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Results for “Tolerability”

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PubMed1989

Effects of dose, interdose interval, and drug-signal parameters on morphine analgesic tolerance: implications for current theories of tolerance.

Some unique predictions of a dual-process priming model of morphine analgesic tolerance were tested. Two experiments in which morphine injections during a tolerance acquisition phase were accompanied by nociceptive testing on a hot plate, confirmed the predictions that tolerance acquisition, retention, and environment-specificity would be augmented under signaled drug conditions when low doses or long interdose intervals (IDIs) were used but not when high doses or short IDIs were used. The implications for current alternative theories of morphine tolerance are discussed.

Animals↗

PubMed1997

Oral tolerance in a murine model of relapsing experimental autoimmune uveoretinitis (EAU): induction of protective tolerance in primed animals.

Oral administration of uveitogenic retinal antigens suppresses the expression of EAU induced by a subsequent immunization with these antigens. Effectiveness and mechanisms of oral tolerance in EAU have mainly been studied in the acute, monophasic model in Lewis rats by feeding antigen prior to induction of disease. In this study we investigated the effect of oral tolerance induction in the acute as well as the chronic-relapsing models in the B10.A mouse. In acute murine EAU we could effectively suppress disease by induction of oral tolerance prior to immunization. In the chronic-relapsing EAU, antigen feeding was started only after the animals had recovered from their first attack of uveitis. Under these experimental conditions the subsequent relapse was largely prevented. These experiments demonstrate that oral tolerance may have practical clinical implications in uveitis, which is predominantly a chronic-relapsing condition in humans.

Acute Disease↗

PubMed2003

Subscapular skinfold thickness distinguishes between transient and persistent impaired glucose tolerance: Study on Lifestyle-Intervention and Impaired Glucose Tolerance Maastricht (SLIM).

AIMS: To assess whether adding anthropometric measurements to an oral glucose tolerance test (OGTT) can help to distinguish between transient and persistent impaired glucose tolerance (IGT). METHODS: From the SLIM project (Study on Lifestyle-Intervention and IGT Maastricht), a study designed to evaluate whether diet and physical activity intervention can improve glucose tolerance in subjects at risk for diabetes, 108 subjects with IGT underwent a repeated OGTT 2-4 months after the initial OGTT. Following the second test, subjects were classified as transient IGT, or persistent IGT. Anthropometric measurements, including body mass index, waist and hip circumference, sagittal and transverse abdominal diameters and skinfold thickness measurements, were done during the second OGTT. RESULTS: Persistent IGT was diagnosed in 47 subjects (44%), transient IGT in 40 (37%), impaired fasting glucose in eight subjects (7%), and diabetes in 13 cases (12%). Two-hour blood glucose levels at the initial OGTT and subscapular skinfold thickness were significantly higher in subjects with persistent IGT (2-h blood glucose 9.8+/-0.1 mmol/l vs. 10.2+/-0.1 mmol/l for transient IGT and persistent IGT, respectively; subscapular skinfold thickness 25.4+/-1.4 mm vs. 29.8+/-1.2 mm for transient IGT and persistent IGT, respectively). After adjustment for age, sex and family history of diabetes mellitus, logistic regression indicated that 2-h blood glucose level during the initial OGTT represented the strongest predictor of persistent IGT (P<0.02), followed by subscapular skinfold thickness (P<0.05). After adjustment for 2-h blood glucose levels during the first OGTT, subscapular skinfold thickness remained significantly associated with persistent IGT (odds ratio 1.84; P<0.05). CONCLUSIONS: In addition to the 2-h blood glucose level, subscapular skinfold thickness was the best predictor of persistent IGT, suggesting that adding simple anthropometric measures to oral glucose tolerance testing may improve the distinction between persistent and transient glucose intolerance.

Anthropometry↗

PubMed2003

Adrenocortical tumors: prevalence of impaired glucose tolerance and of "Paradoxical Rise" of cortisol during an oral glucose tolerance test.

Glucose tolerance and the behaviour of cortisol during an oral glucose tolerance test (OGTT) was investigated in 126 patients with adrenal "incidentalomas" (age: > 45 years) and in 129 age-matched controls. Impaired glucose tolerance (IGT) was found to be more common (p < 0.02) among patients with adrenal incidentalomas. Subdividing these patients by their body weight it was found that 29% (controls: 25%) of those with normal body weight (BMI 20 - 25 kg/m2) had IGT/DM. In overweight (BMI 25 - 30 kg/m2) and obese patients (BMI 30 - 40 kg/m2) the share of IGT/DM was 32% (controls: 19%) and 66% (controls 42%), respectively. The prevalence of a "paradoxical" rise in serum cortisol concentrations during the OGTT was slightly higher (p < 0.05) among patients with adrenal incidentaloma than among controls. Patients as well as controls with this abnormal behaviour of cortisol were characterized by lower basal serum cortisol concentrations (p < 0.01) but no association was seen with either the presence of IGT or with post-dexamethasone concentrations of serum cortisol. Thus both in patients with and without adrenal incidentalomas abnormal glucose tolerance is an age- and weight-dependent phenomenon unrelated to the post-prandial behaviour of serum cortisol concentrations.

Adrenal Cortex Neoplasms↗

PubMedDate not supplied

Targeting the TCR: T-cell receptor and peptide-specific tolerance-based strategies for restoring self-tolerance in CNS autoimmune disease.

A principal theme in autoimmunity is the breakdown of central tolerance resulting in the persistence and eventual activation of autoreactive T cells. Because CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for the onset and progression of most autoimmune diseases, they are a logical target for therapeutic interventions. One technique for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4(+) T-cell activation. In this review, we discuss promising techniques with the common goal of inducing antigen (Ag)-specific tolerance. Emphasis is given to the use of non-mitogenic anti-CD3 and peptide-specific tolerance strategies that specifically target the T-cell receptor (TCR) in the absence of costimulatory signals. These approaches produce a TCR signal of insufficient strength to cause CD4(+) T-cell activation and instead induce functional T-cell anergy or deletion while avoiding generalized long-term immunosuppression.

Animals↗

PubMed1990

Re-irradiation of mouse kidneys: a comparison of re-treatment tolerance after single and fractionated partial tolerance doses.

Mouse kidneys were bilaterally irradiated with fractionated doses of 15 X 1.2 Gy, 15 X 1.6 Gy or 15 X 2.0 Gy. After an interval of 26 weeks the mice were re-irradiated with a range of single doses and functional kidney damage was measured (from clearance of [51Cr]EDTA) at monthly intervals until 36 weeks after re-irradiation. Re-irradiation tolerance was assessed from a comparison of dose-response curves for renal damage in re-treated mice compared with age-matched controls, which received only the re-treatment single doses. Fractionated irradiation markedly reduced the tolerance to subsequent re-irradiation after 6 months. The data indicated a continuous progression of the initial damage, even when the doses used were below the threshold level required to give measurable functional damage. These results were qualitatively similar to those previously published for re-irradiation of mouse kidneys after single doses. A quantitative comparison of the re-treatment tolerance after fractionated and single-dose irradiation indicated, however, that fractionated irradiation to partial tolerance was less damaging than predicted on the basis of the linear-quadratic (LQ) model. These results suggest either the failure of the LQ model for renal irradiation damage at low doses per fraction or, possibly, the presence of two subpopulations in the kidney: one population responsible for overt functional damage and the second population leading to subthreshold damage not normally expressed as functional impairment.

Animals↗

PubMed2004

Immune tolerance to drugs. (II).: Long-term tolerability of nimesulide in patients with NSAID hypersensitivity.

Nimesulide is well-tolerated as an alternative to nonsteroidal antiinflammatory drugs (NSAIDs) in patients with a previous adverse reaction to other classes of NSAIDs. However, there is little information in the literature about its long-term tolerability. The study was carried out on 625 patients who had experienced adverse reactions to one or more NSAIDs. All patients received and tolerated peroral challenges with nimesulide. On the first day, patients were given an equivalent number of placebo doses to the planned number of nimesulide doses. In a successive session, the test was administered by means of increasing doses of nimesulide at 30 min intervals until the common daily therapeutic dose of 100 mg was reached (10 mg-20 mg-30 mg-40 mg). A questionnaire was distributed to all subjects. In particular, they were asked to clarify any reactive symptoms they had developed after ingestion of the drug. It was found that only 2.1% (4/192) of subjects who were given this drug experienced urticaria during treatment. We have identified three significant risk factors: a history of chronic urticaria, a history of antibiotic hypersensitivity and a history of hypersensitivity to more than one class of NSAIDs. In patients with the above risk factors, a prior tolerance test with a selective COX2 antagonist should be administered.

Adult↗

PubMed1971

Nonantigenicity and immunologic tolerance: the role of the carrier in the induction of tolerance to the hapten.

Treatment of adult mice with dinitrophenyl (DNP) bound to isogeneic serum resulted in a specific inability to respond to DNP after challenge with DNP-keyhole limpet hemocyanin (KLH) in complete Freund's adjuvant. The unresponsiveness to the hapten had all the characteristics of immunologic tolerance: it had a definite induction time; it was transient but could be maintained by additional injections of the tolerogen; it was antigen specific and dose dependent. In addition, the induction of tolerance to DNP is dependent on the nature of the carrier. Two main conclusions can be drawn from these data: DNP conjugates of three homopolymers of lysine were found to be nonimmunogenic in mice, yet tolerogenic. Thus, antigenicity is not necessary to induce tolerance. Among the various carriers tested, isogeneic 7S immunoglobulin (IgG) was found to be the most effective to induce and maintain tolerance to the hapten. This suggests that IgG may have a function other than its usual role as an immunoglobulin.

Animals↗

PubMed1992

Cross-species transplantation tolerance: rat bone marrow-derived cells can contribute to the ligand for negative selection of mouse T cell receptor V beta in chimeras tolerant to xenogeneic antigens (mouse + rat----mouse).

Mixed xenogeneic bone marrow reconstitution (mouse + rat----mouse) results in stable mixed lymphopoietic chimerism (1-48% rat), long-term survival, and the induction of stable functional donor-specific transplantation tolerance to xenoantigens in vivo. To examine the role of negative selection of potentially xenoreactive T lymphocytes during tolerance induction across a species barrier, mixed xenogeneic chimeras (mouse + rat----mouse) were prepared and analyzed using a mixture of mouse and rat bone marrow cells for relative T cell receptor (TCR)-V beta expression on mouse T cells. In mixed xenogeneic chimeras (B10 mouse + rat----B10 mouse), T cell maturation proceeded normally in the presence of rat bone marrow-derived elements, and functional donor-specific tolerance to rat xenoantigens was present when assessed by mixed lymphocyte reactivity in vitro. V beta 5, which is expressed at high (undeleted) levels in normal B10 mice, was consistently deleted in B10 recipients of Wistar Furth (WF), but not F344 rat bone marrow, whereas the coadministration of either F344 rat or WF rat bone marrow with B10 mouse bone marrow cells resulted in a significant decrease in expression of TCR-V beta 11. Taken together, these data demonstrate for the first time that rat bone marrow-derived cells can contribute in a strain-specific manner to the ligand for negative selection of specific mouse TCR-V beta during tolerance induction across a species barrier.

Animals↗

PubMed1997

Role of the thymus in transplantation tolerance in miniature swine. I. Requirement of the thymus for rapid and stable induction of tolerance to class I-mismatched renal allografts.

The almost uniform failure in transplant patients of tolerance-inducing regimens that have been found to be effective in rodents, has made it necessary to examine large animal models before testing of new approaches clinically. Miniature swine have been shown to share many relevant immunologic parameters with humans, and because of their reproducible genetics, have proved extremely useful in providing such a large animal model. We have previously shown that indefinite systemic tolerance to renal allografts in miniature swine is induced in 100% of cases across a two-haplotype class I plus minor histocompatibility antigen disparity by a 12-d course of Cyclosporine A (CyA), in contrast to irreversible rejection observed uniformly without CyA treatment. In the present study, we have examined the role of the thymus during the induction of tolerance by performing a complete thymectomy 21 d before renal transplantation. This analysis demonstrated a striking difference between thymectomized and nonthymectomized animals. Thymectomized swine developed acute cellular rejection characterized by a T cell (CD25(+)) infiltrate, tubulitis, endothelialitis and glomerulitis, and anti-donor CTL reactivity in vitro. Nonthymectomized and sham thymectomized animals had a mild T cell infiltrate with few CD25(+) cells and no anti-donor CTL response in vitro. These results indicate that the thymus is required for rapid and stable induction of tolerance.

Animals↗

PubMed1985

Correlation of intrathymic tolerance with intrathymic chimerism in neonatally tolerized mice.

T cell tolerance to alloantigens can be induced in neonatal mice by the injection of semiallogeneic adult spleen cells. The thymus of neonatally injected mice rapidly becomes specifically unresponsive to the alloantigens expressed by the injected cells, even though the level of chimerism in the thymus of such mice is reportedly marginal compared with that of the periphery. In this report, we have studied the immune reactivity and degree of chimerism in the thymuses of 24 neonatally injected mice. In 13 older mice, the proliferative response of the thymocytes from individual mice to the injected alloantigen varied from strong reactivity to complete tolerance. Interestingly, analysis by flow microfluorometry of the same thymocytes for the presence of the inoculated alloantigen revealed an inverse correlation. That is, the thymuses which had a greater degree of chimerism were tolerant and those with fewer or no detectable cells were partially or totally reactive. The thymuses of 11 younger neonatally injected mice were invariably tolerant to both the MHC and Mls alloantigens of the F1 inocula. Analysis by flow microfluorometry of the thymocytes of these mice revealed that significant numbers of F1 cells reside in the thymuses of mice injected as neonates with semiallogeneic cells. These cells represent a possible source of specific tolerogen for thymocytes during their intrathymic differentiation.

Aging↗

PubMed1988

Drug-induced in vitro tolerance to allogeneic antigens. II. Further analysis of in vitro-tolerized spleen cells in a fully allogeneic murine combination.

C3H/HeSlc (C3H, H-2k) spleen cells were made tolerant in vitro to C57BL/6CrSlc (B6, H-2b) at the cell-mediated cytotoxicity (CMC) level by in vitro stimulation for 48 hr with mitomycin C (MMC)-treated B6 spleen cells, and treatment with 5 micrograms/ml of 5-fluorouracil for a further 9 hr. These cells were given intraperitoneally to neonate (C3HxB6) F1 mice to examine whether these tolerized spleen cells would cause lethal graft-versus-host disease (GVHD). Despite the lack of CMC, the tolerized C3H spleen cells caused lethal GVHD in most of the neonate F1 mice. Evaluating from various immune parameters, it was evident that T cell populations responsible for IL-2 production, cytostasis, and delayed footpad reaction (DFR) were retained intact after in vitro tolerance induction, probably because of their less-proliferative characteristics in response to fully allogeneic antigen stimulation, and were considered to be responsible for lethal GVHD. Contribution of natural killer (NK) cells to lethal GVHD was not ruled out.

Animals↗

PubMed1990

Mechanism of tolerance following class I--disparate renal allografts in miniature swine. Cellular responses of tolerant animals.

Previous studies utilizing a recombinant MHC haplo-type in our partially inbred miniature swine herd have demonstrated that some recipients matched only for SLA class II show long-term acceptance of renal allografts without exogenous immunosuppression. Such animals have been shown to develop systemic tolerance as evidenced by prolonged rejection times of subsequent donor-specific, but not third-party, skin grafts. In the present studies in vitro cellular responses of long-term tolerant animals and of 7 animals studied sequentially are presented. Long-term tolerant animals demonstrated responses consistent with the absence of the class I reactive helper populations normally present in naive controls. Animals studied sequentially segregated into two groups based on cellular reactivity and survival. All animals showed complete loss of antidonor class I cell-mediated lymphocytolytic (CML) reactivity by postoperative day 10. However, animals surviving less than 20 days maintained CML reactivity to donor class I plus third-party class II in the posttransplant period, while animals surviving greater than 40 days lost such reactivity. Addition of exogenous interleukin 2 could not reverse this loss. These studies suggest that tolerance induction to a renal allograft across a class I only difference involves effects on both helper and killer class I reactive cell populations.

Animals↗

PubMed1993

Similar levels of granzyme A and perforin mRNA expression in rejected and tolerated heart allografts in donor-specific tolerance in rats.

Congenic LEW.1W (RT1u) heart grafts in LEW.1A (RT1u) recipient rats are rejected within 15 +/- 6 days. Tolerance (> 100 days) can be induced by pretransplant donor-specific blood transfusions. In both cases, the graft is heavily infiltrated by recipient cells, and class I and class II molecules of the major histocompatibility complex are strongly expressed. Moreover, T lymphocytes extracted from both tolerated and rejected grafts are similarly cytotoxic in vitro against donor cells. However, it cannot be excluded that this cytotoxicity does not operate in vivo. To answer this important question, we have studied the expression of granzyme A and perforin mRNA expression, in situ, by Northern blotting. Our data show that the two corresponding mRNAs accumulate with the same kinetic and at the same level in rejected and tolerated grafts. These results strongly suggest that infiltrating cells are cytotoxic in vivo and that a "cellular rejection" does occur in the "tolerated" grafts. In addition, these findings show that cytotoxic T lymphocytes are not sufficient to impair graft survival and lead to a revaluation of the relevance, in general, terms of granzyme and perforin expression as a correlate of rejection.

Animals↗

PubMed1995

Tolerance to class I-disparate renal allografts in miniature swine. Maintenance of tolerance despite induction of specific antidonor CTL responses.

Miniature swine that become tolerant to renal allografts across an MHC class I barrier following a short course of cyclosporine are unresponsive to donor class I antigens in cell-mediated lymphocytotoxicity. However, skin grafts bearing donor class I plus third-party class II antigens are promptly rejected, and the animals then develop marked cell-mediated lymphocytoxic reactivity to donor class I antigens in vitro, but do not reject the kidney transplants. We show here that CTL generation is directed toward the same donor class I antigens as are expressed by the kidney donor, and is not the result of recognition in vitro of the tolerated class I antigen plus peptides of minor antigens shared between the skin graft donor and the stimulator/target cells. We also show that detection by CTLs of peptides expressed by skin but not by kidney is also not a sufficient explantation of the results, since the survival of skin grafts from the kidney donor is also prolonged, even after precursor CTL can be detected in vitro. The data are most consistent with suppression in vivo in tolerant animals of the helper pathways necessary for activation of precursor CTLs. Differences in patterns of cytokine expression by graft infiltrating cells may provide a mechanism for local suppression of help in this model. Finally, we have examined antibody production after sensitizing by skin grafts in long-term tolerant animals and have found that anti-donor class I antibodies are not produced, even though the same animals produce both anti-class II and anti-third-party class I antibodies.

Animals↗

PubMed1997

Preclinical studies of allograft tolerance in rhesus monkeys: a novel anti-CD3-immunotoxin given peritransplant with donor bone marrow induces operational tolerance to kidney allografts.

A major challenge in clinical transplantation today is to design a practical and effective protocol for tolerance induction compatible with cadaver organ transplantation. A preclinical rhesus monkey kidney allograft model using immediate peritransplant anti-CD3 immunotoxin (anti-CD3-IT) and donor bone marrow (DBM) is shown here to induce operational tolerance with prolonged graft survival in the absence of chronic immunosuppressive drugs. Bone marrow harvested from the kidney donor was depleted of mature alloantigen-presenting cells and T cells by removing DR(bright) cells and CD3(bright) cells, respectively. In outbred, major histocompatibility complex-incompatible donor-recipient pairs with high pretransplant mixed lymphocyte response and cytotoxic T lymphocyte precursor activity, four of six allografts survived for periods of 120 days to >1.5 years. Graft acceptance after peritransplant treatment followed robust elimination of both peripheral blood T cells and lymph node T cells. In most recipients given anti-CD3-IT and DBM infusion, anti-donor immunoglobulin G responses were completely inhibited. Microchimerism was observed in all recipients studied, including those not given DBM, but levels of microchimerism did not correlate with graft survival. Anti-CD3-IT induction in combination with modified DBM protocols such as the depletion of mature T cells and DR(bright) antigen-presenting cells may offer new opportunities to improve clinical tolerance protocols beyond those attempted in the clinic to date. Overall, these results with anti-CD3-IT show promise for development of cadaver transplant tolerance induction.

Animals↗

PubMed2005

Rosiglitazone improves insulin sensitivity and glucose tolerance in subjects with impaired glucose tolerance.

OBJECTIVE: This study was designed to evaluate the effects of rosiglitazone (ROS) on insulin sensitivity, beta-cell function, and glycaemic response to glucose challenge and meal in subjects with impaired glucose tolerance (IGT). METHODS: Thirty patients with IGT (ages between 30 and 75 years and BMI (body mass index) < or = 27 kg/m2) were randomly assigned to receive either placebo (n = 15) or ROS (4 mg/day) (n = 15). All participants underwent a 75-g oral glucose tolerance test (OGTT), meal test, and frequently sampled intravenous glucose tolerance test (FSIGT) before and after the 12-week treatment. RESULTS: After 12 weeks of ROS treatment, there were significant increases in total cholesterol (TC) (4.25 +/- 0.22 vs 4.80 +/- 0.17 mmol/l, P < 0.001), high-density lipoprotein cholesterol (HDL-C) (1.25 +/- 0.07 vs 1.43 +/- 0.06 mmol/l, P < 0.05), and low-density lipoprotein cholesterol (LDL-C) (2.70 +/- 0.15 vs 3.37 +/- 0.17 mmol/l, P < 0.05) without changes in triglyceride concentration, TC/HDL-C and LDL-C/HDL-C ratio. Although the acute insulin response (AIR) to intravenous glucose and disposition index (measured as the ability of pancreatic beta-cell compensation in the presence of insulin resistance) remained unchanged, the insulin sensitivity (SI) and glucose effectiveness (SG) were remarkably elevated (0.38 +/- 0.06 vs 0.54 +/- 0.09 x 10(-5) min(-1)/pmol, P < 0.05; 0.017 +/- 0.002 vs 0.021 +/- 0.001 min(-1), P < 0.05, respectively) in the ROS group. The glucose, insulin, and c-peptide areas under curve (AUC) in response to OGTT and the glucose and insulin AUC during meal were significantly ameliorated in the ROS group. Five out of 15 (33%) and two out of 15 (13%) subjects treated with ROS and placebo, respectively, reversed to normal response during OGTT (P < 0.05). CONCLUSION: Rosiglitazone treatment significantly improved insulin resistance and reduced postchallenge glucose and insulin concentrations in patients with impaired glucose tolerance without remarkable effects on beta-cell secretory function.

Adult↗

PubMed1982

Immunological tolerance in the chicken. III. Partial physiochemical characterization of two suppressive fractions from serum of chickens tolerant to bovine serum albumin.

Two soluble non-specific suppressive factors were isolated by gel chromatography from the serum of chickens tolerant to bovine serum albumin (BSA). Fraction I was found by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) to contain five proteins with mol. wts from 200,000 to 900,000 unreduced and six proteins that ranged from 70,000 to 180,000 when reduced. The composition was primarily protein, with a small amount of carbohydrate and lipid. One component was identified as IgM, one as a lipoprotein. The others remain unidentified. No evidence of the tolerogen, BSA, was found. The second factor, fraction III of both tolerant and normal serum, was found by SDS-PAGE to have two proteins with mol. wts of 54,000 and 78,000 in the unreduced form and contained a very small amount of protein, a large amount of carbohydrate, and no detectable lipid. Normal fraction III had two proteins with mol wts of 54,000 and 65,000 when reduced, whereas reduction did not affect tolerant fraction III. A soluble suppressive factor, secreted by cultured adherent cells of tolerant chickens, was found to be comparable to fraction III in molecular weight. Comparison of these results with those of other reported suppressive factors is made and possible identities of the suppressive components of fractions I and II are discussed.

Animals↗