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 127 records · Page 7Linked to original sources
PubMed1990

Induction of transplantation tolerance by intravenous injection of allogeneic lymphocytes across an H-2 class II mismatch. Different mechanisms operate in tolerization across an H-2 class I vs. H-2 class II disparity.

Previously, we have shown that the intravenous (i.v.) injection of allogeneic lymphocytes across an H-2 class I-mutant disparity leads to specific skin allograft tolerance caused by irradiation-sensitive donor T cells, which function as veto cells. In the present study, we show that the i.v. injection of H-2 class II-incompatible spleen cells also results in specific skin allograft tolerance. However, tolerance induction depends on the presence of irradiation-resistant non-T cells in the donor cell inoculum. Thus, different mechanisms operate in tolerance induction across an H-2 class I vs. H-2 class II mismatch. I.v. injection of allogeneic spleen cells across an H-2 class I plus class II disparity does not result in skin allograft tolerance. Finally, our data show that transfusion-induced suppression of the delayed-type hypersensitivity response against alloantigens does not correlate with skin allograft tolerance induced by i.v. injected allogeneic lymphocytes. In conclusion, the type of H-2 mismatch between transfusion donor and recipient not only determines the occurrence of allograft tolerance but also the mechanism leading to tolerization.

Animals↗
PubMed1998

Nasal tolerance to experimental autoimmune myasthenia gravis: tolerance reversal by nasal administration of minute amounts of interferon-gamma.

Tolerance to B cell-mediated experimental autoimmune myasthenia gravis (EAMG), an animal model for myasthenia gravis (MG) in humans, can be achieved by nasal administration of the autoantigen acetylcholine receptor (AChR). Nasal tolerance induction requires only 1/1000 of the amount of AChR used for oral tolerance induction, but is as effective in preventing EAMG. To investigate whether nasally induced tolerance to EAMG can be influenced by nasal administration of cytokines, recombinant rat IFN-gamma (total 5000 U/rat), a combination of AChR and IFN-gamma or AChR alone was given nasally to Lewis rats before immunization with AChR and complete Freund's adjuvant (CFA). One additional group of rats received the same amount of AChR nasally in conjunction with IFN-gamma (total 5000 U/rat) intraperitoneally. AChR given alone nasally induced effective tolerance to EAMG whereas rats receiving AChR + IFN-gamma by the nasal route exhibited a similar disease pattern, and similarly escalated T and B cell responses to AChR when compared to control EAMG rats. In contrast, administration of IFN-gamma i.p. together with AChR nasally did not affect the induction of tolerance to EAMG. IFN-gamma given alone nasally did not affect clinical EAMG. This study demonstrates that nasal tolerance can be modulated by nasal administration of minute amounts of IFN-gamma. Nasal administration of certain cytokines with beneficial effects might broaden the effectiveness of applying nasal tolerance as a potential therapeutic means of preventing autoimmune diseases.

Administration, Intranasal↗
PubMed2001

Induction of tolerance and cross-tolerance to methacrylate contact sensitizers.

Induction of immunological tolerance to contact allergens might prevent undesired sensitization, in particular to occupational sensitizers, e.g., methacrylates (MA). Here, using a guinea pig model, we studied to which extent tolerance to one methacrylate might result in cross-tolerance to other congeners. Strong tolerance to the monomethacrylates hydroxy-ethyl MA (HEMA) and methyl MA, but not to the dimethacrylate ethylene-glycol MA (EGDMA) could be induced. The induced tolerance was stable, could not be broken by repeated sensitization attempts, and was mediated by specific suppressor cells, as demonstrated in T cell transfer experiments. In HEMA-tolerized animals, strong cross-tolerance to methacrylate congeners, including EGDMA, itself being nontolerogenic and showing the lowest cross-reactivity to HEMA, was found. Thus, oral application of contact allergens, to which skin contact cannot be avoided, e.g., in occupational settings, can induce broad cross-tolerance to related substances and might offer a promising preventive approach.

Allergens↗
PubMed2001

Importance of sex and relative efficacy at the mu opioid receptor in the development of tolerance and cross-tolerance to the antinociceptive effects of opioids.

RATIONALE: Recent studies indicate that mu opioids are generally more potent and effective as antinociceptive agents in male than female rodents. OBJECTIVES: To evaluate the influence of sex on the development of tolerance to the antinociceptive effects of morphine and cross-tolerance to the lower efficacy mu opioids buprenorphine and dezocine in F344 and Lewis rats. METHODS: Using a warm-water tail-withdrawal procedure, the antinociceptive effects of morphine, buprenorphine and dezocine were determined before and during chronic morphine (5, 10 and 20 mg/kg, b.i.d., for 7 and 14 days) administration. RESULTS: Under acute conditions, morphine was more potent in males and during chronic morphine administration tolerance development was generally greater in males. As males were more sensitive to the acute effects of morphine, the functional chronic morphine dose (i.e., chronic morphine dose/acute morphine ED50) administered to males was larger than in females. Analyses of the relationship between the functional chronic morphine dose and tolerance indicated that morphine tolerance development was comparable in males and females. Under acute conditions, buprenorphine and dezocine were more potent and effective in males. During chronic morphine administration, cross-tolerance was conferred to these opioids as evidenced by rightward, and in some cases downward, shifts in their dose-effect curves. Decreases in the maximal effects produced by buprenorphine and dezocine were more frequently observed in females. CONCLUSIONS: That comparable levels of morphine tolerance were obtained in males and females when the functional chronic morphine dose was taken into consideration suggests that the mechanism underlying tolerance is not sex-dependent. Sex differences in the effectiveness of buprenorphine and dezocine when administered acutely and during chronic morphine administration further suggest that these opioids have lower efficacy at the mu opioid receptor in females.

Analgesics↗
PubMed1986

Neonatal tolerance induction in the thymus to MHC-class II-associated antigens. I. Preferential induction of tolerance to Mls antigens and resistance to allo-MHC antigens.

Neonatal tolerance inducibility of self-major histocompatibility complex (MHC)-class II-associated antigens was compared with that of allo-class II antigens. BALB/c (H-2d, Mlsb) mice, less than 24 hr after birth, were intravenously injected with bone marrow cells of either (BALB/c X DBA/2)F1 (H-2d, Mlsb/a, semiallogeneic at the Mls locus) or (BALB/c X B10.BR)F1 (H-2d/k, Mlsb; semiallogeneic at the MHC), as antigens. The mice were tested for in vivo immune activity of class II-reactive T cells by means of the popliteal lymph node-swelling assay. They developed tolerance, irrespective of type of antigens, showing profoundly suppressed host-versus-graft reaction, and those tolerized to the allo-MHC antigens accepted skin grafts of the corresponding allogeneic mice. In the thymus and spleen of the Mls-tolerant mice, antigen-specific class II-reactive T-cell activity was completely abolished, without the apparent involvement of suppressor cells. In contrast, the activity in allo-MHC-tolerant mice was not reduced in either thymus or peripheral lymphoid organs, suggesting that systemic hyporesponsiveness is attributable to reversible suppression of immune competent cells. The resistance for cell-level tolerance induction to allo-class II antigens may not be ascribed to the active participation of allo-MHC antigens in prevention of or in escape from tolerance induction or both, since an injection of bone marrow cells of both Mls and H-2-semiallogeneic (DBA/2 X B10.BR)F1 (H-2d/k, Mlsa/b) mice could induce tolerance to Mlsa-H-2d antigens in newborn thymus cells.

Animals↗
PubMed1978

LSD and 5-HTP: tolerance and cross-tolerance relationships.

Tolerance and cross-tolerance relationships between lysergic acid diethylamide (LSD) and 5-hydroxytryptophan (5-HTP) were studied in rats trained on an operant task. The results demonstrated that behavioral tolerance to both compounds occur in the rat and that asymmetrical cross-tolerance relationships exist; that is, animals tolerant to 5-HTP were cross-tolerant to LSD, but animals tolerant to LSD were not cross-tolerant to 5-HTP.

5-Hydroxytryptophan↗
PubMed1982

Tolerance and cross tolerance to morphine after chronic spinal D-Ala2-D-Leu5-enkephalin infusion.

The development of tolerance and cross tolerance to morphine at spinal cord levels on the tall flick inhibition was studied in rats tolerant to D-Ala2-D-Leu5-enkephalin (DADL). The long term intrathecal infusion of DADL was accomplished by means of osmotic minipumps. Chronic intrathecal infusion of DADL for 5 days caused a shift of dose response curves of both DADL and morphine sulfate injected intrathecally to the right indicating that tolerance and cross tolerance to morphine had developed after long term intrathecal infusion of DADL. The shift of the dose response curve of DADL was parallel, whereas that of morphine was non-parallel and flattening. Concomitant intrathecal infusion of naloxone which was more sensitive in blocking mu-opioid receptor than delta-opioid receptor blocked the development of cross tolerance to morphine while the development of tolerance to DADL was left unaffected. The studies present the evidence that two types of opioid receptors, delta- and mu-opioid in the spinal cord of rats are involved in the development of tolerance by chronic DADL exposure.

Animals↗
PubMed1984

Differential tolerance and cross-tolerance to repeated daily injections of mu and kappa opioid agonists in the rat.

This study was designed to compare the development of tolerance to the effects of morphine and ethylketocyclazocine ( EKC ) on EEG, EEG power spectra and behavior and to assess any cross-tolerance. Adult female Sprague-Dawley rats were implanted with chronic cortical EEG and temporalis muscle EMG recording electrodes and with permanent cannulae in the external jugular vein. In non-tolerant rats, 10 mg/kg (i.v.) injections of morphine and of ethylketocyclazocine produced biphasic EEG and behavioral profiles lasting for 3 and 2 hr , respectively. In both cases, a stuporous phase, associated with high-voltage cortical EEG bursts, was followed by a hyperactive phase, associated with low-voltage desynchronized EEG. However, power spectra derived from epochs of EEG bursting produced by morphine and ethylketocyclazocine were qualitatively different. One group of rats was then given a series of automatic, intravenous injections of morphine, while a second group received ethylketocyclazocine. Following chronic treatment, the duration of the biphasic EEG and behavioral profiles induced by morphine and ethylketocyclazocine were both significantly reduced. In both cases, the intensity of EEG bursting was also reduced as reflected by significant quantitative reductions in EEG power spectral densities. In assessments of cross-tolerance, ethylketocyclazocine tolerant rats were found to be cross-tolerant to the effects of morphine. However, no cross-tolerance to the effects of ethylketocyclazocine in morphine-tolerant rats was observed. These data contribute to a further understanding of the relative heterogeneity of mu and kappa receptor populations and to the differential pharmacodynamics of morphine and ethylketocyclazocine.

Animals↗
PubMed1990

Tolerance to nicotine-induced sympathoadrenal stimulation and cross-tolerance to stress: differential central and peripheral mechanisms in rats.

Nicotine stimulates the secretion of catecholamines from sympathetic nerve endings and adrenal medulla by acting on peripheral nicotinic cholinergic receptors. Nicotine is also a potent stimulant in the central nervous system but the significance of nicotinic receptors in brain in mediating cardiovascular and sympathoadrenal responses to nicotine is unclear. The responses of resting plasma catecholamines, blood pressure and heart rate were compared in rats receiving nicotine, administered either systemically or intracerebroventricularly (i.c.v.). Sympathoadrenal stress responses were also studied in rats rendered tolerant to nicotine from repeated systemic or intraventricular injections. Nicotine, given either intraventricularly or systemically, produced dose-related increases in the concentration of epinephrine in plasma. Little effect on norepinephrine in plasma was observed with nicotine given intraventricularly, indicating predominant stimulation of adrenomedullary pathways. In contrast, nicotine, given systemically, produced comparable increases in both epinephrine and norepinephrine. Blood pressure increased and heart rate fell in response to either intraventricular or systemic administration of nicotine. Rats exhibited tolerance to nicotine 24 hr after a single intraventricular injection; however, tolerance was not detected with systemically injected nicotine unless the injections were given at least every 30 min. Whereas rats rendered tolerant to systemic administration of nicotine were cross-tolerant to stress, with respect to sympathoadrenal stimulation, cross-tolerance with stress was not detected in rats treated with nicotine repeatedly by the intraventricular route. These results indicate that nicotinic receptors in brain modulate the central sympathetic outflow and adapt readily to nicotine stimulation with prolonged tolerance, but are probably not involved in sympathoadrenal stress responses. Peripheral nicotinic receptors, regulating sympathoadrenal secretion of catecholamines, displayed much shorter-lasting tolerance.

Adrenal Medulla↗
PubMed1986

Tolerance to and cross-tolerance among ethanol, pentobarbital and chlordiazepoxide.

The acute administration of ethanol, pentobarbital and chlordiazepoxide impaired, in a dose-dependent manner, the performance of rats on the moving-belt and two-way shuttle-box avoidance tests. Administration of these drugs for three weeks resulted in tolerance to their motor-impairing effects. Tolerance to ethanol or pentobarbital was characterized by a parallel shift of the dose-response curve to the right. Tolerance to chlordiazepoxide, however, was of greater extent and was accompanied by an apparent flattening of the dose-response curve. Symmetrical cross-tolerance developed between ethanol and pentobarbital. On the other hand, while chlordiazepoxide treatment conferred full cross-tolerance to ethanol and pentobarbital, only partial cross-tolerance to chlordiazepoxide was observed following treatment with ethanol or pentobarbital. These results suggest that at least part of the tolerance to chlordiazepoxide depends on changes in specific benzodiazepine receptors and is independent of the tolerance associated with non-specific changes in the cell membrane.

Animals↗
PubMed2001

Rapid tolerance to Delta(9)-tetrahydrocannabinol and cross-tolerance between ethanol and Delta(9)-tetrahydrocannabinol in mice.

Motor incoordination in the rota-rod test was used to assess the development of rapid tolerance to Delta(9)-tetrahydrocannabinol and rapid cross-tolerance between ethanol and Delta(9)-tetrahydrocannabinol in mice. Further, the influence of the cannabinoid receptor antagonist SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide) on the motor impairment induced by both drugs was examined. Mice were injected on day 1 with equipotent doses of Delta(9)-tetrahydrocannabinol (28 mg/kg, i.p.) and ethanol (2.25 g/kg, i.p.) and tested at 30, 60 and 90 min after the injections. On day 2, control groups received ethanol or Delta(9)-tetrahydrocannabinol, some groups received the same treatment as the day before, while the remaining groups switched the treatment. All groups were tested to evaluate tolerance. The development of rapid tolerance to Delta(9)-tetrahydrocannabinol was observed and pretreatment with ethanol resulted in rapid cross-tolerance to Delta(9)-tetrahydrocannabinol. SR 141716A (2 mg/kg, i.p.) failed to block the development of rapid tolerance to both drugs, ethanol and Delta(9)-tetrahydrocannabinol. These results suggest that Delta(9)-tetrahydrocannabinol, similarly to ethanol, can induce rapid tolerance to motor incoordination in mice. They also support the use of the 2-day protocol as an effective procedure to reduce the length of drug exposure necessary to induce tolerance.

Animals↗
PubMed1999

Tolerance and morphine-induced cross-tolerance are not shown to Tyr-W-MIF-1 analgesia.

Tolerance and cross-tolerance between Tyr-W-MIF-1, a mixed micro-agonist/antagonist, and morphine were examined. Opiate dependence also was examined. Rats were pretreated with Tyr-W-MIF-1, morphine, or saline for 4 days. On day 5, the animals were tested for Tyr-W-MIF-1 analgesia, morphine analgesia, or naloxone-precipitated withdrawal. Tyr-W-MIF-1- and morphine-pretreated animals showed similar levels of dependence. Animals pretreated with Tyr-W-MIF-1 failed to express tolerance to Tyr-W-MIF-1 analgesia but did display cross-tolerance to morphine analgesia. Animals pretreated with morphine displayed tolerance to morphine analgesia but did not express cross-tolerance to Tyr-W-MIF-1 analgesia. Therefore, tolerance and morphine-induced cross-tolerance were not expressed to Tyr-W-MIF-1 analgesia.

Animals↗
PubMed1997

Tolerance and cross tolerance to the accuracy- and rate-decreasing effects of mu opioids in rats responding under a fixed-consecutive-number schedule.

The purpose of the present investigation was to examine the development of tolerance to the effects of morphine and other mu opioids in rats responding under a fixed-consecutive-number (FCN) schedule of food presentation. To this end, five rats were trained under an FCN schedule and subsequently tested with a variety of mu opioids both before and during chronic exposure to a 0.4 mg/ml morphine drinking solution. Morphine, fentanyl, buprenorphine, butorphanol and nalbuphine produced dose-dependent decreases in both accuracy and response rate when tested prior to the chronic regimen. In most instances, doses of these drugs that decreased accuracy also decreased response rate. During chronic treatment, tolerance developed to the effects of morphine and cross-tolerance was conferred to the effects of fentanyl, buprenorphine and butorphanol. A greater degree of tolerance was conferred to the effects of butorphanol than to the other opioids examined, and the degree of tolerance conferred to butorphanol's rate-decreasing effects was greater than the degree of tolerance conferred to its accuracy-decreasing effects. Doses of naloxone that had no effect prior to morphine treatment produced large decreases in accuracy and response rate when tested during the chronic regimen. In contrast to the other opioids examined, the potency of nalbuphine was not altered by chronic morphine administration. These data emphasize the importance of both pharmacological and procedural variables in the development of tolerance and cross tolerance to the behavioral effects of opioids.

Animals↗
PubMed2002

The immune tolerance network: a new paradigm for developing tolerance-inducing therapies.

Immune tolerance therapies are designed to reprogram immune cells in a highly specific fashion to eliminate pathogenic responses while preserving protective immunity. A concept that has tantalized immunologists for decades, the development of tolerance-inducing therapies, would revolutionize the management of a wide range of chronic and often debilitating diseases by obviating the need for lifelong immunosuppressive regimens. The advances of the past decade have provided a more detailed understanding of the molecular events associated with T-cell recognition and activation. Building on these advances, immunologists have demonstrated the feasibility of various tolerance-inducing approaches in small- and large-animal models of autoimmunity, allergy, and transplant graft rejection. Unprecedented opportunities to test these approaches in a variety of human diseases have now emerged. To capitalize on these advances, the National Institutes of Health recently established the Immune Tolerance Network (ITN), an international consortium of more than 70 basic and clinical immunologists dedicated to the evaluation of novel tolerance-inducing therapies and associated studies of immunologic mechanisms. By using a unique interactive approach to accelerate the development of clinical tolerance therapies, the ITN is partnering with the biotechnology and pharmaceutical industries to examine innovative tolerogenic approaches in a range of allergic and autoimmune diseases and to prevent graft rejection after transplantation. Two years since its inception, the ITN now has approximately 2 dozen clinical trials or tolerance assays studies ongoing or in later stages of protocol development. This report summarizes the rationale for emphasizing clinical research on immune tolerance and highlights the progress of the ITN.

Autoimmune Diseases↗
PubMed1977

B-cell tolerance. II. Trinitrophenyl human gamma globulin-induced tolerance in adult and neonatal murine B cells responsive to thymus-dependent and independent forms of the same hapten.

Neonatal splenic B cells which are responsive to thymus-dependent antigens (TD) are exquisitely susceptible to induction of tolerance (1,2). This state of tolerance is not mediated by suppressor T cells and is not a result of suboptimal macrophage function (1 and footnote one). In adult mice, induction of B-cell tolerance is not achieved with doses of antigen 1,000-fold higher (1) than those required to produce the same degree of unresponsiveness in neonates. In contrast to these results, studies with T-independent (TI) antigens indicate that neonatal and adult splenic B cells are equally susceptible to tolerance induction (3,4). However, such studies have not ascertained whether the neonate is more resistant to tolerance induction or the adult is hypersusceptible, i.e., does the induction of tolerance in cells responsive to TI antigens resemble that of adult or neonatal cells responsive to TD antigens? The answer is pertinent to determining the relative maturity of the B cells which can be tolerized or respond to TI or TD antigens. We report here the direct comparison of tolerogen sensitivity of adult and neonatal TD and TI responses by inducing tolerance in vitro with trinitophenyl human gamma globulin (TNP(17)HgG) and assaying unresponsiveness with TD and TI forms of the TNP determinant.

Animals↗
PubMed1979

The induction of hapten-specific immunological tolerance and immunity in B lymphocytes. VI. Differential tolerance susceptibility in adult spleen as a function of B-cell maturation level.

The maturation level of the B-lymphocyte subpopulations involved in trinitrophenyl (TNP)-specific immunological tolerance in adult mice induced by the injection of trinitrobenzenesulfonic acid (TNBS) was investigated using in vitro antigen-specific and nonspecific polyclonal stimulation. The maturity of the B-cell subsets being studied was defined by the antigen or polyclonal activator which evoked a response. Thus, the thymic independent (TI-1) antigen TNP-lipopolysaccharide (TNP-LPS) and the polyclonal stimulant LPS were used to activate immature, neonatal-type B lymphocytes, whereas mature, adult-type B cells were responsive to the TI-2 antigen, TNP-Ficoll, and the nonspecific activator, purified protein derivative (PPD). Whereas unresponsiveness in TNP-LPS-reactive (immature) B cells 4 d after TNBS treatment was previously shown to be the result of functional deletion, partially reversible receptor blockade was detected in this study early after tolerogen treatment. By the 24-h point, tolerance was irreversible, as assessed by 24-h of antigen-free incubation and cocultivation of tolerant cells with control splenocytes. Tolerance was induced more rapidly in immature, TI-1 B cells than in mature TI-2 B lymphocytes. B lymphocytes reactive to TNP-Ficoll were also less susceptible to receptor blockade. Using LPS as a nonspecific probe for immature B cells, 60% tolerance in high affinity TNP-specific cells was induced within 12 h of TNBS treatment, and complete unresponsiveness by 24 h. In contrast, no significant decrease in response to the mature B-cell activator, PPD, occurred until day 2. Furthermore, the 50% tolerance level was achieved in TNP-specific LPS-reactive B cells by 100 times less tolerogen than required for PPD-responsive cells. Thus, TNBS-induced unresponsiveness in cells reactive to TNP-LPS is initially a result of reversible receptor blockade which leads within 4 d to functional deletion. Immature, TI-1 B lymphocytes, which give polyclonal responses to LPS and antigen-specific responses to TNP-LPS, are rendered tolerant to TNBS more rapidly and at lower tolerogen does than mature, TI-2 mouse B cells which react polyclonally to PPD and specifically to TNP-Ficoll. Moreover, these data show that both the immature and the mature B lymphocyts with these characteristic tolerance susceptibilities and specific and nonspecific immune response patterns are present in the adult mouse spleen.

Age Factors↗
PubMed1982

A natural model of immunologic tolerance. Tolerance to murine C5 is mediated by T cells, and antigen is required to maintain unresponsiveness.

A unique experimental model is described, where natural immunologic tolerance to a well-defined soluble native antigen (murine C5) is examined in congenic strains of mice that differ only by the presence or the absence of C5. A highly sensitive hemolytic assay was developed to detect nanogram amounts of C5 as well as an assay of anti-C5 inhibition of C5 hemolytic activity. The latter was more sensitive than immunodiffusion. Two reciprocal approaches were used to study the cellular basis of tolerance in irradiated hosts of either strain. In the first, lymphoid cells from either strain were transferred to irradiated B10.D2OSN hosts that were lacking C5 and so would not hinder detection of anti-C5 antibody upon challenge with murine C5. Second, lymphoid cells from either strain were transferred to irradiated B10.D2NSN hosts, whose native C5 provided the antigenic stimulus. The immune response of whole nonadherent spleen cell suspension as well as mixtures of T and B cells (separated on the basis of surface immunoglobulin) from either strain were studied. In addition, the duration of tolerance and the antigen requirement to maintain it in irradiated C5-deficient hosts repopulated with C5-sufficient spleen cells was examined. The positive control of irradiated C5-deficient hosts repopulated with syngeneic spleen cells showed a primary and secondary response to immunization. In contrast, C5-sufficient spleen cells failed to respond both in the primary and the secondary response. Because the unresponsiveness was not caused by antigen carryover and was not antigen specific, it represents central tolerance. In C5-sufficient irradiated hosts (where immunization was not required and antigen was present in natural form and physiological concentration), transfer of C5-deficient cells mediated a drop in C5 levels to 10-20% of that noted in unreconstituted controls. T and B cell mixing experiments from the two strains into deficient or sufficient hosts demonstrated that tolerance is T cell dependent and that C5-sufficient or -deficient B cells could cooperate with nontolerant C5-sufficient T cells to produce significant anti-C5 antibody or mediate a significant drop in C5 levels. In addition, the presence of antigen was necessary to maintain tolerance. In conclusion, these results show that (a) natural tolerance to C5 is an active process that is T cell dependent and requires the presence of antigen; (b) in this natural model, clonal abortion does not seem to occur; and (c) both tolerant and nontolerant B cells retain the capacity to produce autoantibody.

Animals↗
PubMed1988

Tolerance to tumor necrosis factor in rats and the relationship to endotoxin tolerance and toxicity.

Treatment of rats with recombinant human TNF initially causes a marked decrease in food intake, a loss of body weight, and a negative nitrogen balance. These alterations normalize with continued twice daily intraperitoneal injections of the same dose. Rats tolerized to TNF in this manner are refractory to a lethal dose of TNF. Also, TNF-pretreated and -tolerized rats have prolonged survival and reversed histopathologic changes after injection of a lethal dose of endotoxin compared with control animals. The TNF-tolerant state is dependent on the dose of TNF used and the length of TNF pretreatment. TNF-induced tolerance is relatively short lived, being present 2-4 d after TNF pretreatment and dissipating by 2 wk. Rats made tolerant to endotoxin are also tolerant to a lethal dose of TNF. A bidirectional crossreacting tolerance exists between TNF and endotoxin. The mechanism of TNF tolerance is unclear, but it does not appear to be due to a humoral immune response or a perturbation of the uptake and clearance of injected TNF.

Animals↗