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PubMed1996

Oral tolerization leads to active suppression and bystander tolerance in adult rats while anergy dominates in young rats.

Oral tolerance was induced in 4-week-old (young) and 12-week-old (adult) rats by feeding ovalbumin (OvA)-containing pellets during 4 weeks. Seven weeks after removal of the OvA-pellets the rats were immunized with a mixture of OvA and human serum albumin (HSA) in Freund's complete adjuvant (FCA), and the following immune response was monitored. Both the young and adult groups of OvA-fed rats had significantly suppressed OvA-specific delayed-type hypersensitivity (DTH) responses and T-cell proliferation, reflecting a long-lasting T-cell tolerance to OvA both in vivo and in vitro. Furthermore, spleen cells from rats tolerized as adults were able to suppress the proliferation of primed T-cells from normal immunized rats, demonstrating the presence of antigen-specific suppressive cells. Accordingly, the adult rats showed bystander suppression of the response to HSA with respect to DTH-reaction, specific proliferation, and reduced enlargement of the draining lymph nodes after immunization. There was no evidence of active suppression in vitro or bystander tolerance in the orally tolerized young group, indicating that anergy rather than active suppression was prevalent in these rats. Furthermore, in the young group there was no suppression of the antibody response since the IgG and IgE anti-OvA antibody levels were indistinguishable from those of the controls. Contrary to the young rats, the adult fed group showed transiently elevated levels of IgG anti-OvA antibodies at 1 week post-immunization, followed by a subsequent significantly suppressed IgG antibody response. In conclusion, the results demonstrate that the induction of anergy or active suppression after antigen feeding can be determined by the age at which the antigen is introduced to the mucosal immune system.

Administration, Oral↗
PubMed1994

Loss of reirradiation tolerance in the kidney with increasing time after single or fractionated partial tolerance doses.

The aim was to determine the influence of initial dose and dose per fractionation on retreatment tolerance of the kidney. Mouse kidney was bilaterally irradiated with various single or fractionated X-ray doses equivalent to about 12-70% of a defined response dose. The mice were retreated with a range of single doses after 2 or 26 weeks. The development of functional kidney damage was followed by monthly testing of clearance of 51CrEDTA until the animals expressed overt renal dysfunction (maximum follow-up 70 weeks after retreatment). Reirradiation tolerance was assessed by probit analysis and Kaplan-Meier actuarial estimates of the incidence of a defined level of renal damage at 40 weeks after retreatment. Doses required to give a 50% incidence of damage (RD50) were compared for animals that had received previous single dose or fractionated irradiations, or that were previously unirradiated. Multivariate analysis of time to expression of renal damage (latency) was also done using the Cox Proportional Hazards model. Results demonstrated that previous irradiation always compromised retreatment tolerance, even for intervals of 26 weeks after initial treatments with < 20% full response dose. Reirradiation tolerance was inversely related to the initial dose and tolerance decreased significantly with increasing interval between treatments, suggesting progression rather than recovery from the initial damage. Linear-quadratic analysis of the data for reirradiation at 26 weeks after partial-response doses gave an alpha/beta = 1.4 Gy. This was significantly lower than the alpha/beta = 3.3 Gy obtained for initial treatments alone (no retreatment), indicating a larger fractionation-sparing effect for the retreatment situation.

Animals↗
PubMed1975

Tolerance induction in B lymphocytes but thymus-dependent antigens. T cells may abrogate B-cell tolerance induction by prevent an antibody response.

Thymus-dependent protein antigens such as fowl gamma globulin (FGG) and dinitrophenylated-human gamma globulin (DNP-HGG), readily induced tolerance of the B cell in the absence of T cells even when these antigens were not deaggregated. However, when the same doses of antigen were given in the presence of T cells, the B-cell population was shown to be protected from tolerance induction, especially when the antigen was not in a deaggregated form. In this case, there was in fact evidence of a priming effect, manifest in both the B-cell and T-cell populations. The priming effect on the B-cell population was demonstrated by an increased response of mice pretreated with DNP-HGG, upon challenge with DNP conjugated to a heterologous carrier. The priming effect on the T-cell population was evident in a helper effect demonstrated in vitro. However, when euthymic mice which had been pretreated with large doses of FGG or DNP-HGG were challenged with the homologous carrier, the results were different. In this case, there was a profound suppression of the response against the carrier or the hapten on that carrier. Suppressor activity was also demonstrated in vitro and was shown to be sensitive to treatment with anti-theta-serum plus complement. Additionally it was shown that the effector phase of the suppression had a definite nonantigen-specific component. Thus, in pretreated euthymic mice, provided the homologous carrier was present, the response to a heterologous carrier was also suppressed. To account for the observation that nondeaggregated antigens can induce B-cell tolerance in athymic mice, but B-cell priming and T-cell-mediated suppression in euthymic mice, it is proposed that B-cell tolerance occurs when antigen at some critical dose interacts with the B cell in the absence of some second signal. This second signal is normally provided by the macrophage, probably with the assistance of the T cell, and its effect is to divert the result of the interaction of the B cell with antigen towards immunization and away from tolerance induction. When a large dose of an antigen that tends to form aggregates is given to an animal possessing functional T cells, both T-dependent helper and T-dependent suppressor activities are generated, thus accounting for a situation where the B-cell population is immunized, but B-cell activation is suppressed in the presence of the original carrier.

Animals↗
PubMed1977

B-cell tolerance. III. Effect of papain-mediated cleavage of cell surface IgD on tolerance susceptibility of murine B cells.

Under defined conditions, papain removes IgD from cells while leaving IgM, H-2, Ia, Lyb-2, and complement receptor intact. The effect of such treatment with papain on the induction of tolerance in murine splenic B cells was determined in an in vitro system. Treatment of the cells with papain has no effect on subsequent antibody responsiveness presumably because surface receptors regenerate before and during incubation with immunogen. Removal of increasing amounts of IgD results in increasing susceptibility of thymus-dependent responsive cells to tolerance induction. The tolerance susceptibility of thymus-independent responsive cells, which we have previously suggested are immature cells that bear only IgM, is unaffected by cleavage of IgD. If cells are incubated for 24 h after treatment with papain, cell surface IgD and tolerance resistance return. These results indicate that a surface molecule affects susceptibility of B cells to induction of tolerance and suggest that this molecule may be IgD.

Animals↗
PubMed1986

Induction of tolerance to one determinant on a synthetic peptide does not affect the response to a second linked determinant. Implications for the mechanism of neonatal tolerance induction.

To investigate the mechanism underlying neonatal T cell tolerance, we used synthetic peptides to induce tolerance. We found that induction of tolerance to one determinant on a 23-amino acid peptide did not affect the response to an adjacent determinant on the same peptide. There was no evidence of suppression of the response to the second determinant. Furthermore, even small peptides near the minimal size for a determinant, which would be very unlikely to possess a suppressor T cell-inducing determinant as well as a proliferative T cell-inducing determinant, could induce tolerance. These studies provide in vivo experiments supporting clonal inactivation as the mechanism of neonatal tolerance to immunogenic peptides.

Animals↗
PubMed2025

Comparison of stress tolerance mechanisms between Saccharomyces cerevisiae and the multistress-tolerant Pichia kudriavzevii.

Yeasts play a vital role in both research and industrial biomanufacturing. Saccharomyces cerevisiae has been extensively utilized as a model system. However, its application is often constrained by limited tolerance to the diverse stress conditions encountered in bioprocesses. These challenges have driven increasing interest in nonconventional, multistress-tolerant yeasts as alternative biomanufacturing hosts. This review highlights Pichia kudriavzevii as a promising nonconventional yeast for industrial applications. Unlike S. cerevisiae, P. kudriavzevii exhibits exceptional tolerance to high temperatures, elevated concentrations of furanic and phenolic inhibitors, osmotic stress, salinity, and extreme pH. These traits make it an attractive candidate for industrial processes without requiring extensive genetic modifications to enhance stress resistance. As a result, P. kudriavzevii has emerged as a flagship species for advancing bioeconomy. Despite its industrial potential, the molecular mechanisms underlying P. kudriavzevii's superior stress tolerance remain poorly understood. This review compiles current knowledge on P. kudriavzevii and compares its stress tolerance mechanisms with those of S. cerevisiae, providing insights into its innate resilience. By expanding our understanding of nonconventional yeasts, this review aims to facilitate their broader adoption as robust microbial platforms for industrial biomanufacturing.

Saccharomyces cerevisiae↗
PubMed1985

Drug-induced tolerance to allografts in mice. IV. Mechanisms and kinetics of cyclophosphamide-induced tolerance.

Mechanisms and kinetics of tolerance in AKR mice induced using i.v. priming with viable C57BL/6 spleen cells and treatment with cyclophosphamide 2 days later were analyzed. In this tolerance induction system, some lymphocyte populations mediating delayed foot-pad reaction and cytotoxic activity were resistant to tolerance induction and remained in a sensitized state after cyclophosphamide treatment. These populations were considered to be qualitatively distinct from populations sensitive to cyclophosphamide, because delayed foot-pad reaction and cytotoxic lymphocyte activity were stronger in tolerant mice than in control mice in the early stages of tolerance induction, but were not augmented after immunization with C57BL/6 spleen cells, C57BL/6 skin grafts, or EL4 tumor grafts in the absence of suppressor T cells. One of the important differences in these two lymphocyte populations may be the capacity for clonal expansion.

Animals↗
PubMed1996

Recipient cells expressing single donor MHC locus products can substitute for donor-specific transfusion in the induction of transplantation tolerance when pretreatment is combined with anti-Cd4 monoclonal antibody. Evidence for a vital role of Cd4+ T cells in the induction of tolerance to class I molecules.

Syngeneic cells expressing single donor MHC locus products have been shown to induce specific immunological hyporesponsiveness, but not tolerance, to an allograft. In this study we have attempted to potentiate the beneficial effect of pretreatment with single donor MHC locus products by the addition of anti-Cd4(2) monoclonal antibody to the pretreatment protocol. We show that pretreatment with recipient L cells expressing the products of a single donor locus (K, D, or IA) can induce tolerance to a C57BL/10 (H2b) cardiac allograft in C3H/He (H2k) mice, when given in combination with the depleting anti-Cd4 monoclonal antibody YTA 3.1.2. Both the induction and maintenance phases of tolerance were found to be antigen-specific. Cells expressing donor class II antigens, IA(b) were found to be most effective. Interestingly, donor class I molecules were also found to be capable of inducing specific unresponsiveness in combination with anti-Cd4, provided an optimal antigenic load was delivered at the time of pretreatment. Pretreatment with cells expressing donor class I and anti-Cd8 monoclonal antibody had no beneficial effect on graft survival. These data show that single donor MHC locus products can induce immunologic tolerance to fully MHC and minor histocompatibility antigen-mismatched heart grafts when given under the cover of anti-Cd4 mAb. They also show that Cd4+ T cells play an important role in the induction of specific unresponsiveness to class I alloantigen in vivo and suggest that the blockade of T cells capable of recognizing class I alloantigen presented indirectly is important in the induction of tolerance.

Animals↗
PubMed1999

Indirect allorecognition in acquired thymic tolerance: induction of donor-specific tolerance to rat cardiac allografts by allopeptide-pulsed host dendritic cells.

BACKGROUND: Presentation of peptides either by recipient or donor MHC molecules displayed on the surface of antigen-presenting cells is an essential element in the induction of T cell responses to transplant antigens. The finding that intrathymic (IT) injection of an immunodominant peptide induces acquired thymic tolerance suggests an indirect pathway of allorecognition in the thymus. To address this theory, we studied the effects of IT injection of host bone marrow (BM)-derived dendritic cells (DC)-pulsed with the immunodominant Wistar Furth (WF) MHC class I (RT1.Au) peptide 5 (93-109) on cardiac allograft survival in the WF-to-ACI rat combination. METHODS: DC were propagated from cultures of ACI (recipient) bone marrow (BM) maintained in a medium supplemented with granulocyte-macrophage colony-stimulating factor and IL-4. The BM-derived DC after 8 days of culture were pulsed in vitro with a single WF MHC class I peptide (Residue 93-109) with the dominant epitope, washed, and injected into the thymus of ACI rats. The ACI recipients received donor-type (WF) or 3rd party (Lewis) cardiac allografts 7 days after IT immunization with peptide-pulsed DC. RESULTS: BM-derived DC cultured in granulocyte-macrophage colony-stimulating factor and interleukin-4 for 8 days have a strong allostimulatory ability and present peptide 5 to naive syngeneic T cells in mixed lymphocyte reaction. IT inoculation of 300 microg RT1.Au peptide 5 combined with transient antilymphocyte serum immunosuppressive therapy induced donor-specific tolerance to cardiac allografts. Extension of this finding to peptide-pulsed self DC showed that IT injection of peptide 5-pulsed host DC consistently led to permanent acceptance (>150 days) of donor-type (WF) cardiac allografts, whereas third-party (Lewis) grafts were acutely rejected. The long-term unresponsive recipients challenged with second-set grafts accepted permanently (>100 days) donor-type(WF) grafts while rejecting third-party (Lewis) grafts without the rejection of the primary WF grafts. CONCLUSION: This novel finding that allopeptide-pulsed host DC induces tolerance to cardiac allografts suggests that the induction of acquired tolerance is dependent on the indirect allorecognition pathway. The results further suggest that genetically engineered DC expressing donor MHC class I or II molecules or a peptide analogue might have therapeutic potential in the induction of transplant tolerance and in the treatment of autoimmune diseases.

Animals↗
PubMed2006

Role of the thymus in transplantation tolerance in miniature swine: V. Deficiency of the graft-to-thymus pathway of tolerance induction in recipients of cardiac transplants.

BACKGROUND: We have previously shown that both thymic immigrants (graft to thymus pathway) and thymic emigrants (thymus to graft pathway) are involved in tolerance to renal allografts in miniature swine treated with a short course of calcineurin inhibitors. This study investigates the role of these pathways in cardiac transplant survival in recipients treated with a short course of tacrolimus. METHODS: Eleven animals received two-haplotype fully MHC-mismatched cardiac grafts with a 12-day course of tacrolimus. Recipients were thymectomized on day -21 (n=5) or day 0 (n=3), or were left euthymic (n=3). Two of the day -21 thymectomized animals received a day 0 host-MHC matched thymocyte infusion. RESULTS: Euthymic recipients of cardiac grafts treated with an immunosuppressive regimen identical to that previously shown to induce tolerance in euthymic recipients of renal allografts all rejected their grafts. Although no animal became tolerant, animals that were euthymic or thymectomized on day 0, as well as recipients of day 0 host-type thymocyte infusions following thymectomy on day -21, developed donor-specific hyporesponsiveness and maintained their cardiac grafts for markedly prolonged periods. In contrast, all animals thymectomized on day -21 that did not receive thymocyte infusions developed strong antidonor CTL responses and rejected their grafts by day 35. CONCLUSIONS: The graft-to-thymus pathway that plays an important role in tolerance induction to renal allografts appears to be relatively deficient in recipients of cardiac grafts. Strategies to increase donor antigen migration to the host thymus might therefore assist in tolerance induction to cardiac allografts.

Animals↗
PubMed1978

Immunological tolerance to the thymus-independent antigen dextran can be abrogated by thymus-dependent dextran conjugates: evidence against clonal deletion as the mechanism of tolerance induction.

Tolerance to the alpha1--6 epitope of native dextran B512 was found to be very stable and could not be broken by the injection of dextran conjugated to several substances, such as protein A, keyhole limpet haemocyanin, edistin, concanvalin A or Staphylococcus bacteria, strain Cowan. However, when tolerant mice were injected with dextranase, all the above conjugates induced a strong anti-alpha1--6 immune response. In contrast, native dextran itself never induced a response in tolerant, dextranase-treated mice. It was concluded that tolerance only affects the specific B-cell subpopulation that can respond to the polyclonal B-cell-activating (PBA) property of dextran, whereas other specific B cells having PBA receptors for, e.g., signals delivered by collaborating T cells remain in a resting state. These B cells can respond in a specific immune response against the tolerogen after removal of the antigen, which blocks the Ig receptors and therefore prevents them from passively focusing the antigen. Thus, immunological tolerance is not caused by clonal elimination of the antigen-specific clone, but only affects a small subfraction of cells with Ig receptors against the tolerogen.

Animals↗
PubMed1981

Experimentally induced transplantation tolerance. I. Dissociation of effector lymphocytes specific for alloantigens by neonatal tolerance induction.

Neonatal tolerance was induced in CBA mice to alloantigens expressed by lymphoid cells of the A/Sn strain. 50% of the grafted animals maintained viable skin grafts for greater than 120 days and thus were considered operationally tolerant. However, splenic lymphocytes from these animals were capable of in vitro activation of DNA synthesis in response to the tolerizing alloantigens. Likewise, the spleen contained precursors of cytotoxic effector cells capable, upon activation, of similarly recognizing the major histocompatibility complex alloantigens used for tolerance induction. In contrast, in vivo graft-versus-host (GVH) effector function was absent, suggesting a possible dissociation of cells involved in the in vitro cell-mediated lympholysis and the in vivo GVH. Determination of potential serum-blocking factors as a possible mechanism of graft survival in these tolerant animals proved negative.

Animals↗
PubMed1992

Tolerance to adenosine's accentuation of ethanol-induced motor incoordination in ethanol-tolerant mice.

Our previously published reports have provided data that have supported a functional correlation between ethanol-induced changes in the characteristics of adenosine receptor, adenosine uptake and release in the brain, and ethanol-induced motor incoordination. The present data demonstrated a cross-tolerance between ethanol and adenosine further supporting the hypothesis that brain adenosine modulates the motor impairing effects of ethanol. Mice that received (-)-N6-cyclohexyladenosine (CHA) [0.25 mg/kg/day, intraperitoneally (ip)] for 10 days exhibited marked attenuation (cross-tolerance) to acute ethanol-induced motor incoordination compared with chronic saline (ip) controls. The attenuation of acute ethanol-induced motor incoordination was essentially same in animals that received CHA (25 ng/5 microliters/day for 10 days) by the intracerebroventricular (icv) route as opposed to the controls that chronically received artificial cerebral spinal fluid by the same route. Similarly, tolerance was exhibited to acute CHA (0.125 mg/kg ip and 12.5 ng/5 microliters icv) by animals fed liquid ethanol (19.5 g/kg/24 hr) for 10 days compared with none in the pair-fed sucrose controls. Scatchard plots using cerebellar tissue homogenates from animals given chronic CHA or chronic ethanol indicated no change in Bmax and/or Kd values for CHA binding when compared with CHA binding in tissues from their respective controls. However, a lack of any change in the binding characteristics cannot rule out the involvement of adenosine receptors in the observed cross-tolerance between ethanol and CHA. The results may suggest desensitization of adenosine A1 receptors due to chronic CHA and ethanol as an alternate possible explanation in the development of cross-tolerance between adenosine (CHA) and ethanol.

Adenosine↗
PubMed1982

Vascular smooth muscle relaxation by nitro compounds: reduced relaxation and cGMP elevation in tolerant vessels and reversal of tolerance by dithiothreitol.

Smooth muscle preparations obtained from bovine mesenteric artery were incubated with high concentrations of nitroglycerin (NG) or nitroprusside (NP) at elevated pH. This treatment was found to make the vessels tolerant towards both the relaxant and cGMP elevating action of a challenging dose of nitrocompounds when tested on the histamine contracted vessels. Also, some cross-tolerance between NP and NG could be found since pretreatment of the vessels with NP caused a reduction in both the relaxant and the cGMP elevating action of NG. The NG induced tolerance could be partly reversed by treatment with the disulfide reducing agent dithiothreitol (DTT). These results are suggested to strengthen the evidence for cGMP as a mediator of vascular smooth muscle relaxation induced by nitrocompounds. The ability of DTT to partly reverse this tolerance indicates the existence of critical tissue sulfhydryl groups with which the nitrocompounds interact. There also seemed to exist certain differences in the mechanism of action between NG and NP since the tolerance induced against NG was much more pronounced than was the case for NP.

Animals↗
PubMed1988

Studies on vascular smooth muscle tolerance to different cGMP-mediated vasodilators and cross-tolerance to glyceryl trinitrate.

In the present study the possible existence of cross-tolerance between GTN, atrial natriuretic peptide and the endothelium-dependent vasodilators acetylcholine and calcium ionophore A23187 was investigated. Pretreatment of bovine mesenteric arteries (BMA) with GTN (0.44 mM) for 2 hrs caused a significant (P less than 0.001) right-shift of the concentration-effect curve for GTN as compared to controls (pD2 = 6.96 +/- 0.208 and 4.57 +/- 0.148 in controls and GTN treated vessels, respectively), thus indicating the development of tolerance. Cross-tolerance between GTN and the endothelium-dependent vasodilators acetylcholine and calcium ionophore A23187 was found as judged from cumulative concentration-effect curves. The cGMP response evoked by 1 microM GTN was markedly blunted in the GTN-pretreated vessels (P = 0.0056). Similarly the cGMP elevation induced by 10 microM acetylcholine and 0.1 microM calcium ionophore A 23187 was significantly reduced in GTN-pretreated muscle specimens (P = 0.0475 and P = 0.0103, respectively). No cross-tolerance between GTN and atrial natriuretic peptide (ANP) could be established from tension studies. Furthermore, the cGMP response induced by atrial natriuretic peptide was not significantly different in GTN-tolerant vessels as compared to in controls (P = 0.2097). BMA specimens were also incubated with acetylcholine and ANP (2 hrs and 6 hrs, respectively) and the vessels were thereafter tested for their responsiveness to acetylcholine, ANP and GTN. Preincubation with acetylcholine (10 microM) for 2 hrs did not affect the relaxant response to a subsequent challenge with acetylcholine or GTN. Preincubation of BMA with ANP (0.1 microM) for 6 hrs was also without effect on the responsiveness to ANP or GTN.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1975

Stimulation-produced analgesia: development of tolerance and cross-tolerance to morphine.

Analgesia resulting from focal electrical stimulation of the brain of the rat shows tolerance with repeated exposures; this tolerance dissipates after a period of nonstimulation. Addiction to morphine reduces greatly the analgesia produced by electrical stimulation of the brain, which demonstrates cross-tolerance between morphine analgesia and stimulation-produced analgesia. Recovery of the stimulation-produced analgesia is seen after discontinuing administration of morphine. These results suggest that morphine and electrical stimulation produce analgesia by common mechanisms. The fact that tolerance occurs to the analgesic effect of electrical stimulation indicates that tolerance may be an alteration of an endogenous neuronal process.

Analgesia↗
PubMed1979

The use of hapten-polysaccharide conjugates for the induction of B-cell tolerance involving IgE responses. II. Specific tolerance induced by sulphonamide-substituted levan in the mouse.

Normal and sulphonamide-sensitised mice were made tolerant with 4-sulphanilamido-benzoic-diaminopropyl-carboxymethyl-levan (4-SABA-Le). The tolerance was demonstrably specific for the sulphanilamide moiety of the hapten and extended to related compounds sharing this determinant. Mice sensitised with a 4-SABA-chicken gamma-globulin conjugate developed fatal anaphylactic shock after the injection of sulphanilamide or 4-SABA-ovalbumin, whereas allergic mice subsequently tolerised with 4-SABA-Le did not. The tolerance induced was long lasting since mice were still tolerant 7 months after an injection of an optimal dose of tolerogen. Suppressor cells play little or no part in the maintenance of this unresponsive state since even a 10-fold excess of splenic cells from tolerant animals failed to inhibit the responsivenss of 4-SABA-primed cells when they were transferred together into irradiated recipients.

Animals↗
PubMed2004

Genetic selection for resistance or susceptibility to oral tolerance to ovalbumin affects general mechanisms of tolerance induction in mice.

To study the genes involved in oral tolerance susceptibility, two strains of mice were genetically selected for susceptibility (TS) and resistance (TR) to oral tolerance to ovalbumin by bidirectional breeding. Herein we show that the genetic selection process is restricted neither to ovalbumin nor to oral tolerance. It affected oral tolerance to other proteins, such as casein, and tolerance induced the intravenous route.

Animals↗