Immunological tolerance to Nippostrongylus brasiliensis: the response of the tolerant host to late reinfection.
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Animals↗
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[Clinical study of prothionamide (1321 Th) administered by venous route in treatment of tuberculosis. General tolerance. Neuropsychic tolerance (apropos of 76 cases)].
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Adult↗
[Study of the levels of plasma free fatty acids during 3 dynamic tests of carbohydrate metabolism (induced hyperglycemia, insulin tolerance, test, tolbutamide tolerance test) in different clinical types of diabetes mellitus].
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Blood↗
[Tolerance of intraduodenal tube feeding. Prospective studies of the tolerance of a 10-day, continuous intraduodenal administration of a peptide diet and its effects on various serum parameters in healthy subjects].
Filiform nasoduodenal nutrition tubes in connection with portable infusion pumps are now available and by this way continuous enteral nutrition is given to a certain number of patients, thus avoiding expensive parenteral nutrition which demands a great deal of nursing care and bears a greater risk of complications. In order to study the acceptance and effects of this nutrition, 10 healthy persons were fed by the new system with a fiber-free, low molecular peptide diet. The probands had to write a daily protocol and, at the end of the test, had to answer a questionnaire regarding the effectivity and social consequences of the system and their subjective sensations. Before and after the enteral nutrition phase, different serum parameters were also determined. The results show that a continuous intraduodenal nutrition by tube can be achieved outside the clinic allowing to exercise the profession. The general well-being of the probands was moderately disturbed only by the tube whereas the other points from the questionnaire were less disturbing. Regarding the serum parameters only a reduction in the serum potassium was remarkable.
Adolescent↗
Cellular basis of immunologic tolerance following total bowel transplantation in rats. II. Dominant role of suppressor T cells in adoptive transfer of acquired tolerance to vascularized allografts.
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Animals↗
Insulin tolerance test and tolbutamide tolerance test in acromegaly.
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Acromegaly↗
Perspectives on opioid tolerance from basic research: behavioural studies after spinal administration in rodents.
For tolerance development studies, computer modelling and statistical tests suggested that the equation which best described the decrement of analgesic effect was best served by an exponential decay function. Further analysis of the time course data led to the tentative conclusion that all groups of animals became tolerant at the same rate, regardless of drug or dose. A literature search revealed then, as it does now, that although there are many statements regarding the rate of opioid tolerance, there has been little systematic investigation of this. The Holy Grail of obtaining the rates of tolerance for a number of opioid agents in a systematic study is well within grasp. This information will be needed in clinical practice for the rational choice of opioid with regard to rate of the development of tolerance. The working hypothesis that emerges for the magnitude of opioid tolerance is that more potent agonists produce less tolerance. Further confirmation of this hypothesis has been forthcoming. This suggests that clinical use of more potent opioids, such as fentanyl, should be considered as a substitute for morphine in long term treatment regimens. The working hypothesis for cross-tolerance is that agents acting on the same receptors will show cross-tolerance. Cross-tolerance will also be observed among agents acting on different receptors, but only those that exhibit pharmacological synergy after short term administration. Asymmetry of cross-tolerance can occur, as the magnitude of this cross-tolerance is determined by the relative potency of the toleragen with regard to that of the probe agent. Given the additional factor of receptor selectivity with agents of different receptor classes, types and subtypes, new studies need to be designed combining the toleragen with a selective antagonist to determine the precise receptor mediation of the magnitude of tolerance, and thus cross-tolerance. For example, the delta opioid DADLE infused with a mu selective opioid antagonist would produce an animal strictly tolerant at delta receptors, as DADLE has been implicated to have some effects at mu receptors. In any event, consideration of the quantitative measures of cross-tolerance are extremely important to help shape a rationale treatment plan for patients who may become tolerant to a particular class of analgesics. In general, direct toleragen administration by constant dose, constant rate infusion into local central nervous system (CNS) regions will provide the most rigorous tolerance studies for examination of the pharmacodynamic theories of tolerance, as adaptations in processes affecting central bioavailability, such as dispositional changes in the blood-brain barrier or fibrous encapsulation of an implanted subcutaneous pellet, are circumvented. The above considerations also are relevant for studies of tolerance and cross-tolerance after intracerebroventricular administration or, in general, for tolerance studies after systemic administration. The possibility of probe administration to the same region of CNS that was rendered tolerant, as in the Y-catheter method, further enhances the focus on the pharmacodynamic mechanisms of tolerance without the ancillary and literally peripheral concerns of a dispositional nature. A posological approach to these studies cannot be overemphasized, as it is only through such time consuming and costly experiments that rigorous, quantitative data can be obtained. Such data may help to guide the hand of the physician towards rational therapeutic intervention in the treatment of patients with chronic pain and opioid tolerance.
Analgesics, Opioid↗
[Development of opioid tolerance -- molecular mechanisms and clinical consequences].
INTRODUCTION: One often identified effect of opioid administration is that of the development of tolerance to the analgesic effect. While it is generally agreed that tolerance to opioid analgesia does occur, it does not appear to be a limiting factor. Dose escalation in chronic pain therapy is considered to be predominantly a consequence of increasing pain, which is a result of increasing nociceptive input as the disease progresses. The underlying cause of tolerance to opioids, however, as commonly identified in the ICU can be identified as an adaptation process. When the opioid is given continuously several causes of adaptation can be identified, all of which can be traced back to the cellular and molecular level. RECEPTOR RELATED CHANGES INVOLVED IN TOLERANCE: Initial effects of opioid administration in most individuals are analgesia, sedation, nausea/vomiting, respiratory depression, pupillary constriction, constipation and euphoria or dysphoria. However, numerous studies and clinical experience suggest that tolerance to different opioid effects develop at different rates, which has been termed selective tolerance. While tolerance to nausea, vomiting, sedation, euphoria and respiratory depression occur rapidly, there is minimal development of tolerance to constipation and miosis. Such diversity suggest receptor-related differences in the speed of development of tolerance. In the ICU other compounds such as benzodiazepines, when given together with opioids, seem to speed up the rate of development of tolerance of the latter. Such an effect very likely is due to a reduction in activity of the descending inhibitory nervous system. In addition, there is surmountable data suggesting that the higher the intrinsic activity of the opioid at only one receptor site, lesser receptors are needed in order to induce a potent analgesic effect. As a net result the incidence of tolerance is less likely to become clinically apparent when potent ligands such as fentanyl or sufentanil are administered. N-METHYL-D-ASPARTATE (NMDA) ACTIVATION, OPIOID RECEPTOR INTERNALIZATION AND DESENSITIZATION: An altered metabolism has little effect on the rate of development of tolerance. In chronic pain treatment with morphine, however, an increased ratio of the metabolite morphine-3-glucuronide, with antiopioid effects, to morphine-6-glucuronide is associated with staggering doses of the analgesic. Opioids which interact with micro - and/or kappa-binding sites, demonstrate an adaptation process called desensitization which is due to a reduced interaction with the internal second messenger system called G-protein. This is only a short-lived phenomenon following binding of the ligand. Another underlying mechanism of tolerance development is that of internalization of the opioid receptors. This short-lived phenomenon, termed endocytosis, results in lesser binding sites available for the mediation of analgesia. Another and more relevant mechanism of long-term opioid binding is that of subsequent protein kinase C (PKC), phospholipase C (PLC) translocation and activation of nitric oxide synthetase (NOS). All of this contributes to a N-methyl-D-aspartate (NMDA) receptor activation with ensuing antiopioid effect and tolerance. CLINICAL CONSEQUENCES FOLLOWING THE DEVELOPMENT OF TOLERANCE: Most likely genetic difference in opioid receptor synthesis and difference in their affinities for various ligands is the cause for the wide margin of dose variability in patients (genetic polymorphism). Once tolerance to the analgesic effect of the opioid is observed and in order to avoid unnecessary further development of tolerance, simultaneous administration of other receptor mediated analgesics is advocated. In the perioperative period strategies like the multimodal analgesic concept is fostered. It consists of the simultaneous administration of low-dose ketamine, co-administration of an alpha 2-agonist, and the administration of a selective COX-2 inhibitor (refecoxib, parecoxib) respectively. In chronic pain therapy combined administration with either dextromethorpharphane, or opioid rotation of a more potent ligand such as methadone, fentanyl TTS or oxycodone is suggested. Since conversion factors are not reliable in opioid rotation, it is best to start off with 50 % of the equivalent dose and rapidly titrate to the desired effect. With regard to tolerance development in the ICU, co-administration of an alpha 2-agonist (clonidine, dexmedetomidine), and daily intermittent cessation of benzodiazepine administration are advocated. Since continuous dosing of an opioid, commonly handled in the ICU setting is more likely to induce tolerance, intermittent administration is advocated. Taken together, there is an abundance of experimental data which suggests, that with every dose of an opioid several adaptive processes are being initiated. Due to genetic polymorphism such adaptation is seen clinically with striking individual different dosages, the degree and the time of onset of tolerance. Although tolerance development may result in staggering doses of an opioid, there is no reason to evade the use of such agents. On the contrary, the concept of multimodal analgesia consisting of the simultaneous use of analgesics with a different mode of action can counteract tolerance development.
Analgesics, Opioid↗
Chronic tolerance to nicotine in humans and its relationship to tobacco dependence.
Chronic tolerance to any drug of abuse traditionally has been thought critical to understanding drug dependence. This paper reviews research on chronic pharmacodynamic tolerance to nicotine in humans. An overview of tolerance and a discussion of methodological issues are first presented, followed by examination of cross-sectional comparisons of tolerance between groups differing in smoking history, as well as the few prospective studies of change in tolerance after quitting smoking. The relationship of nicotine tolerance to tobacco dependence is then evaluated. While somewhat modest in size, the literature on chronic tolerance to nicotine in humans is reasonably consistent in showing clear evidence of tolerance to subjective mood effects but little or no tolerance to cardiovascular, performance or other nicotine effects, within the limitations inherent in most human research on tolerance. However, this research also indicates that chronic tolerance to nicotine is not closely associated with tobacco dependence: non-dependent and dependent smokers are equally tolerant; tolerance declines very little even years after quitting; and tolerance before quitting may have no relationship to clinical outcome of a cessation attempt. Recent research from the alcohol and substance abuse fields is consistent with the notion that tolerance has little clinical utility in determining dependence. These results question the relevance of nicotine tolerance to dependence and suggest that research into mechanisms of tolerance, while important for understanding biological adaptation, may not elucidate factors responsible for nicotine dependence. Future research should focus on whether dependence may be related to tolerance or to other, as yet unexamined, effects of nicotine, including conditioned tolerance effects, and on the possibility that tolerance may influence the early onset of dependence in teens even if apparently unrelated to maintenance of dependence in adult smokers.
Cross-Sectional Studies↗
Rapid and chronic: two distinct forms of ethanol tolerance in Drosophila.
BACKGROUND: Ethanol tolerance, defined as a reduction in the intensity of the effects of ethanol upon continuous or repeated exposure, is a hallmark of alcoholism. Tolerance may develop at the cellular or neural systems levels. The molecular changes underlying ethanol tolerance are not well understood. We therefore explored the utility of Drosophila, with its accessibility to genetic, molecular, and behavioral analyses, as a model organism to study tolerance development in response to different ethanol-exposure regimens. METHODS: We describe a new assay that quantifies recovery from ethanol intoxication in Drosophila. Using this recovery assay, we define ethanol pre-exposure paradigms that lead to the development of tolerance. We also use the inebriometer, an assay that measures the onset of intoxication, to study the effects of pharmacological and genetic manipulations on tolerance development. RESULTS: We show that flies develop different forms of ethanol tolerance: rapid tolerance, induced by a single short exposure to a high concentration of ethanol, and chronic tolerance, elicited by prolonged exposure to a low concentration of the drug. Neither rapid nor chronic tolerance involves changes in ethanol pharmacokinetics, implying that they represent functional rather than dispositional tolerance. Chronic and rapid tolerance can be distinguished mechanistically: chronic tolerance is disrupted by treatment with the protein synthesis inhibitor cycloheximide, whereas rapid tolerance is resistant to this treatment. Furthermore, rapid and chronic tolerance rely on distinct genetic pathways: a mutant defective for octopamine biosynthesis shows reduced rapid tolerance but normal chronic tolerance. CONCLUSIONS: Flies, like mammals, develop tolerance in response to different ethanol-exposure regimens, and this tolerance affects both the onset of and the recovery from acute intoxication. Two forms of tolerance, rapid and chronic, are mechanistically distinct, because they can be dissociated genetically and pharmacologically.
Animals↗
Barbitone-induced tolerance to the effects of sedative-hypnotics and related compounds on operant behaviour in the rat.
1 Pretreatment doses of barbitone, pentobarbitone, ethanol, and phenytoin (diphenylhydantoin) in non-tolerant rats produced increases in operant responding at low doses and at higher doses resulted in decreases in responding.2 Daily barbitone injections (100 mg/kg, i.p.) resulted in the development of functional tolerance to both the stimulant and depressant effects of barbitone on responding.3 Barbitone tolerance development did not result in any change in the brain or plasma pharmacokinetics of barbitone.4 Barbitone-tolerant rats were cross-tolerant to the behavioural effects of pentobarbitone, ethanol, and phenytoin. The dose-effect curves for all of these drugs were shifted to the right in tolerant rats, compared to non-tolerant rats.5 Comparison of the brain and plasma levels of these drugs in non-tolerant and tolerant rats provided a means of separating functional cross-tolerance from dispositional cross-tolerance. Barbitone-tolerant rats appeared to be functionally cross-tolerant to ethanol in that there was no change in the brain and blood ethanol levels at times when the degree of behavioural impairment was substantially reduced. In contrast to ethanol, cross-tolerance to phenytoin appeared to be due to a decrease in the brain and plasma levels (dispositional tolerance). Cross-tolerance to pentobarbitone appeared to be comprised of both functional and dispositional cross-tolerance.6 The usefulness of a multidisciplinary approach in the analysis of sedative hypnotic tolerance and cross-tolerance is discussed. It is concluded that without the concurrent determination of both brain and plasma drug levels it would not be possible to distinguish between functional and dispositional tolerance.
Animals↗
UV radiation-induced enterobacterial responses, other processes that influence UV tolerance and likely environmental significance.
The ability of enterobacteria to become UV-tolerant is important because such tolerance may enable organisms to resist irradiation in the environment, in water treatment, in shell-fish, in stages of food processing, and at locations in the domestic, commercial and hospital environment The mechanism for regulation of tolerance induction and SOS response induction has been studied for many years, and is well understood, except for the early stages of induction. Such early stages, namely sensing of the stimulus (UV irradiation) and the way in which such sensing leads to signal production, have until now been poorly understood. The claim has been made that DNA is the sensor and that either damage to DNA or production of SS regions in DNA (following interaction of UV with DNA) triggers the signal that sets in train RecA activation and other stages of tolerance induction. This claimed induction mechanism is a "classical" one in the sense that it involves intracellular sensing (by DNA) of the stressing stimulus (UV), and production of an intracellular signalling molecule. It is not, however, firmly established as the mechanism for initiation of UV tolerance induction and SOS response induction. The results reviewed here give firm evidence for a different and unique mechanism for sensing of UV and production of the signal. These results establish without doubt that, for UV tolerance induction, the UV sensor is an extracellular protein, which is a UV tolerance-specific extracellular sensing component (ESC). This component is formed by unstressed cells and on interacting with the stimulus (UV) in the medium, is converted to the tolerance induction signalling molecule, which is a UV tolerance-specific extracellular induction component (EIC). It is this extracellular signal which interacts with the sensitive organisms and triggers tolerance induction. This pair of extracellular components (ECs) may offer the only means of switching-on such tolerance induction; certainly they offer the only known way for early warning to be given of impending UV challenge. Thus, the EIC can diffuse from a region of UV stress to a stress-free region and there warn organisms of impending stress and prepare them to resist it. As indicated here, UV irradiation not only induces UV tolerance, but also switches-on acid tolerance, alkali tolerance and thermotolerance responses. The fact that all three responses involve ESC/EIC pairs strongly supports the view that functioning of such EC pairs form the major, if not the only, means for UV tolerance induction. The UV tolerance-specific ESC can detect other stresses and becomes activated, leading to cross-tolerance responses. Of particular interest, this ESC acts as a biological thermometer, detecting increases in temperature, such increases leading to gradually increasing formation of the EIC and, accordingly, gradual increases in UV tolerance. This UV tolerance-specific ESC can also detect other stresses e.g. acting as a pH sensor. In all cases, on activation, the EIC formed (from this specific ESC) only induces UV tolerance. It is proposed that the interaction of EICs with stress-sensitive organisms should be examined, and it is suggested that such EICs may, directly or indirectly, interact with and activate the same stress response regulators as are used to detect internal stressors and which, on activation, also trigger the switching-on of stress responses. For example, EICs either a in a protonated or oxidised state (formed by activation of ESCs by H+ or H2O2) or b produced by irradiation, may lead to protonation or oxidation or other forms of activation of the appropriate regulator (e.g. Fur or OxyR or RecA etc), leading to response induction.
DNA Damage↗
Multiple heavy metal tolerance of soil bacterial communities and its measurement by a thymidine incorporation technique.
A thymidine incorporation technique was used to determine the tolerance of a soil bacterial community to Cu, Cd, Zn, Ni, and Pb. An agricultural soil was artificially contaminated in our laboratory with individual metals at three different concentrations, and the results were compared with the results obtained by using the plate count technique. Thymidine incorporation was found to be a simple and rapid method for measuring tolerance. Data obtained by this technique were very reproducible. A linear relationship was found between changes in community tolerance levels obtained by the thymidine incorporation and plate count techniques (r = 0.732, P < 0.001). An increase in tolerance to the metal added to soil was observed for the bacterial community obtained from each polluted soil compared with the community obtained from unpolluted soil. The only exception was when Pb was added; no indication of Pb tolerance was found. An increase in the tolerance to metals other than the metal originally added to soil was also observed, indicating that there was multiple heavy metal tolerance at the community level. Thus, Cu pollution, in addition to increasing tolerance to Cu, also induced tolerance to Zn, Cd, and Ni. Zn and Cd pollution increased community tolerance to all five metals. Ni amendment increased tolerance to Ni the most but also increased community tolerance to Zn and, to lesser degrees, increased community tolerance to Pb and Cd. In soils polluted with Pb increased tolerance to other metals was found in the following order: Ni > Cd > Zn > Cu. We found significant positive relationships between changes in Cd, Zn, and Pb tolerance and, to a lesser degree, between changes in Pb and Ni tolerance when all metals and amendment levels were compared. The magnitude of the increase in heavy metal tolerance was found to be linearly related to the logarithm of the metal concentration added to the soil. Threshold tolerance concentrations were estimated from these linear relationships, and changes in tolerance could be detected at levels of soil contamination similar to those reported previously to result in changes in the phospholipid fatty acid pattern (A. Frostegård, A. Tunlid, and E. Bååth, Appl. Environ. Microbiol. 59: 3605-3617, 1993).
Journal Article↗
In vivo tolerization of Th1 lymphocytes following a single feeding with ovalbumin: anergy in the absence of suppression.
Oral tolerance is a biologically relevant pathway for inducing peripheral tolerance to foreign antigens. The mechanisms responsible for the tolerant state following feeding with antigen have been shown to involve both anergy and suppression. The demonstration of anergic T lymphocytes following oral tolerance has so far been limited in in vitro systems, and a primary objective of the present study was to provide evidence, in vivo, for the existence of a state of anergy in mice orally fed with ovalbumin (OVA). In addition, it has been shown that peripheral anergy following the intravenous administration of antigen is selectively induced in Th1 lymphocytes. Thus, a second objective of this study was to investigate whether tolerance induced by a feeding regimen known to cause anergy could be selectively limited to Th1 lymphocytes, and whether tolerance induction could be explained by antigen absorption from the gut into the circulation. Oral tolerance was induced by a single feeding with OVA, and was demonstrated by diminished antibody production in vivo, and by reduced cytokine secretion or proliferation in vitro. Anergy, as a mechanism for tolerance, was demonstrated by the ability to reverse the tolerant state after culturing tolerant cells in recombinant interleukin-2 (rIL-2). Reversal of the tolerant state in vivo was established by antibody production in irradiated mice adoptively transferred with cells cultured in the presence of rIL-2. The possibility that suppression was also an in vivo mechanism for tolerance was studied by adoptive transfer experiments. Our results show: 1) that a single dose of orally administered OVA leads to the selective tolerization of Th1 responses (diminished IgG2a, IL-2 and interferon-gamma production) with intact Th2 responses (IgG1, and IL-4), 2) that tolerance in vivo is explained by anergy in the absence of active suppression, 3) that exposure of tolerant cells to rIL-2 in vitro abrogates the anergic state both in vitro (proliferation and cytokine secretion) and in vivo (IgG2a production), and 4) that the induction of oral tolerance is inhibited by the presence of antibodies specific for the tolerizing antigen. These findings indicate that the induction of anergy via the oral route might depend on the dissemination of antigen absorbed from the gut. It is suggested that tolerance is guaranteed by the fact that this absorbed antigen is presented to Th1 lymphocytes in the absence of inflammatory and co-stimulatory molecules; these foreign antigens are thus not different from self antigens.
Administration, Oral↗
Mechanisms in CD4 antibody-mediated transplantation tolerance: kinetics of induction, antigen dependency and role of regulatory T cells.
CBA/Ca mice may be made tolerant to minor histoincompatible B10.BR skin grafts by treatment with a short course of non-depleting anti-mouse CD4 and CD8 monoclonal antibodies (mAb), during the transplantation period. We wished to determine when, in relation to antibody therapy, the T cells became tolerant. This was investigated by a series of adoptive transfer experiments in which mAb-treated cells were removed from therapeutic antibody at defined times after skin grafting, and exposed to fresh antigen in the absence of further mAb treatment. We show here that T cells do not become fully tolerant until 5 weeks after skin grafting. If antibody therapy is continued for the full 5 weeks, T cell tolerance can still be established, suggesting that antibody therapy does not prevent lymphocytes from registering the presence of antigen. Once the tolerant state is established, it is difficult to break that tolerance by lymphocyte infusions from normal donors. This "resistance" is mediated by T cells of the tolerant host. We show that the maintenance of both tolerance and "resistance" requires a continuous supply of antigen. When tolerant cells were "parked" in T cell-depleted mice, tolerance and "resistance" were eventually lost by 6 months. In contrast, "parked" cells exposed to fresh antigen at any time up to 4 months remained tolerant and "resistant" indefinitely. Finally, we wished to establish whether "resistance" was peculiar to this form of peripheral tolerance, or whether it might also be present in tolerance considered to be classically central. We observed resistance to be greater in the mAb-treated peripherally tolerant group, but noted that some of the centrally tolerant animals also exhibited a level of resistance above that of T cell-ablated controls. This suggests that a tolerance mechanism whose role is only minor in central tolerance may have a major role in antibody-mediated peripheral tolerance.
Animals↗
Cross tolerance between nitroglycerin and neural relaxation of the rabbit sphincter of Oddi.
We studied whether non-adrenergic, non-cholinergic (NANC) relaxation of the rabbit sphincter of Oddi was influenced by tolerance to nitroglycerin (NG) in vitro. Sphincter of Oddi (SO) muscle rings precontracted with EC50 concentrations of cholecystokinin octapeptide (CCK8) were exposed to cumulative increases in NG concentrations and tested for relaxation by measurement of isometric tension. A separate group of six rings was subjected to a preceding exposure to 275 microM nitroglycerin over 60 min to induce in vitro tolerance to nitroglycerin. The rings (both tolerant and non-tolerant) were subjected to electrical field stimulation (FS: 50 V, 0.1 ms, 20 Hz, 3 and 10 stimuli). The rings were then preincubated with NANC solution: phentolamine, oxprenolol and atropine (all 1 microM) for 20 min and FS was applied again. FS was repeated after additional incubation with NG-nitro-L-arginine methyl ester (L-NAME), and inhibitor of NO synthase (30 microM) and after a successive incubation with 3 mM L-arginine (20 min). Maximum contractions produced by CCK8 in 'tolerant' and 'non-tolerant' sphincters were 29.9 +/- 5.8 and 28.3 +/- 5.2 mN, respectively. The sensitivity to CCK8 also was not different between the two groups with EC50 (-log M) values of 8.5 +/- 0.2 and 8.3 +/- 0.1, respectively. FS evoked twitchlike contraction followed by relaxation in the ampullary SO in both 'tolerant' and 'non-tolerant' preparations. Incubation in NANC solution resulted in monophasic relaxations in response to FS in non-tolerant sphincters but not in tolerant ones. L-NAME (30 microM) reversed NANC relaxation in non-tolerant muscle rings whereas it failed to modify NANC contractions in the tolerant preparations. L-arginine (3 mM) reversed the inhibitory effect of L-NAME on NANC relaxation in the 'non-tolerant' rings and it was without effect on FS-induced contractions in the 'tolerant' SO. As measured by radioimmunoassay, tolerance to NG was without any significant effect on tissue content of both cyclic adenosine 3':5' monophosphate (cAMP) and cyclic guanosine 3':5' monophosphate (cGMP). FS significantly increased tissue cAMP and cGMP content in 'non-tolerant' preparations. FS failed to increase the level of either cyclic nucleotide in 'tolerant' tissue. We conclude that NANC relaxation of the ampullary part of the rabbit SO is significantly impaired in the state of tolerance to NG 'in vitro'.
Animals↗
Genetic Constraints and Selection Acting on Tolerance to Herbivory in the Common Morning Glory Ipomoea purpurea.
Tolerance to herbivory minimizes the effects of herbivory on plant fitness. In the presence of herbivores, maximal levels of tolerance may be expected to evolve. In many plant species, however, tolerance is found at an intermediate level. Tolerance may be prevented from evolving to a maximal level by genetic constraints or stabilizing selection. We report on a field study of Ipomoea purpurea, the common morning glory, in which we measured three types of costs that may be associated with tolerance and the pattern of selection acting on tolerance to two types of herbivore damage: apical meristem damage and folivory. We used genetic correlations to test for the presence of three types of costs: a trade-off between tolerance and fitness in the absence of herbivore damage, a trade-off between tolerance and resistance, and genetic covariances among tolerance to different types of damage. We found no evidence that tolerance to apical meristem damage or tolerance to folivory was correlated with resistance, although these two types of tolerance were positively correlated with one another. Tolerance to both types of damage involved costs of lower fitness in the absence of herbivory. Selection acting on tolerance to either type of herbivory was not detected at natural levels of herbivory. Selection is expected to act against tolerance at reduced levels of herbivory and favor tolerance at elevated levels of herbivory. In addition, significant correlational selection gradients indicate that the pattern of selection acting on tolerance depends on values of resistance. Although we found no evidence for stabilizing selection, fluctuating selection resulting from fluctuating herbivore loads may be responsible for maintaining tolerance at an intermediate level.
Ipomoea purpurea↗
Allo-I-J determinants participate in maintenance of neonatal H-2 tolerance.
To evaluate the role of IJ antigens in maintenance of the tolerant state in adult H-2 tolerant mice, we have attempted to abolish tolerance by injecting monoclonal antibodies (mab) specific for host, donor, or third party IJ antigens into adult H-2 tolerant mice. Abolition of tolerance was evidenced by the rejection of fresh test skin grafts bearing the tolerated antigens. Whole H-2 tolerant mice treated with anti-IJ mab specific for donor (allo) IJ antigens rejected their test skin grafts, indicating that tolerance had been abolished. When two other types of tolerant mice were tested, we found that mice tolerant of class II antigens alone, but not mice tolerant of an IJ thru D disparity, were susceptible to the anti-donor IJ mab treatment. In addition, adult tolerant mice were unaffected by treatment with either anti-host or anti-third party IJ mab. When tested in vitro, lymphoid cells from tolerant mice, the tolerance of which was abolished by anti-IJ mab, remained unresponsive to the tolerogen, just as untreated (control) tolerant mice, in several in vitro assays (e.g., mixed lymphocyte reaction, cytotoxic T cell precursor frequency and bulk cell-mediated lysis without growth factor). Mice treated with antidonor IJ mab, however, unlike mice treated with anti-host or third party IJ mab, were capable of generating tolerogen-specific T cells in the absence of exogenous growth factor. Thus in the strain combinations we used, adult mice tolerant of either the entire H-2 region or of the class II major histocompatibility complex region alone are susceptible to abolition of the tolerant state by treatment with anti-donor IJ mab. Coincidentally, lymphoid cells from these mice generate sufficient endogenous T helper activity to activate the tolerogen-specific cytotoxic T cells. We suspect that these latter cells may be responsible for rejection of grafts bearing the tolerated antigens.
Animals↗