Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Tolerance”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,027 records · Page 57Linked to original sources
PubMed1989

Effect of intermittent exposure and drug-free intervals on the in vitro vascular tolerance to nitroglycerin.

Recent reports suggest that intermittent nitroglycerin (NTG) treatment, incorporating a daily nitrate-free interval, can avoid the tolerance associated with continuous NTG therapy. This study has investigated whether an in vitro model of NTG tolerance could be used to examine the mechanisms of tolerance avoidance (by intermittent NTG exposure) and tolerance reversal. Isolated rat abdominal aortic rings were exposed to 55 microM NTG at varying intervals over a 60 min period, and the concentration-relaxation curves to NTG were subsequently determined. Intermittent NTG exposure (either 12 x 0.5 min or 3 x 2 min) significantly reduced NTG tolerance compared to continuous exposure over the same period of time (60 min). The diminished tolerance was apparently due to the reduced total exposure time, since the NTG responsiveness of aortic rings exposed to NTG intermittently or continuously for 6 min of the incubation period was not significantly different. Under the present conditions, in vitro NTG tolerance could be reversed if sufficient washout time was allowed. Thus, aortic rings exposed to NTG for the initial, but not the final, 6 min of incubation were not tolerant to NTG. In addition, rings exposed to NTG for 3 min exhibited near-maximal tolerance after 5 min washout, but no tolerance after 60 or 120 min washout. It appears, therefore, that the isolated vessel retains the "repair" mechanism responsible for tolerance reversal under the present conditions. This study suggests that the in vitro model of NTG tolerance may be useful for investigating the characteristics and mechanisms of tolerance avoidance and reversal, as well as tolerance induction.

Animals↗
PubMed1995

Modulation of free intracellular calcium levels [(Ca++)i] in brain and spinal cord of morphine-tolerant rats and mice.

Evaluation of the effects of tolerance to morphine in vivo on free intracellular calcium levels [(Ca++)i] in whole brain synaptosomes from rats and synaptosomes from brain regions and spinal cords of both rats and mice indicated that in whole brain and spinal cord synaptosomes, [Ca++]i levels are significantly higher in morphine-tolerant mice. Although levels do not differ between nontolerant and tolerant preparations from the rat spinal cord, [Ca++]i brain levels are significantly higher in morphine-tolerant rats. Evaluation of three brain regions from both nontolerant and tolerant rats and two brain regions from mice indicated no significant differences in basal [Ca++]i, with the exception that lower basal levels of calcium were observed in the midbrain of the tolerant rat. In vivo, mice tolerant to morphine (SC) were cross tolerant to DAMGO (IT and ICV). Cross tolerance between morphine and DAMGO was observed in vitro. No cross-tolerance was observed between morphine (SC) and the delta-agonist, DPDPE (IT or ICV), or the kappa-agonist, U50,488H (U50, IT or ICV) in vivo. Similarly, no cross tolerance was observed between morphine (SC) and DPDPE or U50 in vitro. These data indicate that tolerance in vivo induced a change in synaptosomal calcium modulation such that tolerance could be observed in vitro. Thus, a membrane component may be altered by the development of tolerance to morphine leading to an alteration in [Ca++]i in both the brain and spinal cord.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1985

Neuropeptides differentially effect various forms of morphine tolerance.

Two different forms of tolerance to morphine were shown to develop. One form, environment dependent (ED), was associated with cues paired with the arrival of the drug. The second form of tolerance, environment independent (EI), was not dependent on any cues. ED tolerance was induced using a multiple injection model in which a cue (orange scent) preceeded each morphine injection (ip). After 12 days the animals were tolerant to the i.p. injection. However if morphine was injected i.c.v. tolerance was no longer evident. EI tolerance was induced by a pellet implant method. These animals were tolerant to morphine regardless of the route of administration. Peptides arginine vasopressin (AVP) and cyclo (Leu-Gly) (cLG) were tested for their ability to alter tolerance. AVP was found to facilitate the development of ED tolerance but had no effect on EI tolerance. On the other hand cLG blocked the development of EI tolerance without affecting ED tolerance. The determination of brain morphine levels indicated that the ED tolerance produced by this method is dispositional while EI tolerance is functional.

Animals↗
PubMed2006

A mathematical theory for temporal changes in tolerance to the behavioral effects of alcohol.

Temporal changes in the tolerance to alcohol are rarely discussed. In the behavioral theory proposed here, the rate of increase in tolerance during alcohol exposure is described by linear equations with zero intercept. These equations describe the rate of tolerance growth for acute tolerance, the rate of tolerance growth after alcohol dosing (chronic tolerance), and, for cases in which tolerance has been conditioned, the equations also describe changes in the rate of growth of tolerance when the stimulus set changes. This theory does not explain tolerance acquisition, but may be useful in investigating the physiological basis for tolerance acquisition because it provides numerical values for momentary tolerance that can be compared with concurrent physiological changes. The theory is testable and most of the published behavioral data on non-conditioned tolerance are consistent with the proposed theory. New empirical data on conditioned tolerance are needed to evaluate the proposed theory, and the design for an evaluation is suggested here. Despite its limitations, the theory serves as one example of what a mathematical theory for tolerance might be and may stimulate the development of competing theories with which it could be compared empirically.

Behavior↗
PubMed1996

Islet dysfunction in obese women with impaired glucose tolerance.

Insulin sensitivity and islet function were examined in 22 obese women: 11 with normal glucose tolerance (mean +/- SD body mass index [BMI], 32.2 +/- 2.8 kg/m2) and 11 with impaired glucose tolerance (BMI, 30.1 +/- 2.2 kg/m2). Thirteen non-obese women with normal glucose tolerance (BMI, 20.9 +/- 1.3 kg/m2) served as controls. All women were 58 to 59 years of age. Insulin sensitivity was measured with the euglycemic, hyperinsulinemic clamp. Insulin secretion was studied after intravenous arginine (5 g) at fasting, and at blood glucose levels of 14 and greater than 25 mmol/L. Insulin sensitivity was higher in non-obese (99.8 +/- 11.5 nmol/kg/min/pmol insulin/L) than in obese subject (P < or = .002), but did not differ between obese subjects with normal versus impaired glucose tolerance (47.2 +/- 8.8 v 45.5 +/- 5.2 nmol/kg/min/pmol insulin/L, difference not significant [NS]). Obese subjects with normal glucose tolerance had a higher insulin response to both glucose (P < or = .004) and arginine (P < or = .02) than nonobese women, and higher glucose potentiation of insulin secretion, slopeAIR (P = .05). Compared with obese subjects with normal glucose tolerance, the obese subjects with impaired glucose tolerance had a lower insulin response to glucose (P = .03) and to arginine at blood glucose levels of 14 mmol/L (P = .03), as well as a lower slopeAIR levels ( P = .03). Fasting glucagon was higher in obese subjects with normal glucose tolerance than in non-obese subjects with normal glucose tolerance (P = .006). In obese subjects with impaired glucose tolerance, the glucose inhibition of glucagon secretion, slope AGR, was lower than in obese subjects with normal glucose tolerance (P = .04). Thus, obese subjects with impaired glucose tolerance have altered glucose modulation of islet function, mainly manifested as reduced slope AIR and slope AGR, yet insulin sensitivity is not different than in equally obese subjects with normal glucose tolerance. We therefore conclude that islet dysfunction, and not a further reduction of insulin sensitivity, determines the development of impaired glucose tolerance in obesity.

Arginine↗
PubMed1998

Learning and tolerance to the ataxic effect of ethanol.

It has been well documented that drug-associated cues are important for the development and expression of drug tolerance. The Pavlovian conditioning analysis of tolerance emphasizes the importance of a drug-associated cues to tolerance by equating a drug administration with a learning trial. According to this analysis, tolerance should be subject to external inhibition, the disruption of a conditional response by a novel stimulus. We previously reported that tolerance to the ataxic effect of ethanol was attenuated by a novel strobe/noise presentation (31). In this article we report evidence of a compensatory CR in rats tolerant to the ataxic effect of ethanol as tested on the tilting plane. Both the compensatory CR and tolerance were disrupted by the presentation of a novel strobe/noise stimulus providing converging evidence that the attenuation of tolerance by a novel stimulus results from external inhibition of Pavlovian conditioning. The disruption of ethanol tolerance and the conditional response mediating tolerance was also apparent when the novel omission of the strobe/noise stimulus was used as the external inhibitor in rats made tolerant to ethanol with the stimulus on. Finally, we have shown that the disruptive effect of a novel stimulus on ethanol tolerance is decreased when there is a 10-day delay between the final tolerance development session and testing, demonstrating that the interval between training and testing is important when assessing associative tolerance.

Animals↗
PubMed1989

The necessity of both allogeneic antigens and stem cells for cyclophosphamide-induced skin allograft tolerance in mice.

We have reported that in an H-2 identical murine combination of AKR/J (AKR, H-2k, Thy1.1) and C3H/HeJ (C3H, H-2k, Thy 1.2), specific tolerance to C3H skin in AKR mice is induced only when both intravenously (i.v.) 1 x 10(8) viable C3H spleen cells and, two days later, intraperitoneally (i.p.) 200 mg/kg cyclophosphamide (CP) have been given. To further examine this mechanism of tolerance, we used 2000R-irradiated C3H spleen cells as an antigen source and bone marrow cells depleted of Thy1.2+ cells and Ia+ cells as a stem cell source. When a mixture of 1 x 10(8) irradiated spleen cells and 3 x 10(7) bone marrow cells was used as tolerogen and 200 mg/kg CP was administered two days later, a profound and specific long-lasting tolerance was induced. This tolerant state, however, was less profound than that induced with spleen cells plus CP. When the number of irradiated spleen cells was fixed at 1 x 10(8), the tolerant state was dose-dependent on the quantity of bone marrow cells. On the other hand, when the number of bone marrow cells was fixed at 1 x 10(6), tolerance induction depended on the dosage of irradiated spleen cells. Tolerance induced with irradiated spleen cells plus bone marrow cells and CP was tolerogen specific. Tolerance was never induced when the bone marrow cells had been irradiated with 2000R prior to injection. Transfer experiments showed that the tolerant state, in its acute phase, appeared to be predominantly based on reduction of functionally reactive cells. The prolongation of skin allograft survival in tolerant mice could not be attributed directly to suppressor cells, nor was any evidence of suppressive factor induction observed. In the chronic phase, however, the importance of the suppressive mechanisms appeared to be relatively increased. EPICS analysis of the thymocytes using fluorescein-conjugated anti-Thy1.1 and anti-Thy1.2 antibodies showed that a minimal degree of mixed chimerism had been established in the tolerant mice. Moreover, both T cells and Ia+ cells had beneficial effects on the induction of tolerance. We conclude that in the tolerance induced by spleen cells plus CP, histocompatibility antigens expressed on the surface of the spleen cells were essential to the antigen-stimulated cell destruction mechanism. Stem cells contained in the spleen cells also appeared to be crucial for maintaining tolerance by establishing a minimal degree of mixed chimerism.

Animals↗
PubMed1999

Role of superoxide dismutase in in vivo and in vitro nitrate tolerance.

We assessed whether pharmacological inhibition of CuZn-superoxide dismutase (SOD) mimics the molecular mechanism of either in vitro or in vivo nitrovasodilator tolerance. In endothelium-intact aortic rings from in vivo tolerant rabbits the GTN- and acetylcholine (ACh)-induced maximal relaxation was attenuated by 36 and 23%, respectively. In vitro treatment of control rings with GTN (1 h 10 microM) similarly attenuated the vasorelaxant response to GTN, but not to ACh. Formation of superoxide radicals (*O2-) in endothelium-intact rings (lucigenin-chemiluminescence) increased 2.5 fold in in vivo tolerance, but significantly decreased in in vitro tolerance. The membrane associated NADH oxidase activity was increased 2.5 fold in homogenates of in vivo tolerant aortae, but was not changed in in vitro tolerant aorta. Conversely, SOD activity and protein expression was halved in in vivo tolerance, but SOD activity was not altered by in vitro tolerance. The *O2- scavenger tiron (10 mM) effectively restored the vasorelaxant response to GTN in in vivo tolerant aortic rings, but not the reduced response to GTN in in vitro tolerant rings. Pretreatment (1 h) of vessels with diethyldithiocarbamate (DETC; 10 mM) attenuated vasorelaxant responses to GTN and ACh, increased vascular *O2- production, and inhibited SOD activity in vessel homogenates to a similar degree as observed in in vivo tolerance. DETC-treatment of in vivo-tolerant vessels induced an additional increase in *O2- production. Increased *O2- production in in vivo nitrate tolerant aorta is associated with activation of vascular NADH oxidase and inactivation of CuZnSOD. Therefore, in vivo tolerance can be mimicked by in vitro inhibition of CuZnSOD, but not by in vitro exposure to GTN, which does not affect vascular *O2- production, NADH oxidase and CuZnSOD.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1975

T and B cell in hapten-specific carrier-determined tolerance.

BDF1 mice were made tolerant by a single i.v. injection of 1 mg of DNAP-gamma1 or by weekly i.v. injections of 0.2 mg of DNP-gamma1 given for a month. In both instances, spleen cells of tolerant animals were fractionated to obtain pure populations of T cells (nonimmunoglobulin-bearing cells), referred to as tolerant T cells, and B cells (immunoglobulin-bearing cells) referred to as tolerant B cells (immunoglobulin-bearing cells) referred to as tolerant B cells. The control cells were similarly fractionated to obtain normal T and B cells. Mixtures of tolerant T cells and normal B cells, or conversely, normal T cells and tolerant B cells were used to repopulate lethally irradiated recipients. These recipients were then immunized with dinitrophenyl-keyhole limpet haemocyanin and in certain instances with other antigen horse red blood cells. The immune response to both antigens was measured using the direct hemolytic plaque assay. It was found that both T and B cells were tolerant and that tolerance was hapten specific at both T- and B-cell levels. While B-cell tolerance was demonstrated at a 1/1 T/B ratio, a 4/1 T/B ratio was necessary to show T-cell tolerance. Thus, the hapten-specific carrier-determined tolerance involves not only B cells but also T cells. The implication of this finding for the cellular mechanism of tolerance in an experimental model closely related to self tolerance is discussed.

Animals↗
PubMed1977

Ontogeny of B-lymphocyte function. III. In vivo and in vitro studies on the ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice.

The ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice was studied in vivo, in a cell transfer system, and in vitro. Three different tolerogens were used: ultracentrifuged BGG, DNP(6)-D-GL, and ultracentrifuged DNP(22)-BGG. Irradiated thymectomized mice were reconstituted with B cells from fetal or neonatal liver or adult spleen or bone marrow. The mice were injected with tolerogen 1 day later. They were given normal thymus cells and challenged with either BGG or DNP(44)-BGG between 4 and 14 days after tolerance induction. With BGG no difference in ease of B-cell tolerance induction was observed in mice reconstituted with B cells from 17-day fetal liver, neonatal liver, 8- day-old spleen, adult spleen, or adult bone marrow. B cells from 14-day fetal donors are relatively resistant to tolerance induction. In contrast, with DNP(6)-D-GL and DNP(22)-BGG B cells from neonatal donors were clearly more susceptible to tolerance induction than were B cells from adult donors. Comparable results were obtained in studies on tolerance induction in vitro. Neonatal B cells were more susceptible than adult B cells to tolerance induction upon culture with DNP(6)-D-GL or DNP(22)-BGG. However, neonatal and adult B cells were identical with respect to ease of tolerance induction in vitro with deaggregated BGG. The results suggest that there are multiple mechanisms for B-cell tolerance induction. Immature B cells appear to be more susceptible to tolerance induction by some mechanisms but not by others. It is suggested that immature B cells are more susceptible to tolerance induction with moderately polyvalent antigens such as hapten-carrier conjugates. With antigens like BGG which do not haverepeated epitopes no difference between mature and fetal B cells in regard to ease of tolerance induction is observed. These observations raise questions about the importance of relative ease of tolerance induction in immature B cells as a mechanism controlling the normal induction of self tolerance.

Animals↗
PubMed1982

Genetic control of the immune response to myoglobins. Both low and high responder T cells tolerant to the other major histocompatibility complex help high but not low responder B cells.

We sought to examine the role of immune response (Ir) genes in helper T cells. To eliminate allogeneic effects, we used neonatally tolerized mice. The results bear not only on the mechanism of Ir genes, but also on the development of the T cell repertoire. B 10.BR (H-2(k)) or C57BL/10 (H-2(b)) mice, which were low responders to myoglobin (Mb), were neonatally tolerized to high responder H-2(d) alloantigens, and B10.D2 mice, which were high responders to Mb, were neonatally tolerized to low responder H-2(k) or H-2(b) alloantigens. Spleen cells from these tolerized mice did not show any reactivity in mixed-lymphocyte reaction or cell-mediated lympholysis against alloantigens used in tolerization. Mb-immune F(1) B cells were helped comparably by Mb-immune tolerized low or high responder T cells. Thus, low responder T cells functioned equivalently to high responder T cells. The failure of nonimmune T cells from tolerized low responder mice to help F(1) B cells and antigen-presenting cells (APC) indicated that collaboration between B10.BR or C57BL/10 T cells and F(1) B cells was not caused by a positive allogeneic effect. Spleen cells from tolerized mice were contaminated with 2-4 percent chimeric F(1) cells, as judged by fluorescence-activated cell sorter analysis, and no F(1) alloantigens were detectable in the thymus. However, removal of chimeric F(1) T cells from the tolerized cell population by treatment with anti-H-2 and complement did not change the helper activity of tolerized low responder T cells. These data indicated that helper activity in the T cell population from low responder mice was not due to F(1) cells. Also, the level of contamination was not sufficient to quantitatively account for the help. In examining the genetic restriction of these tolerized T cells, we found that T cells from tolerized low responder B10.BR or C57BL/10 mice helped F(1) or high responder B10.D2 B cells and APC but not syngeneic B10.BR or C57BL/10 B cells and APC, which were immunized with Mb-coupled fowl gamma globulin instead of Mb to prime low responder B cells with Mb. On the other hand, high responder B 10.D2 tolerized T cells helped syngeneic B 10.D2 B cells but not allogeneic low responder B10.BR B cells. These data indicated that clones of helper T cells specific for Mb exist in low responder mice, and these are not phenotypically different from those in high responder mice, in that both help high responder and F(1) but not low responder B cells and APC. These data are discussed in terms of the mechanism for Ir gene control, and the mechanism of T cell repertoire development- whether intra- or extrathymically-in neonatally tolerized mice.

Animals↗
PubMed1992

Defective maintenance of T cell tolerance to a superantigen in MRL-lpr/lpr mice.

In normal mice neonatal injection of staphylococcal enterotoxin B (SEB) induces tolerance in T cells that express reactive T cell receptor (TCR) V beta regions. To determine if a T cell neonatal defect was present in MRL-lpr/lpr mice, 20 micrograms of SEB was injected intraperitoneally every other day into V beta 8.2 TCR transgenic and nontransgenic MRL(-)+/+ and MRL-lpr/lpr mice from birth to 2 wk of age. At 2 wk of age, V beta 8+ T cells were depleted, and SEB reactivity was lost, in spleen, lymph node, and thymus. These effects were equivalent in +/+ and lpr/lpr SEB-tolerized mice. However, MRL-lpr/lpr mice failed to maintain neonatal tolerance. By 4 wk of age, there was a dramatic increase in T cells expressing V beta 8.2 in the peripheral lymph nodes of MRL-lpr/lpr mice but not MRL(-)+/+ mice. In vitro stimulation with SEB or TCR crosslinking revealed a total loss of neonatal tolerance 2 wk after cessation of SEB treatment in lpr/lpr mice, but not +/+ mice. The time-course of recovery of V beta 8+ T cells and reactivity to SEB and TCR crosslinking in the thymus of MRL-lpr/lpr mice was similar to that in the lymph node. Thymectomy at 2 wk of age eliminated tolerance loss in lymph nodes of MRL-lpr/lpr mice at 4 wk of age, indicating that loss of peripheral tolerance was due to the emigration of untolerized T cells from the thymus. Challenge of neonatally tolerized MRL-lpr/lpr mice with SEB (100 micrograms, i.p.) at 8 wk of age resulted in a dramatic onset of T cell-mediated autoimmune disease characterized by 30% weight loss and 60% morality. This indicated that loss of tolerance to SEB also occurred in vivo. In contrast, neonatally tolerized MRL(-)+/+ mice remained totally unresponsive to SEB challenge and did not undergo any detectable weight loss. These results suggest that there is normal induction of neonatal tolerance to SEB in lpr/lpr mice, but that tolerance is not maintained after the tolerizing antigen is removed. This loss of neonatal tolerance can lead to severe weight loss and death on exposure to the tolerizing antigen later in life.

Animals↗
PubMed2000

Dominant tolerance and linked suppression induced by therapeutic antibodies do not depend on Fas-FasL interactions.

BACKGROUND: Nonlytic anti-CD4 monoclonal antibody therapy can be used to induce transplantation tolerance in rodent models. Such tolerance is often associated with dominant regulation, mediated by CD4+ cells, and characterized by infectious tolerance and linked suppression. Understanding the mechanisms by which CD4+ regulatory cells function may improve the manner in which current immunosuppressants are applied and may lead to the development of new tolerance-inducing therapeutics. Fas-mediated apoptosis has been characterized as an important mechanism of peripheral self-tolerance and we here examine whether it has any role in anti-CD4 monoclonal antibody-induced dominant tolerance. METHODS: Tolerance to transplanted skin and bone marrow, mismatched for multiple minor histocompatibility antigens, was induced in Fas mutant and control mice using anti-CD4 and anti-CD8 monoclonal antibodies. To test for linked suppression, animals were transplanted with a second graft-bearing tolerated and third party antigens. The ability of splenocytes from tolerant animals to suppress graft rejection was assessed by transfer into partially immunocompromised recipients. RESULTS: Monoclonal antibody therapy rendered Fas mutant mice tolerant of minor disparate skin and bone marrow. Splenocytes from these and control tolerant animals when transferred into partially immunocompromised Fas mutant or control recipients, induced antigen-specific suppression of graft rejection. Additionally, tolerant Fas mutant mice accepted grafts bearing tolerated and third party antigens. CONCLUSIONS: Signal transduction through the Fas receptor plays no essential role in the induction of tolerance using anti-CD4 and anti-CD8 monoclonal antibodies or its maintenance by active regulation.

Animals↗
PubMed2004

A novel combination of opiates and endothelin antagonists to manage pain without any tolerance development.

Several neurotransmitter mechanisms have been proposed as playing a role in the development of morphine tolerance. We provide evidence for the first time that endothelin antagonists can restore morphine analgesia in morphine-tolerant rats and prevent the development of tolerance to morphine. Studies were carried out in rats and mice treated with implanted placebo or implanted morphine pellet. The maximal tail-flick latency in morphine pellet + vehicle-treated rats (7.54 seconds) was significantly lower when compared with placebo pellet + vehicle-treated rats (10 seconds), indicating that tolerance developed to the analgesic effect of morphine. BQ123 potentiated tail-flick latency by 30.0% in placebo-tolerant rats and 94.5% in morphine-tolerant rats compared with respective controls. BMS182874 potentiated tail-flick latency by 30.2% in placebo-tolerant rats and 66.7% in morphine-tolerant rats. The enhanced analgesic effect of morphine after treatment with endothelin antagonists could be blocked by naloxone, indicating an opiate-mediated effect; but naloxone binding to brain membranes was not affected by BQ123. Guanosine triphosphate binding was stimulated by morphine and endothelin-1 in non-tolerant mice and not in morphine-tolerant mice; however, guanosine triphosphate binding was stimulated by BQ123 in morphine-tolerant mice and was unaffected in non-tolerant mice. These results suggest that uncoupling of G-protein occurs in morphine tolerance and endothelin antagonist restores the coupling of G-protein to its receptors. A combination use of endothelin antagonist and opiates could provide a novel approach in improving analgesia and eliminating tolerance.

Analgesics, Non-Narcotic↗
PubMed1996

Evidence for a thymus-dependent form of tolerance that is not based on elimination or anergy of reactive T cells.

The avian embryo has provided an appropriate model to study the ontogeny of the primary lymphoid organs, thymus and bursa of Fabricius. By using the quail-chick marker system the embryonic origin of the highly intricate cell components which form these organs could be traced back to the initial endodermal, mesodermal and ectodermal germ layers. The timing and dynamics of the incoming and outcoming flows of hemopoietic cells which characterize their lymphopoietic activity could be revealed in both quail and chick embryos. This knowledge served as a basis for an investigation on the role of the epithelial component of the thymus (derived from the pharyngeal endoderm) on tolerance to tissue graft and, by extension, tolerance to self. When this work was undertaken, the prevailing view was that exposure of the developing immune system to foreign antigens in the embryo allows them to be assimilated to self components in the mature animal. In fact, this was found to be true for allogeneic grafts between MHC-distinct chickens, of certain tissues, such as for instance wing tissues. However, in heterospecific transplantations, i.e. when a limb bud was grafted from quail to chick embryos, the chick host acutely rejected the foreign limb soon after birth. In contrast, grafts of the quail thymic epithelial (TE) rudiment resulted in the development of a chimeric thymus in which the foreign epithelial component was not only tolerated but able to induce full tolerance of the grafted wing from the same donor. By monitoring the amount of quail TE implanted we showed in addition that only part of the peripheral T-cell population had to differentiate in the context of the quail epithelial cells to induce tolerance to quail tissues. This pointed to the generation in the thymus of regulatory T cells, coexisting with specific anti-quail reactive T cells, but able to inhibit them from reacting against the quail wing antigenic determinants. A mammalian model was then devised to further study this mechanism of tolerance that we have qualified as "dominant" by opposition to the current model based on either clonal elimination or anergy which can be considered as recessive or passive. Nude mice of MHC type A were grafted with TE of E10 type B embryos. They became reconstituted for T-cell function but tolerant for B skin allografts. Spleen cells from such tolerant animals injected to naive A nude mice reconstituted T cell function in the recipient and transferred the tolerance to B skin grafts. Reducing the number of donor cells resulted in the segregation of the two phenomena. For low numbers the recipients were restored but not tolerant, thus showing the coexistence in the tolerant donor of anti-B reactive T cells together with regulatory cells able to abolish their reactivity against B determinants. Other experiments demonstrated that TE-induced tolerance does not rely on clonal deletion or anergy. This was shown on systems where elimination of cells directed toward superantigens was screened. It turned out that tolerance to skin grafts and superantigen T-cell deletion are unrelated phenomena. These observations strongly suggest that tolerance to self results at least in part from the interplay between cells potentially harmful for self component and others which exert a strong control on their reactivity. The latter cell type depends upon interactions of thymocytes with the endodermal component of the thymus.

Animals↗
PubMed2001

Cellular mechanisms that cause suppressed gamma interferon secretion in endotoxin-tolerant mice.

Endotoxin (lipopolysaccharide [LPS]) tolerance is a state of altered immunity characterized, in part, by suppression of LPS-induced gamma interferon (IFN-gamma) expression. However, the cellular mediators regulating LPS-induced production of IFN-gamma in normal mice and the effect of LPS tolerance on these mediators has not been well characterized. Our studies show that macrophage dysfunction is the primary factor causing suppressed IFN-gamma expression in LPS-tolerant mice. Specifically, LPS-tolerant macrophages have a markedly impaired ability to induce IFN-gamma secretion by T cells and NK cells obtained from either control or LPS-tolerant mice. However, T cells and NK cells isolated from LPS-tolerant mice produce normal levels of IFN-gamma when cocultured with control macrophages or exogenous IFN-gamma-inducing factors. Assessment of important IFN-gamma-regulating factors showed that interleukin-12 (IL-12) and costimulatory signals provided by IL-15, IL-18, and CD86 are largely responsible for LPS-induced IFN-gamma expression in control mice. IL-10 is an inhibitor of IFN-gamma production in both the control and LPS-tolerant groups. Expression of IL-12 and the IL-12 receptor beta1 (IL-12Rbeta1) and IL-12Rbeta2 subunits are suppressed in the spleens of LPS-tolerant mice. LPS-tolerant splenocytes also exhibit decreased production of IL-15 and IL-15Ralpha. However, expression of IL-18 and the B7 proteins CD80 and CD86 are unchanged or increased compared to controls after induction of LPS tolerance. CD28, a major receptor for B7 proteins, is also increased in the spleens of LPS-tolerant mice. Expression of the inhibitory cytokine IL-10 and the IL-10R are sustained after induction of LPS tolerance. These data show that suppression of IFN-gamma production in LPS-tolerant mice is largely due to macrophage dysfunction and provide insight into the cellular alterations that occur in LPS tolerance. This study also better defines the factors that mediate LPS-induced IFN-gamma production in normal mice.

Animals↗
PubMed1980

Comparison of neonatally and adoptively induced transplantation tolerance in mice.

Transplantation tolerance induced by the semiallogeneic cells in newborn mice or by the adoptive transfer of syngeneic spleen cells from neonatally tolerant donors in adult mice was studied in the strain combination with the H-2D region disparity (B10.A recipients--B10.A(2R) donors). Tolerance could be transfered adoptively already from 3-week-old mice that had been rendered tolerant at birth and the ability for the transfer of tolerance persisted for long periods even when neonatally tolerant animals were not skin grafted. Both neonatally and adoptively induced tolerance could not be abolished by the adoptive transfer of 100 x 10(6) immunocompetent cells from normal syngeneic donors. It was observed in the in vitro experiments that cells from tolerant mice in the two types of tolerance reacted to the tolerated antigens in the mixed lymphocyte culture, did not react to the tolerated antigens in the microcytotoxicity test (only some mice with adoptively induced tolerance showed a certain degree of reactivity), but cells from both types of tolerant mice inhibited the in vitro sensitization of cells from normal syngeneic animals. This suppression was stronger with cells from neonatally tolerant mice.

Animals↗
PubMed1994

Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C.

In a rat model of morphine tolerance, we examined the hypotheses that thermal hyperalgesia to radiant heat develops in association with the development of morphine tolerance and that both the development and expression of thermal hyperalgesia in morphine-tolerant rats are mediated by central NMDA and non-NMDA receptors and subsequent protein kinase C (PKC) activation. Tolerance to the analgesic effect of morphine was developed in rats utilizing an intrathecal repeated treatment regimen. The development of morphine tolerance and thermal hyperalgesia was examined by employing the tail-flick test and paw-withdrawal test, respectively. Intrathecal MK 801 (an NMDA receptor antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; a non-NMDA receptor antagonist), or GM1 ganglioside (an intracellular PKC inhibitor) treatment was given to examine the effects of these agents on the development and expression of thermal hyperalgesia in morphine-tolerant rats. Tolerance to the analgesic effect of morphine was reliably developed in rats following once daily intrathecal (onto the lumbosacral spinal cord) injection of 10 micrograms of morphine sulfate for 8 consecutive days as demonstrated by the decreased analgesia following morphine administration on day 8 as compared to that on day 1. In association with the development of morphine tolerance, thermal hyperalgesia to radiant heat developed in these same rats. Paw-withdrawal latencies were reliably decreased in morphine-tolerant rats as compared to nontolerant (saline) controls when tested on day 8 before the last morphine treatment and on day 10 (i.e., 48 hr after the last morphine treatment). The coincident development of morphine tolerance and thermal hyperalgesia was potently prevented by intrathecal coadministration of morphine with MK 801 (10 nmol) or GM1 (160 nmol), and partially by CNQX (80 nmol). MK 801 (5, 10 nmol, not 2.5 nmol) and CNQX (80, 160 nmol, not 40 nmol), but not GM1 (160 nmol), also reliably reversed thermal hyperalgesia in rats rendered tolerant to morphine when tested 30 min after each drug treatment on day 10 (48 hr after the last morphine treatment). The data indicate that thermal hyperalgesia develops in association with the development of morphine tolerance and that the coactivation of central NMDA and non-NMDA receptors is crucial for both the development and expression of thermal hyperalgesia in morphine-tolerant rats. Furthermore, intracellular PKC activation plays a critical role in the development of thermal hyperalgesia in morphine-tolerant rats.(ABSTRACT TRUNCATED AT 400 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗