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At least 109 records · Page 6Linked to original sources
PubMed2002

Lipopolysaccharide- and lipoteichoic acid-induced tolerance and cross-tolerance: distinct alterations in IL-1 receptor-associated kinase.

Human Toll-like receptor (TLR) 4 and TLR2 receptors recognize LPS or lipoteichoic acid (LTA), respectively. Prolonged exposure of human macrophages/monocytes to bacterial LPS induces a state of adaptation/tolerance to subsequent LPS challenge. Inflammatory gene expressions such as IL-1beta and TNF-alpha are selectively repressed, while certain anti-inflammatory genes such as secretory IL-1R antagonist are still induced in LPS-adapted/tolerant cells. In this report, we demonstrate that LPS-tolerized human promonocytic THP-1 cells develop cross-tolerance and no longer respond to LTA-induced IL-1beta/TNF-alpha production, indicating that disruption of common intracellular signaling is responsible for the decreased IL-1beta/TNF-alpha production. We observe that down-regulation of IL-1R-associated kinase (IRAK) protein level and kinase activity closely correlates with the development of cross-tolerance. IRAK protein levels and kinase activities in LPS-tolerized cells remain low and hyporesponsive to subsequent LPS or LTA challenges. We also demonstrate that THP-1 cells with prolonged LTA treatment develop LTA tolerance and do not express IL-1beta/TNF-alpha upon further LTA challenge. Strikingly, cells tolerized with LTA are only refractory to subsequent LTA challenge and can still respond to LPS stimulation. Correspondingly, stimulation of TLR2 by LTA, although activating IRAK, does not cause IRAK degradation. IRAK from LTA-tolerized cells can be subsequently activated and degraded by further LPS challenge, but not LTA treatment. Our studies reveal that LTA-induced tolerance is distinct compared with that of LPS tolerance, and is likely due to disruption of unique TLR2 signaling components upstream of MyD88/IRAK.

Enzyme Activation↗
PubMed1992

Tolerance to host minor histocompatibility antigens after allogenic bone marrow transplantation. Specific donor-host unresponsiveness is maintained by peripheral tolerizing cells.

The development of graft-host tolerance after allogeneic bone marrow (BM) transplantation is more demanding than the acquisition of self-tolerance because both donor-derived mature T cells and immature thymocytes encounter host Ag. The mechanism involved in tolerization of mature T cells, contained in unmanipulated BM, remains undefined. In previous experiments, we showed in vivo unresponsiveness to host minor histocompatibility Ag (MiHA) in immunocompetent chimeras obtained after MiHA-incompatible BM transplantation. In this study, we wanted to determine: first, what was the specificity of this graft-host unresponsiveness, and second, whether peripheral cells were involved in tolerization? LP recipients were irradiated (9, 5 Gy), injected with 10(7) undepleted BM cells from B10 donors and studied 100 to 150 days later. (B10-->LP) chimeras were immunized in vivo and restimulated in vitro with cells displaying one or multiple incompatible MiHA. In bulk culture experiments, chimeras demonstrated specific CTL unresponsiveness to host MiHA but responded normally to third party MiHA. In limiting dilution analysis conditions, chimeras showed a profound deficit, but not a complete absence of anti-host CTL precursor. Studies with congenic stimulators/targets showed that graft-host tolerance was induced against both immunodominant (e.g., H-3.2) and nonimmunodominant (e.g., H-8.2) MiHA although at the CTL precursor level, it was more complete against the former. Furthermore, chimera spleen cells inhibited the generation of CTL activity against host- and donor-type MiHA but not against third party Ag. This specific suppressor activity was not T cell dependent, and was mediated by radiosensitive cells that are not found in freshly explanted organs from normal mice. Taken together, our results suggest that peripheral tolerization can be a remarkably efficient process to maintain tolerance to MiHA after BM transplantation. Thus, peripheral tolerizing mechanisms may contribute not only to the induction of tolerance to Mls superantigens or to the product of transgenes (if expressed at high levels) but also to a wide array of MiHA.

Animals↗
PubMed1979

Electroencephalographic and behavioral tolerance to and cross-tolerance between D-Ala2-methionine-enkephalinamide and morphine in the rat.

Rats were given repeated intraventricular (i.vt.) injections of D-enkephalin (20 microgram/4 hr) or morphine (20 microgram/4 hr) for 72 to 96 hr during electroencephalograman(EEG) recording. Initial epileptiform EEG and associated wet-dog shakes occurred following D-enkephalin but not morphine. The epileptoid EEG progressed to a continous high-voltage EEG synchrony similar to morphine and was associated with behavioral stupor. Rapid eye movement sleep was also suppressed. Repeated administration of D-enkephalin or morphine produced tolerance to their effects. When challenged with i.vt. morphine, D-enkephalin-tolerant rats were cross-tolerant to morphine. Likewise, morphine-tolerant rats were cross-tolerant to D-enkephalin. While the morphine-tolerant rats demonstrated a marked abstinence syndrome when challenged with naloxone (10 mg/kg i.p.), no abstinence signs were observed in the D-enkephalin-tolerant rats. The demonstration of tolerance and cross-tolerance between morphine and D-enkephalin suggests a similar mechanism of action, but the differential development of physical dependence may entail different mechanisms or receptor sensitivities for this effect. These findings of similarities and differences in the acute and chronic effects of D-enkephalin and morphine support the contention that heterogenous opiate receptors may mediate their pharmacologic actions.

Animals↗
PubMed1989

Tolerance and cross-tolerance between SIN-1 and nitric oxide in bovine coronary arteries.

The molecular mechanism of tolerance development to nitrovasodilators, most prominent with nitroglycerin, associated with desensitization of guanylate cyclase is still unclear. Nitric oxide (NO) appears to be the common denominator of this group of drugs that leads to guanylate cyclase activation, followed by increases in levels of cyclic GMP and relaxation. It was therefore decided to study whether NO itself, which causes some tolerance, interferes with the actions of (a) SIN-1 and sodium nitroprusside, both of which are thought to act directly by NO formation, which explains why they cause little tolerance; and (b) with the actions of nitroglycerin, which stimulates cyclic GMP formation only in the presence of cysteine and causes pronounced (large) tolerance. Experiments were performed in circular strips of isolated de-endothelialized bovine coronary artery by measuring isotonic changes in length and cyclic GMP determined by radioimmunoassay. When the strips were treated with submaximal effective concentrations of NO, some tolerance was observed, as shown by moderate attenuation of the rises in cyclic GMP, and a rightward shift of the dose-response curve of the relaxing effects by a dose factor of 10 (DF = 10). Exposure to nitroglycerin, SIN-1, or sodium nitroprusside rendered the strips cross-tolerant to NO to a comparable extent as NO itself, suggesting that under these conditions the NO component of all of these drugs that caused similar tolerance is displayed. When the strips were treated with NO and subsequently challenged with nitroglycerin, SIN-1, or sodium nitroprusside, the NO cross-tolerance was uniformly lower than the tolerance to the challenging agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1978

T cell tolerance in the chicken. I. Parameters affecting tolerance induction to human gamma-globulin in agammaglobulinemic and normal chickens.

T cell-mediated delayed hypersensitivity (DH) to human gamma-globulin (HGG) can be induced in chickens by subcutaneous injection of the antigen in complete Freund's adjuvant (CFA). In the present work, it has been demonstrated that specific tolerance of the cells mediating this DH can readily be induced in both normal and bursectomized (BX) FP strain chickens by simple i.v. injection of soluble antigen, regardless of the presence of antibody production to the tolerogen. A significant degree of tolerance at the DH and helper T cell levels could be generated in BX birds by injection of as little as 0.5 mg of HGG; such a dose only induced tolerance in normal birds when it had been previously deagregated by ultracentrifugation. Regular, nondeaggregated antigen could produce tolerance in normal animals, but only at doses of greater than 5 mg. The tolerizing injection induced a primary antibody response in normal birds in all cases, but a secondary response could not be obtained in animals rendered tolerant at the T cell level. Establishment of tolerance appeared to be very rapid, and animals remained refractory to induction of DH for at least 3 weeks after the tolerizing injection. The mode in which the antigen was presented to the animals appeared to be crucial in determining whether tolerance or sensitivity would be established.

Agammaglobulinemia↗
PubMedDate not supplied

Tolerance to aspirin in aspirin-sensitive asthmatics. Methods of inducing the tolerance state and its influence on the course of asthma and rhinosinusitis.

Aspirin-sensitive asthma is a serious clinical problem, frequently involving dramatic exacerbation and sometimes even death after the accidental ingestion of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). The majority of such asthmatics usually suffer from chronic rhinosinusitis and nasal polyps as well, and almost half of them from headaches. Widal et al. in 1922, and later, Zeiss and Lockey were able to elicit tolerance to aspirin (ASA). In all the studies performed so far, tolerance to ASA was achieved by giving double threshold ASA doses every day or every few hours. This method elicited severe dyspnea and sometimes pronounced extrabronchial sensitivity symptoms. From our previous studies, it appeared that the smaller the aspirin dose, the weaker the sensitivity symptoms, and that it is possible to induce tolerance after eliciting only very slight sensitivity reactions. Based on this observation, we elaborated a new method of eliciting aspirin tolerance by the daily administration of gradually increasing doses of aspirin starting with subthreshold doses. Applying this method, we achieved tolerance to aspirin without any adverse reactions. The patients in a tolerance state to ASA also tolerated well other NSAIDs, i.e. indomethacin and diclofenac. It is possible to maintain a tolerance state for a long time by the administration of ASA at proper intervals. It was shown that such a procedure may have a beneficial influence on the course of asthma and rhinitis. In our opinion, inducing and maintaining aspirin tolerance in aspirin-sensitive asthmatics is indicated in the following situations: 1) the need to treat coexisting rheumatic diseases; 2) the need to treat coexisting intractable headaches; and 3) the need for symptomatic treatment of ASA-sensitive asthma and rhinitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin↗
PubMed2005

Do copper tolerant fathead minnows produce copper tolerant adult offspring?

The objective of this study was to determine if the relative Cu tolerance of fathead minnow parents determines the relative Cu tolerance of their adult offspring. It was hypothesized that the adult offspring of Cu-tolerant minnows would inherit Cu tolerance from their parents. The relative Cu tolerance of 96 adult fish was determined based upon their reduction in swim performance following a sublethal exposure to 150 microg Cu/l. Control, Cu-tolerant and Cu-susceptible lines of fish were produced and fish within each line were allowed to breed. The offspring were raised to adults, then exposed to one of two sublethal Cu concentrations (150 or 225 microg Cu/l) for 8 days. There were no significant differences in relative Cu tolerance, as measured by reduction in swim performance, among the three lines of fish at either dose. However, significant differences in whole body Na+ occurred among the fish lines after exposure to 150 microg Cu/l, but not after exposure to 225 microg Cu/l. Significant differences in whole body Cu occurred between Cu-tolerant and Cu-susceptible fish lines after exposure to either Cu dose. The offspring did not inherit the relative Cu tolerance of their parents, however, the selection lines had diverged from each other, particularly with respect to their whole body Cu concentrations after exposure.

Analysis of Variance↗
PubMed1989

Long-lasting skin allograft tolerance in adult mice induced across fully allogeneic (multimajor H-2 plus multiminor histocompatibility) antigen barriers by a tolerance-inducing method using cyclophosphamide.

A new method of cyclophosphamide (CP)-induced skin allograft tolerance in mice that can regularly overcome fully allogeneic (major H-2 plus non-H-2) antigen barriers in mice has been established. The components of the method are intravenous or intraperitoneal administration of 50-100 micrograms of anti-Thy-1.2 mAb on day -1, intravenous injection of 90 x 10(6) allogeneic spleen cells mixed with 30 x 10(6) allogeneic bone marrow cells from the same donor on day 0, and intraperitoneal injection of 200 mg/kg CP on day 2. In each of four fully allogeneic donor----recipient combinations, including C3H/HeJ (C3H; H-2k)----C57BL/6J(B6; H-2b), B6----C3H, BALB/cByJ (BALB; H-2d)----B6, and BALB----C3H, long-lasting survival of skin allografts was induced in most of the recipient mice. The specific tolerant state induced was dependent on the doses of the antibody and bone marrow cells used. The optimal timing of CP treatment to induce tolerance was found to be 1-3 d after the stimulating cell injection. Treatment with the anti-Thy-1.2 antibody together with CP on day 2 after the cell injection on day 0 also induced profound tolerance. In the B6 mice made tolerant of C3H with antibody, C3H spleen cells plus C3H bone marrow cells, and then CP, a minimal degree of stable mixed chimerism was established and the antitolerogen (C3H) immune responses examined here, including delayed footpad reaction (DFR), CTL activity, and capacity for antibody production against donor-strain antigens were abrogated in a tolerogen-specific manner. From cell transfer experiments, the mechanism of tolerance could be largely attributed to reduction of effector T cells reactive against the tolerogen, and strong suppressive influences that might prolong skin allograft survival directly were not detected in the tolerant mice. Moreover, pretreatment with anti-Thy-1.2 antibody or anti-L3T4 (CD4) antibody was more effective than pretreatment with anti-Lyt-1 (CD5) antibody or anti-Lyt-2 (CD8) antibody as an initial step in tolerance induction. These results suggest that permanent tolerance to fully allogeneic skin grafts may be induced because antibody given before the stimulating cell injection reduces the number of reactive T cells in the recipient mice. This antibody treatment may facilitate an antigen-stimulated destruction of responding and thus proliferating cells with CP by preventing a possibly less proliferative, more rapid maturation of reactive T cells or by destroying residual effector T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Differences in penicillin-binding protein patterns of penicillin tolerant and non-tolerant group A streptococci.

The penicillin-binding proteins (PBPs) of five penicillin tolerant group A streptococci and their isogenic non-tolerant strains, and seven unrelated non-tolerant group A streptococci were compared. PBPs from late logarithmic cultures were labelled in vitro with 3H-benzylpenicillin and analysed by SDS-PAGE and fluorography. The PBP patterns for all non-tolerant strains were identical. This pattern differed markedly from that for penicillin tolerant strains, both qualitatively and quantitatively. The most striking change in penicillin tolerant strains was decreased binding of 3H-penicillin to PBP 3 and increased binding to PBP 5, while PBP 2a was replaced by a new PBP (PBP 2a') of lower electrophoretic mobility. Tolerance was lost during storage but could be restored by consecutive transfers on to penicillin gradient agar plates. At the same time the PBP profiles of these strains became identical to those found for stable tolerant strains. These results suggest the possibility that PBP 2a' and PBP 5 in combination with other PBP alterations play a role in penicillin tolerance found in group A streptococci.

Bacterial Outer Membrane Proteins↗
PubMed1996

Adaptive acid tolerance response in Listeria monocytogenes: isolation of an acid-tolerant mutant which demonstrates increased virulence.

The ability of Listeria monocytogenes to tolerate low-pH environments is of particular importance because the pathogen encounters such environments in vivo, both during passage through the stomach and within the macrophage phagosome. In our study, L. monocytogenes was shown to exhibit a significant adaptive acid tolerance response following a 1-h exposure to mild acid (pH 5.5), which is capable of protecting cells from severe acid stress (pH 3.5). Susceptibility to pH 3.5 acid is growth phase dependent. Stationary-phase Listeria cultures are naturally resistant to the challenge pH (pH 3.5), while exponential-phase cultures require adaptation at pH 5.5 to induce acid tolerance. Adaptation requires protein synthesis, since treatment with chloramphenicol prevents the development of acid tolerance. Induction of the acid tolerance response also protects L. monocytogenes against the effect of other environmental stresses. Acid-adapted cells demonstrate increased tolerance toward thermal stress, osmotic stress, crystal violet, and ethanol. Following prolonged exposure of L. monocytogenes to pH 3.5, we isolated mutants which constitutively demonstrate increased acid tolerance at all stages of the growth cycle. These mutants do not display full acid tolerance, but their resistance to low pH can be further increased following adaptation to mild-acid conditions. The mutants demonstrated increased lethality for mice relative to that of the wild type when inoculated by the intraperitoneal route. When administered as lower inocula, the mutants reached higher levels in the spleens of infected mice than did the wild type. The data suggest that low-pH conditions may have the potential to select for L. monocytogenes mutants with increased natural acid tolerance and increased virulence.

Acids↗