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Results for “Tolerability”

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PubMed2000

T cell receptor complementarity determining region 3 length analysis reveals the absence of a characteristic public T cell repertoire in neonatal tolerance. The response in the "tolerant" mouse within the residual repertoire is quantitatively similar but qualitatively different.

All adult BALB/c mice immunized with hen egg white lysozyme (HEL) or its dominant determinant, peptide (p)106-116, mount a T cell response using a "public" Vbeta8.2Jbeta1.5 T cell clone. Neonatal exposure to tolerance-inducing doses of antigen can drastically diminish responsiveness in the draining lymph nodes but not in the spleens of animals challenged as adults with the cognate antigen. To determine the role of T cell deletion or anergy within the mechanisms of observed neonatal "tolerance," we treated neonatal BALB/c mice with HEL and directly followed the characteristic public clone using complementarity determining region 3 length T cell repertoire analysis. Our results confirm that despite intraperitoneal injection of neonates with a high dose of HEL emulsified in incomplete Freund's adjuvant, a strong splenic proliferative response to HEL was observed upon recall. However, the adult splenic T cell response of these neonatally treated mice lacked the usual Vbeta8.2Jbeta1.5 public clone characteristic of HEL-primed BALB/c mice. After challenge with HEL-complete Freund's adjuvant as adults, immunoglobulin (Ig)G2a isotype antibody was drastically reduced, and IgG1 was found to be the predominant anti-HEL IgG isotype expressed, indicating a deviation of cytokine response toward T helper type 2. 5-wk-old mice, nasally instilled with tolerogenic doses of HEL p106-116, also showed significant inhibition of this public T cell expansion. These results demonstrate that during neonatal and adult nasal tolerance induction, deletion/anergy removes the public clone, exposing a response of similar specificity but that is characterized by the T helper type 2 phenotype and a splenic residence.

Administration, Intranasal↗

PubMed1977

Immune status of mice tolerant of living cells. III. Presence and evolution of cells cytotoxic to the tolerated strain.

Spleen cells from CBA mice neonatally rendered highly tolerant to A/Jax (keeping a skin graft in perfect shape for more than 1 year and without detectable hemagglutinating or cytotoxic antibodies) contain cells cytotoxic for YAC 222 (A/Jax) in Cr release assay. The degree of the cytotoxicity depends on the age of the mouse, following a curve lower than, but parallel to, the one followed by the cytotoxicity of cells from CBA rendered immune by injecting them with A/Jax cells 1 week previously. The maximum of the cytotoxicity curve is reached during the 9th and 10th weeks. Normal CBA cells themselves are moderately cytotoxic to YAC 222. This "natural" cytotoxicity, significantly less intense and presumably directed against Moloney virus-related determinants, does not follow the same time pattern. The cytotoxic indices from both immune and tolerant cell populations are significantly reduced by CBA and anti-A/Jax immune serum. The tested sera of the tolerant mice did not contain hemagglutinating or in vitro-blocking antibodies in the Cr release assay (only the sera from unsuccessfully treated mice, having rejected their skin grafts, had some degree of blocking activity). However (and in agreement with previous experiments), these sera often contained synergistic hemagglutinins and in vivo enhancing properties of A/Jax tumors (Sal) grafted on CBA recipients.

Age Factors↗

PubMed1981

Suppressor cells in transplantation tolerance. I. Suppressor cells in the mechanism of tolerance in radiation chimeras.

Histoincompatible-complete radiation chimeras, after resolving acute graft-versus-host disease (GVHD), establish specific tolerance to host and donor alloantigens. This tolerance can be perturbed with immunosuppressive agents and infusions of small numbers of donor-type cells, with infusions of massive numbers of donor-type cells, or with infusions of a small number of donor-type cells, that were sensitized against host antigens prior to transfer. These chimeras possess T lymphocytes in the spleen that specifically suppress donor to host mixed lymphocyte reactions and adoptively transfer suppression of GVHD to secondary hosts. Nylon-wool fractionation of chimeric spleen cells restores the response of chimeric lymphocytes to host alloantigens, suggesting that transplantation tolerance is not attributable to clonal deletion but the activity of nylon-wool-adherent T suppressor spleen cells.

Animals↗

PubMed1983

Induction of transplantation tolerance in guinea pigs by spleen allografts. III. Transfer of tolerance to normal hosts.

Spleen allografts from (2 X 13)F1 donors survive indefinitely in immunologically intact strain 2 recipients. Such strain 2 hosts with long-term surviving F1 grafts had markedly suppressed anti-13 MLR responses and cells capable of suppressing the response of normal strain 2 cells to strain 13 stimulators were present in some long-term surviving animals. In order to further analyze the cellular basis for this tolerant state, we transferred cells from tolerant donors to normal syngeneic strain 2 hosts. We showed that such suppressor cells transfer MLR unresponsiveness to primary or secondary hosts, but that the period of MLR suppression is rather short-lived. Strain 13 cardiac allografts survived indefinitely in cell-transferred primary or secondary hosts and further enhanced MLR suppression, whereas most cardiac allografted controls had vigorous MLR responses for strain 13 stimulator cells after rejection of their transplants. Attempts to abrogate established tolerance in transferred hosts, either by donor antigen or by host cytolytic T cells were unsuccessful.

Animals↗

PubMed1997

Permanent and specific transplantation tolerance induced by a nonmyeloablative treatment to a wide variety of allogeneic tissues: I. Induction of tolerance by a short course of total lymphoid irradiation and selective elimination of the donor-specific host lymphocytes.

The long-term success of organ transplantation is limited by complications resulting from consistent nonspecific immunosuppression. Induction of stable, donor-specific tolerance remains the main goal of transplantation immunology. In this article, a new, nonmyeloablative method is described for induction of transplantation tolerance to fully mismatched bone marrow cells (BMC), bone marrow stromal precursors, heart muscle, and skin allografts. The method is based on pretransplant conditioning with no postgraft immunosuppression, and consists of a short course (six daily fractions of 200 cGy) of total lymphoid irradiation (sTLI), followed by selective elimination of donor-specific alloreactive cells of the host escaping low-dose sTLI. Donor-specific alloreactive cells were activated by intravenous inoculation with a high dose of donor BMC (3 x 10(7) cells) 1 day after sTLI, and eliminated by a single intraperitoneal dose (200 mg/kg) of cyclophosphamide given 1 day after cell transfer. Infusion of a low number of T cell-depleted BMC (3 x 10(6) cells) after tolerogenic preconditioning converted recipients to stable mixed chimeras free of graft-versus-host disease. The same treatment provided long-lasting acceptance of heterotopically transplanted allografts of the heart muscle and of the stromal precursors to the hematopoietic microenvironment. This treatment also led to acceptance and life-long survival of full-thickness donor skin allografts. However, skin allografts survived only in mice that received donor T cell-depleted BMC after cyclophosphamide and had 20-50% donor cells in the blood. Our results suggest that after sTLI, additional selective clonal deletion of residual host cells induces a state of long-lasting specific tolerance to a wide variety of donor-derived tissues.

Animals↗

PubMed2002

Heart allograft tolerance without development of posttransplant cardiac allograft vasculopathy in chimerism-based, drug-induced tolerance.

BACKGROUND: Recently, we have described a drug (cyclophosphamide [CP] plus busulfan [BU])-induced skin allograft tolerance in mice that can regularly overcome fully H-2-mismatched barriers. Using this method, we have investigated whether or not this regimen can prolong the survival of heart allografts and inhibit the development of posttransplant cardiac allograft vasculopathy (CAV). METHODS: The components of the method are intravenous administration of 1 x 108 allogeneic spleen cells on day 0, intraperitoneal injection of 200 mg/kg of CP and 30 mg/kg of BU on day 2, and intravenous injection of T cell-depleted 1 x 107 allogeneic bone marrow cells from the same strain of mice on day 3. Heart grafting was performed on day 28. Chimerism in peripheral blood was followed by flow cytometric analysis, and histological analysis was performed at various times after grafting. RESULTS: In a fully major histocompatability complex (MHC)-mismatched combination of B10.D2 (H-2d, IE+)-->B10 (H-2b, IE-), stable, multilineage-mixed chimerism was observed permanently. B10.D2 heart grafts were accepted permanently in a donor-specific manner, and posttransplant CAV did not develop. CONCLUSIONS: These results demonstrated that the drug-induced tolerance recently established by us can regularly induce a long-lasting heart allograft tolerance without development of CAV.

Animals↗

PubMed2001

The Immune Tolerance Network: tolerance at the crossroads.

Immune tolerance therapies are designed to reprogramme immune cells in a highly specific fashion in order to eliminate pathogenic responses but preserve normal immune function. A concept that has tantalized immunologists for decades, tolerogenic therapies would replace current lifelong immunosuppressive regimens and their often debilitating side-effects with short-term immunosuppressive regimens and their often debilitating side-effects with short-term, effective cures. Significant advances have been made over the past decade that have provided a more detailed understanding of the molecular events associated with T-cell recognition and activation. Unprecedented opportunities to test these approaches in a variety of human diseases have now emerged. As a result of these advances, the Immune Tolerance Network (ITN), a group of 70 expert immunologists spanning multiple disciplines, has been created to identify and promote the use of tolerogenic therapies in the clinic. Using a unique interactive approach designed to speed the development of clinical tolerance therapies, the ITN is examining new and innovative therapeutic approaches and bioassays in a range of autoimmune diseases and transplantation settings, as well as asthma and allergies. This work has been funded by the National Institutes of Health (in collaboration with the Juvenile Diabetes Foundation International).

Asthma↗

PubMed1980

B cell tolerance: B cells rendered tolerant are present in the immune system in a potentially responsive form.

The mechanisms of B cell tolerance were studied in an attempt to learn whether B cells rendered tolerant are present in the immune system in a potentially responsive form. The author tested the in vitro anti-trinitrophenyl (TNP) antibody-forming cell (anti-TNP AFC) response to TNP-immunogens and polyclonal B cell activators (PBA) of spleen cells taken from mice injected with a tolerogen, TNP-carboxymethylcellulose (TNP-CMC). Spleen cells from mice injected 5 days previously with 10 microgram of TNP-CMC did not respond to TNP-sheep red blood cells (TNP-SRBC), T-dependent (TD) antigen or TNP-Ficoll, T-independent (TI) antigen. However, the same spleen cells responded to PBA, lipopolysaccharide (LPS) of Salmonella enteritidis and purified protein derivative (PPD) of BCG. The results indicate that B cells specific for TNP are present in a potentially responsive form. Spleen cells from mice injected with 500 microgram of TNP-CMC did not respond to either TNP-immunogens or PBA. The state of unresponsiveness to PBA reappeared within the short period of 2 days, whereas unresponsiveness to TNP-immunogens lasted much longer. Unresponsiveness to PBA was relieved considerably by treating tolerant spleen cells with the proteolytic enzyme trypsin before in vitro stimulation. These results indicate that B cells rendered refractory are present in the immune system in a potentially responsive form.

Animals↗

PubMed1984

Hepatic drug-metabolizing enzyme system and endotoxin tolerance: structural requirement of LPS in induction of an early tolerance.

The alteration of hepatic drug-metabolizing enzyme activities in mice given Salmonella endotoxin by single or multiple intraperitoneal injections was investigated. An essentially the same biphasic, early and late phase, endotoxin tolerance was observed in the animals receiving a single injection of endotoxin or repetitive daily injections. The results of reciprocal cross tolerance tests using lipopolysaccharide and free lipid A preparations derived from Salmonella minnesota, Salmonella typhimurium, E. coli, Pseudomonas aeruginosa, and Chromobacterium violaceum suggested that lipid A moiety plays an important role in the induction of early endotoxin tolerance to endotoxin response.

Animals↗

PubMed1991

A comparison between nicotinic acid and acipimox in hypertriglyceridaemia--effects on serum lipids, lipoproteins, glucose tolerance and tolerability.

Serum and lipoprotein lipid levels, oral glucose tolerance and side-effects were compared in an open cross-over study of 31 non-diabetic patients with hypertriglyceridaemia (type II B and IV) before and after 6 weeks of treatment with nicotinic acid (3 g daily) and acipimox (0.75 g daily), a new nicotinic acid-like drug, respectively. Acipimox was about equally potent in reducing serum and VLDL lipid levels and in increasing HDL cholesterol levels. Acipimox had no significant negative effects on glucose metabolism measured by an oral glucose tolerance test compared with nicotinic acid, which decreased the late glucose tolerance as well as the area under the glucose curve (P less than 0.05 for the difference between the two treatments). The incidence and severity of flush or any other recorded side-effects was higher after nicotinic acid treatment than after acipimox. In addition, no effects on laboratory parameters such as liver enzymes and uric acid were seen after treatment with acipimox. The results of this study demonstrate that acipimox is a satisfactory alternative to nicotinic acid in patients with hypertriglyceridaemia.

Adult↗

PubMed2006

CD8+ T-cell tolerance can be broken by an adenoviral vaccine while CD4+ T-cell tolerance is broken by additional co-administration of a Toll-like receptor ligand.

T-cell tolerance to tumor antigens is a considerable challenge to cancer immunotherapy. The existence of a murine model transgenic for human carcinoembryonic antigen (CEA) allows CEA vaccination efficacy to be studied in a physiologically tolerant context. Immunization of CEA-transgenic mice with an adenoviral vector coding for CEA induced a significant CD8+ T-cell response specific to CEA but failed to induce CEA-specific CD4+ T cells and antibodies. To overcome CD4+ T-cell tolerance, we explored the effect of adjuvants inducing in vivo dendritic cell maturation. Two different Toll-like receptor ligands, monophosphoryl lipid A (MPL) and CpG motif-containing oligodeoxynucleotides (CpG-ODN), were tested. CD4+-mediated IFN-gamma production was induced in the CEA-transgenic mice only when the genetic immunization was performed in the presence of these adjuvants. Moreover, CpG-ODN had a greater effect than MPL in inducing CD4+ T-cell response and enabling anti-CEA antibody production.

Adenoviridae↗

PubMed1985

Copper toxicosis and tolerance in the rat. II. Tolerance--a liver protective adaptation.

Copper tolerance was induced in rats to determine the effective dose, duration and subsequent response to copper challenge on liver copper and associated changes. Male weanling rats were fed powdered diets supplemented with copper as follows: a) 3000, 4000, 5000 and 6000 mg/kg Cu for 15 weeks, b) 3000 mg/kg Cu for 52 weeks, c) 6000 mg/kg Cu for 3 weeks to animals which had previously received either 3000 mg/kg Cu or the control diet (10-20 mg/kg Cu) for 15 weeks. Animals in Groups (a) and (b) were weighed and killed at regular intervals. All livers were examined histologically and by Atomic Absorption Spectroscopy for copper. Animals on the copper-supplemented diets accumulated copper in the liver with associated damage. Subsequently, in rats receiving up to 5000 mg/kg copper, liver copper concentration declined, regeneration occurred, growth resumed and the animals became tolerant. This adaptation continued for 52 weeks in animals on 3000 mg/kg copper with an inverse correlation between body weight and liver copper concentration. Rats on 6000 mg/kg copper maintained their hepatic overload and did not recover. Copper primed animals were less susceptible to a test dose of Cu than previously unchallenged animals. Tolerance to high dietary copper can be invoked within a dose range determined by the level of previous exposure. The adaptation is liver-sparing and involves the progressive readjustment of copper homeostasis.

Adaptation, Physiological↗

PubMed1983

Adult transplantation tolerance induced by lentil lectin. III. Induction of transplantation tolerance by lentil lectin in mouse strain combinations with different H-2 disparities: tolerogenic effect of H-2D region antigens.

The survival time of skin allografts was investigated in 28 combinations of mouse strains differing at various loci, in adult recipients treated with lentil seed lectin (LCA). The recipients were given 1 mg of LCA daily (i.v. or i.p.) after transplantation of the skin graft. The immunosuppressive effect of LCA was generally inversely related to the conventional strength of the allotransplantation reaction, i.e. the rate of rejection of allografts on untreated recipients. In the case of H-2D antigenic disparities, the grafts usually survived for more than 100 days. The H-2A or H-2K disparity appeared to be relatively resistant to induction of tolerance by LCA treatment. The relative resistance of various H-2 antigens toward the induction of tolerance by LCA differs to some extent from that observed in experiments on the induction of neonatal tolerance by semiallogeneic lymphocytes as described in literature.

Animals↗

PubMed1982

Can experimental B cell tolerance serve as a model for self tolerance?

We have examined the abilities of the mature and immature immune systems to discriminate between tolerogenic and nontolerogenic forms of a hapten-carrier conjugate; both forms are multivalent nonimmunogenic polymers of the same molecular weight, and have the same avidity for free, hapten-specific antibody and hapten-binding B cells. Hapten-specific tolerance was induced in adult B cells by nonimmunogenic dinitrophenylated carboxymethyl cellulose or methyl cellulose. Oxidation and subsequent reduction of the vicinal hydroxyl groups of both carriers aborgated tolerogenicity, although they remained nonimmunogenic. This chemical modification did not affect the carrier's molecular weight, and it did not reduce the binding avidity of their hapten derivatives to hapten-specific antibody or to antigen-binding B cells. The same experiments, when carried out in either neonatal mice or mice that had been lethally irradiated and given the above compounds during treatment with 13-day-old fetal liver cells, invariably yielded the same results. Like adult mice, these immunologically immature animals were capable of distinguishing between the tolerogenic and the nontolerogenic form of each antigen. It has also been shown (C. A. Waters et al., in preparation) that neonatally induced tolerance to TNP-HGG is irreversible, whereas tolerance to TNP-BSA is reversible by challenge with TNP-LPS. These results are in conflict with the clonal abortion hypothesis.

Aging↗

PubMed1991

Studies to determine whether there is tolerance or cross-tolerance to the antisecretory effect of morphine and clonidine in the rat intestine.

Intra-arterial infusions (4 micrograms min-1) of prostaglandin E2 (PGE2) were used to stimulate intestinal fluid secretion in anaesthetized rats. Morphine (0.625-40 mg kg-1) produced a dose-dependent restoration of fluid transport from secretion to the normal rate of absorption. Pretreatment with up to eight doses of morphine (20 mg kg-1) did not induce tolerance, rather it enhanced the antisecretory effect of a subsequent acute dose of morphine. It seems probable that this was caused by the accumulation of morphine in the intestine. Clonidine (4-1000 micrograms kg-1, like morphine, produced a dose-dependent reversal of stimulated fluid secretion. Pretreatment with clonidine (4 x 0.25 mg kg-1) caused a shift of the clonidine antisecretory dose-response curve to the right, demonstrating tolerance. Pretreatment with clonidine also caused cross-tolerance to the antisecretory effect of morphine. The results suggest that there is a close relationship between opioid- and alpha 2-adrenoceptors in controlling inhibition of intestinal fluid secretion.

Animals↗

PubMed1977

Abnormal glucose tolerance and arginine tolerance tests in Huntington's disease.

Neuropathological studies of Huntington's disease reveal neuronal atrophy, lipofuscin accumulation and other findings characteristic of the aged brain, although the onset of disease is only the fourth decade. The pathology is limited to specific areas such as the caudate nucleus, cerebral cortex and hypothalamus. 14 patients with documented Huntington's disease (mean age of 44.4 years with a range of 27-79 years) were studied by oral glucose tolerance tests (GTT) and intravenous arginine tolerance tests performed under standardized metabolic conditions. Seven of the 14 patients had impaired carbohydrate tolerance. Mean plasma glucose level at 2h was 90.4+/-6.2 mg/100 ml in the patients with a normal GTT and 148.1+/-8.9 mg/100 ml in the patients with a diabetic type GTT. Mean peak insulin level in the nondiabetic group occurred at 1/2 h and was 60.2+/-10.1 muU/ml, but in the diabetic group the peak insulin level occurred at 2h and was 155.9+/-33.8 mgU/ml. There was failure of suppression of growth hormone during the GTT, with a rise to abnormally high levels at 5h (18.6+/-5.6 ng/ml). Arginine infusion resulted in normal glucose and insulin rise in the nondiabetic patients with Huntington's disease. However, arginine infusion provoked an elevated insulin response in those with a diabetic GTT, and an exaggerated growth hormone response in the majority of the patients. It is uncertain whether these observations are related to abnormal cerebral aging per se, direct hypothalamic neuronal degeneration, or perhaps a relative imbalance of intracerebral neurotransmitters including dopamine.

Adult↗

PubMed2004

Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance.

The development of malignant disease might be seen as a failure of immune surveillance. However, not all tumors are naturally immunogenic, and even among those that are immunogenic, the uncontrolled rapid growth of a tumor may sometimes out-run a robust immune response. Nevertheless, recent evidence suggests that mechanisms of tolerance that normally exist to prevent autoimmune disease may also preclude the development of an adequate antitumor response and that tumors themselves have the ability to thwart the development of effective immune responses against their antigens. A major challenge has been to develop approaches to breaking this tolerance in tumor-bearing hosts, and recent advances in our understanding of antigen presentation and tolerance have led to some promising strategies. An alternative approach is to use T cells from nontumor-bearing, allogeneic hosts in the form of lymphocyte infusions, with or without hematopoietic cell transplantation. Immunotherapy may occur in this setting via the response of nontolerant, tumor antigen-specific T cells from nontumor-bearing hosts or via the powerful destructive effect of an alloresponse directed against antigens shared by malignant cells in the recipient. Approaches to exploiting this beneficial effect without the deleterious consequence of graft-versus-host disease in allogeneic hematopoietic cell recipients are discussed.

Antigens, Neoplasm↗

PubMed1978

The size of the loading dose as an important determinant of the results of the oral glucose tolerance test: a study in subjects with slightly impaired glucose tolerance.

In the oral glucose tolerance test (OGTT), divergent doses of glucose remain in use by virtue of the prevailing conviction that the size of the loading dose hardly affects the outcome of the test. We compared the results of OGTTs with 100-gm. and 50-gm. loads in 85 patients, who were selected for slightly impaired glucose tolerance (plasma glucose at 120 minutes after 100 gm. of glucose was between 130 and 200 mg./dl.) The mean between-load difference in this group appeared to be nearly three times as great (54 mg./dl. at 120 minutes) as reported in the literature for normal subjects. The small impact of the dose in normal subjects could be confirmed in a group of 22 controls. As subjects with normal and with slightly impaired glucose tolerance react divergently to a change in the glucose dose, tests with different loads are not comparable and select different populations. The results can therefore also not be converted to one another by conversion formulas. The finding might be explained by the delay of the additional rise of the plasma insulin in patients after the higher load.

Adult↗