally effective in tolerization of IL 2Tp, and G10-nonadherent cells are ineffective, suggesting that macrophages or another type of G10-adherent accessory cell may be required for tolerization of IL 2Tp, although it is not clear whether they are sufficient; and tolerization of CTLp can occur in the presence of a normal IL 2Tp compartment when certain inocula, such as T cells, are used for tolerance induction at birth.

Animals↗
PubMed1986

Endotoxin tolerance diminishes endotoxin-induced alterations in carbohydrate kinetics.

This study was designed to determine if attenuated mortality to a challenge dose of endotoxin was accompanied by or separated from alterations in glucose metabolism in endotoxin-tolerant rats. The in vivo effects of endotoxin were studied in catheterized endotoxin-tolerant rats and nontolerant control animals. Tolerance was induced by iv injections of 100 micrograms endotoxin/100 g BW (tolerance dose) for either 2 or 4 consecutive days; control rats received daily saline injections. On the day after the final tolerance dose, glucose kinetics were assessed by the constant infusion of [6-3H]-glucose prior to and after a challenge dose of endotoxin (1,000 micrograms/100 g) in tolerant and nontolerant rats. Following the challenge dose, 2-day tolerant animals exhibited an improved survival at 72 hr (LD 14 vs LD 92), a significantly smaller reduction in mean arterial blood pressure (20 vs 34%), and smaller increases in plasma glucose (9.4 +/- 0.6 vs 11.4 +/- 0.6 mM) and lactate (3.2 +/- 0.3 vs 8.5 +/- 1.4 mM) concentrations, compared to those in nontolerant control rats. However, increases in the rates of glucose appearance (Ra) and metabolic clearance (MCR) were not diminished. In 4-day tolerant rats, lethality to endotoxin was abolished, and no alterations in blood pressure or glucose kinetics were seen during the 4-hr period after endotoxin. However, the basal glucose Ra and MCR determined prior to endotoxin challenge were elevated in these rats compared to controls. Hyperglucagonemia was evident following the endotoxin challenge in control and 2-day tolerant rats, but not in 4-day tolerant animals. The hypothermia seen in nontolerant rats 4 hr after endotoxin was not present in either group of tolerant animals. The results show that after 2 days, tolerant animals have improved survival rates when challenged with endotoxin but still demonstrate acute changes in glucose kinetics. A complete protection against a normally lethal dose of endotoxin exists after 4 days. At this stage, rats showed no transient hemodynamic or metabolic alterations following endotoxin challenge.

Animals↗
PubMed1983

A rapid and simple method for the quantitative determination of tolerance development to opiates in the guinea-pig ileum in vitro.

The rate and degree of tolerance development of morphine, normorphine and methadone were assessed in vitro on the guinea-pig ileum. After the half-maximal concentration to inhibit electrically induced contractions (IC50) for each compound was determined, tolerance to a fixed concentration representing 0.5, 1 or 2 times its IC50 was induced by incubation at 37 degrees C for 1, 2 or 4 hr. The IC50 was then redetermined and the ratio of the IC50 after and before incubation provided a quantitative index of the degree of tolerance development to each agonist. For any given concentration or time, morphine induced the highest, whereas normorphine the intermediate and methadone the lowest degree of tolerance. Tolerance to opiates was associated with some degree of physical dependence as evidenced by the fact that the application of naloxone at the end of each experiment elicited a muscular contraction. Specificity of tolerance development to opiates was demonstrated by several experiments. Coincubation of morphine with naloxone under the same conditions resulted in an inhibition of tolerance development. The stereospecificity of the process was demonstrated by the fact that levorphanol and I-methadone induced a high degree of tolerance, whereas, under the same conditions the less active d-isomers, dextrorphan and d-methadone, did not. Moreover, subsensitivity to acetylcholine, norepinephrine and adenosine monophosphate did not develop in the presence of tolerance to morphine. The validity of this method for investigating mechanisms involved in tolerance and physical dependence was further demonstrated by obtaining data compatible with earlier experiments in vivo that cyclic AMP enhances tolerance development and cycloheximide inhibits this phenomenon. The present method should facilitate studies on the mechanisms involved in opiate tolerance and physical dependence development.

Animals↗
PubMed1983

[Breakfast tolerance test: application to the detection of gestational diabetes].

There is general agreement that diagnosis of diabetes mellitus in pregnancy is requisite but the means of achieving it are still under discussion. The plasma glucose, insulin and C peptide responses to an oral glucose tolerance test were compared with the intravenous glucose tolerance test and a standardized breakfast tolerance test in 26 pregnant women, in order to define a simple diagnostic criterion for gestational glucose intolerance. The results of the oral glucose tolerance test distinguished between a group of 19 normal women and a group of 7 diabetic women with abnormal glucose tolerance tests. The breakfast tolerance test used (84 g carbohydrates, 22,6 g protein, 9,4 g fat, 690 calories) was followed by blood glucose modifications very similar to those observed with the oral glucose tolerance test, but the insulin response was significantly greater. The consistency between the breakfast tolerance and intravenous glucose tolerance tests was confirmed by the existence of correlations between the glucose area of the breakfast tolerance test and the coefficient K in the two groups studied. Our results suggest that the breakfast tolerance test could be as sensitive as the oral glucose tolerance test for detecting glucose intolerance; the most discriminative glycemic value appeared to be that at the 180 th minute, usually under 1 g/l in the normal pregnant women. This test could be proposed as an easy and economic method for diagnosing gestational diabetes. These preliminary results require confirmation by a study in a larger population.

Administration, Oral↗
PubMed1995

Increased severity of experimental autoimmune encephalomyelitis in rats tolerized as adults but not neonatally to a protective TCR V beta 8 CDR2 idiotope.

The ability of synthetic V region peptides to induce regulatory T cells and Abs in rodents and humans provides clear evidence that these idiotopes do not naturally induce tolerance. In this study, we investigated the ability of TCR V beta 8.2 peptides to experimentally induce specific T cell tolerance, as measured by loss of Ag-specific proliferation and delayed-type hypersensitivity responses, and by increased susceptibility to experimental autoimmune encephalomyelitis (EAE). We found that both neonatal and adult exposure to V beta 8.2-39-59 or V beta 8-44-54 peptides could induce efficient T cell tolerance, resulting in a significant inhibition of peptide-specific proliferative responses. In addition, neonatal tolerance resulted in a partial reduction in delayed-type hypersensitivity response and an inability to vaccinate against EAE after adult immunization with the tolerizing peptide. We further evaluated the contribution of naturally induced TCR-specific responses to EAE resistance induced by challenging neonatally or adult tolerized rats with myelin basic protein in adjuvant. The clinical course of EAE was not significantly altered in rats tolerized neonatally to V beta 8.2 peptides, but both the severity and incidence of mortality from EAE was increased in rats tolerized as adults with V beta 8.2 peptides conjugated to syngeneic splenocytes. These results demonstrate that V beta 8.2 peptides are tolerogenic as well as immunogenic. Moreover, the observation of different effects of neonatal vs adult tolerization on the course of EAE suggests either the emergence of additional protective idiotopes after neonatal tolerization and/or mechanistic differences in the two tolerance-inducing protocols. Most importantly, the enhancement of clinical EAE in rats tolerized as adults with V beta 8.2 peptides provides evidence for an innate regulatory role of the CDR2 idiotope in recovery from EAE.

Aging↗