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Macrophage-mediated suppression of immune responses in Toxoplasma-infected mice. III. Suppression of antibody responses to parasite itself.

In acute Toxoplasma infection, anti-sheep erythrocytes (SRBC) antibody responses were strongly suppressed in the infected C57BL/6 mice, and the mice produced low titers of only 2-mercaptoethanol (2-ME)-sensitive antibodies but not 2-ME-resistant antibodies. By contrast, the infected BALB/c mice produced much higher titers of both 2-ME-sensitive and -resistant anti-SRBC antibodies than the infected C57BL/6 mice. In anti-Toxoplasma antibody responses, the 2-ME-resistant antibody titers were significantly lower in the infected C57BL/6 mice than in the BALB/c mice in the early phase of infection, suggesting that the suppressive effect of Toxoplasma infection affects antibody responses to Toxoplasma itself as well as to the unrelated antigen, SRBC. A histological study revealed that in the infected C57BL/6 mice, a large number of acid phosphatase-positive, macrophage-like cells infiltrated into the follicles of their spleens, and an involution of follicles occurred in the acute phase of infection. This histological change was not observed in the infected BALB/c mice. The infected C57BL/6 mice, which had the suppressed anti-Toxoplasma antibody responses, made five times as many as cysts in their brains as compared with the BALB/c mice at the fifth week of infection.

Animals↗

Suppression of agglomeration in fluidized bed coating. IV. Effects of sodium citrate concentration on the suppression of particle agglomeration and the physical properties of HPMC film.

We previously reported that sodium citrate (Na citrate), which is a high order salt in the Hofmeister's series, greatly suppressed particle agglomeration in fluidized bed coating (Pharm. Res., 16 (1999), 1616-1620). In this paper, we studied the effects of Na citrate concentration on the particle agglomeration in fluidized bed coating and on the structure of coated film on the particles. Spherical granules made of crystalline cellulose (Celphere) containing phenacetin were coated in a fluidized bed with the aqueous coating solution of hydroxypropylmethyl cellulose (HPMC) containing Na citrate at various concentrations. The particle diameter and drug release profile of coated particles, and the physical properties, i.e. tensile strength, elongation percentage at break, porosity and pore size distribution, of the HPMC cast film were investigated. The particle agglomeration was suppressed with the increasing Na citrate concentration. It is considered that the increase in the suppression effect was caused by the salting-out effect of the increased Na citrate. In the HPMC cast film system, the tensile strength and elongation percentage decreased and the porosity and cumulative pore volume increased with an increase in Na citrate concentration. It is considered that the increase in the porosity by adding Na citrate resulted from a phase separation due to the salting-out during the film forming process. The drug release rate from coated particles also increased with the increasing Na citrate concentration. It can be concluded that the increase in the release rate was due to the increase in porosity of the HPMC coated film caused by the increased Na citrate concentration.

Algorithms↗

Fat-suppressed 3D-T1-weighted-echo planar imaging: comparison with fat-suppressed 3D-T1-weighted-gradient echo in imaging the cartilage of the knee.

This study was conducted to compare a three-dimensional (3D) multi-shot echo-planar imaging (EPI) sequence with fat-suppression (FS) with the 3D-fat-suppressed gradient echo (GRE-FS) sequence in imaging the cartilage of the knee. One hundred sixty-nine patients were studied prospectively. The cartilage was imaged in the sagittal plane with: (a) 3D-T1-EPI-FS and (b) 3D-T1-GRE-FS sequences using a 1T MR scanner. The signal-to-noise ratio (SNR) of bone (b) and cartilage (c), and relative contrast (ReCon) between bone and cartilage and meniscus and cartilage were measured in 60 patients with arthroscopically normal cartilage. The imaging accuracy was assessed by comparing with linear regression analysis (length and depth) 32 defects in the cartilage of cadaveric (human and bovine) knees. The 3D-T1-EPI-FS provided better bone marrow signal suppression, better SNRc and better ReCon(bc) and ReCon(cm) (p<0.01). The 3D-T1-EPI-FS showed better accuracy concerning the depth of the defects and the 3D-T1-GRE-FS better accuracy concerning the length of the defects. In conclusion, the 3D-T1-EPI-FS pulse sequence could be included in the routine protocol in imaging the cartilage of the knee because it achieves high SNR of the cartilage and high ReCon compared to the surrounding structures, at a reduced scan time.

Adipose Tissue↗

Suppression of immunoglobulin G synthesis as a result of antibody-mediated suppression of immunoglobulin M synthesis in chickens.

Development of heterogeneity of immunoglobulin classes has been investigated in the chicken by studying the effects of antibody-mediated suppression of IgM synthesis. Treatment of 13-day embryos with purified goat antibodies to IgM resulted in the elimination of IgM-containing cells from the bursa of Fabricius of 16- and 19-day embryos. When combined with bursectomy at hatching, administration of anti-IgM in ovo suppressed the synthesis not only of IgM but also of IgG. A number of experimental birds lacked detectable circulating immunoglobulins, plasma cells, and germinal centers when killed at 10 weeks of age. Contrasting results were obtained when IgM synthesis was suppressed after bursectomy at hatching. Birds so treated produced little or no IgM but synthesized normal amounts of IgG. The results suggest that, within the bursal environment, IgG-producing cells arise exclusively from cells that previously synthesized IgM. A model for generation of antibody variability is presented.

Animals↗

Purification of murine suppressive factor of allergy into distinct CD23-modulating and IgE-suppressive proteins.

The murine suppressive factor of allergy (SFA) has been purified from a T-cell hybridoma and found to consist of two functionally and biochemically distinct protein molecules. One protein (17 kDa) modulates the low-affinity Fc receptor for IgE on lymphocytes (i.e., CD23); it decreases the binding avidity of IgE to CD23-bearing B cells without affecting quantitative expression of CD23 and is thus designated epsilon-receptor-modulating protein. The second protein (30 kDa) suppresses IgE biosynthesis (i.e., SFA). This purified SFA suppresses interleukin 4-induced IgE and IgG1 synthesis by lipopolysaccharide-activated spleen cells but has no effect on other antibody isotypes; since the activity of SFA is not blocked by anti-interferon gamma monoclonal antibody, it is thus distinct from interferon gamma. The data presented indicate that epsilon-receptor-modulating protein and SFA are protein molecules that are involved in modulating the CD23 molecule and IgE antibody synthesis, respectively.

Animals↗

R104H may suppress transthyretin amyloidogenesis by thermodynamic stabilization, but not by the kinetic mechanism characterizing T119 interallelic trans-suppression.

The tetrameric protein transthyretin (TTR) forms amyloid fibrils upon dissociation and subsequent monomer misfolding, enabling misassembly. Remarkably, the aggregation of one of over 100 destabilized TTR variants leads to familial amyloid disease. It is known that trans-suppression mediated by the incorporation of T119M subunits into tetramers otherwise composed of the most common familial variant V30M, ameliorates disease by substantially slowing the rate of tetramer dissociation, a mechanism referred to as kinetic stabilization of the native state. R104H TTR has been reported to be non-pathogenic, and recently, this variant has been invoked as a trans-suppressor of amyloid fibril formation. Here, we demonstrate that the trans-suppression mechanism of R104H does not involve kinetic stabilization of the tetrameric structure, instead its modest trans-suppression most likely results from the thermodynamic stabilization of the tetrameric TTR structure. Thermodynamic stabilization increases the fraction of tetramer at the expense of the misfolding competent monomer decreasing the ability of TTR to aggregate into amyloid fibrils. As a consequence of this stabilization mechanism, R104H may be capable of protecting patients with modestly destabilizing mutations against amyloidosis by slightly lowering the overall population of monomeric protein that can misfold and form amyloid.

Amino Acid Substitution↗

Contact-mediated reversible suppression of myogenesis. II. Reversal of suppression by bromodeoxyuridine.

Chondrocytes from the vertebral columns of 11-day chick embryos were cultured in the continuous presence of 5-bromodeoxyuridine (BUdR) Under these conditions the cells form multilayers but synthesize little extracellular matrix as determined by toluidine blue metachromasia or sulfate-(35)S incorporation into polysaccharide. Myogenic cells from the breast muscles of 11-day chick embryos formed myotubes when plated into BUdR-treated chondrocyte cultures. When plated on untreated chondrocyte multilayers or on multilayers which had been permitted to recover from BUdR treatment for 3 days, myogenic cells failed to form myotubes Since extracellular matrix is present in untreated chondrocyte cultures and reappears in multilayers recovering from BUdR treatment, it is suggested that extracellular matrix is the active agent in the suppression of myogenesis An attempt was made to duplicate the suppressing activity of multilayer cultures by using ion exchange resins as substrates for myogenic cells Myotubes formed on acidic and basic resin particles If extracellular matrix is the active suppressing agent, it may have to fulfill certain spatial distributional requirements before its activity is expressed

Animals↗

Regulation of IgE antibody production by serum molecules. III. Induction of suppressive activity by allogeneic lymphoid cell interactions and suppression of IgE synthesis by the allogeneic effect.

Antibody responses of the IgE class are, like other immunoglobulin classes, regulated by a finely-tuned network of complex cellular and molecular interactions (1). Previous studies conducted in our laboratory (2, 3) have provided new insights into the differences in control mechanisms that result in individuals manifesting either the high (allergic) or low (nonallergic) IgE responder phenotype. These experiments have shown that certain manipulations (i.e. low dose X-irradiation) convert normally low responder mice to high IgE responders, apparently by diminishing a suppressor T-cell mechanism which normally dampens, rather selectively, IgE antibody production in such individuals. Similar findings have been made by Watanabe et al. (4). Recently, we have been studying the types of manipulations that could reverse the high IgE responsive state back to a low one. These studies (2, 3, 5, 6) have demonstrated that the high IgE responses induced in low responder mice can be substantially diminished, and even abolished, by passively transfusing serum or ascetic fluid from donor mice previously inoculated with mycobacterial-containing complete Freund's adjuvant (CFA). Because the suppressive activity of CFA-immune serum or ascitic fluid is so highly selective for IgE antibody production, we have recently termed these serum substances suppressive factors of allergy (SFA) (2, 3). The present study was undertaken to determine whether alternative means, particularly those that avoid administration of CFA, could be devised for the induction of SFA. Herein, we report the effectiveness of allogeneic lymphoid cell interactions in inducing SFA, both in vivo and in vitro, as well as the potent suppressive effects of an in vivo allogeneic effect on irradiation enhanced IgE antibody production in low responder mice.

Animals↗

Thiobarbiturates suppress depolarization-induced contraction of vascular smooth muscle without suppression of calcium influx.

We have studied the effects of barbiturates on vascular smooth muscle tension and cytosolic calcium concentrations ([Ca2+]i) in endothelium-denuded rat aortic rings, preloaded with fluo-3. Changes in [Ca2+]i were estimated by the fluorescence intensity of the calcium-bound form of fluo-3. In aortic rings under basal conditions, thiobarbiturates (thiopentone and thiamylal 100-300 mumol litre-1) increased [Ca2+]i, concomitantly with an increase in tension, although oxybarbiturates (pentobarbitone and secobarbitone up to 300 mumol litre-1) had no effect. Thiopentone (300 mumol litre-1)-induced increases in tension and fluorescence intensity were mean 25.1 (SD 3.2)% and 55.0 (6.0)%, respectively, of those induced by KCl 30 mmol litre-1 (n = 8, each). In KCl (30 mmol litre-1)-precontracted aortic rings, thiopentone decreased tension without reduction of [Ca2+]i, whereas pentobarbitone decreased tension and [Ca2+]i, KCl (30 mmol litre-1)-induced contraction was suppressed by pretreatment with all barbiturates (100-300 mumol litre-1); thiopentone 300 mumol litre-1 suppressed contraction to 64.8 (2.5)% (n = 6) and pentobarbitone 300 mumol litre-1 to 57.5 (2.2)% (n = 9). However, the increase in [Ca2+]i was suppressed by oxybarbiturates (pentobarbitone 300 mumol litre-1 to 77.9 (5.2) %; n = 9), but not altered by thiobarbiturates. These results suggest that thiobarbiturates and oxybarbiturates affect vascular smooth muscle differently and that the affected site in thiobarbiturate-induced vasodilatation is distal to regulation of [Ca2+]i.

Anesthetics, Intravenous↗

TGF-beta1 suppresses IFN-gamma-induced NO production in macrophages by suppressing STAT1 activation and accelerating iNOS protein degradation.

TGF-beta1 is a well-known immunosuppressive cytokine; however, little is known of the effect of TGF-beta1 on antigen-presenting cells (APCs). In this report, we investigated the molecular mechanisms of the suppressive effects of TGF-beta1 on APCs including dendritic cells and macrophages. Although TGF-beta1 did not greatly affect the activation of APCs, as assessed by the induction of IL-12 or the upregulation of CD40 in response to LPS, it strongly inhibited IFN-gamma-induced nitric oxide (NO) production from macrophages and dendritic cells. Using murine macrophage-like cell line RAW 264.7, we demonstrated that TGF-beta1 not only reduced the inducible NO synthase (iNOS) protein stability but also suppressed the iNOS gene transcription. We also found that TGF-beta1 directly inhibited IFN-gamma-induced STAT1 activation by reducing STAT1 tyrosine phosphorylation. The IFN-gamma Type I receptor (IFNGR1) was found to be associated with the TGF-beta1 Type I receptor (TGF-betaRI) and was phosphorylated by the TGF-betaRI. Reduced activation of STAT1 by TGF-beta1 was abrogated by the mutation in the IFNGR1 in which the serine residues of potential sites of phosphorylation by TGF-betaRI were replaced by alanine residues. Thus, multiple mechanisms are present for the TGF-beta1-mediated reduction of iNOS production, and we propose a novel mechanism for regulating inflammatory cytokine by an anti-inflammatory cytokine, TGF-beta1; i.e. suppression of IFN-gamma-induced STAT1 activation by an association of the IFNGR1 with the TGF-betaRI.

Animals↗

Features of haemocyanin-induced suppression in vivo. Study of the fractionation of T lymphocytes involved in suppression over unsolubilized conjugated histamine columns.

Haemocyanin (KLH, 4 mg), given intraperitoneally, induces in mice a state of unresponsiveness related only to the activity of two independent pathways of suppression. The early pathway is characterized by the depression of the anti-trinitrophenyl response to TNP KLH within 24 h of KLH injection, and the ability of spleen cells from KLH-treated animals to transfer unresponsiveness in normal recipients. These features of suppression are stopped after fractionation of spleen cells from KLH-treated mice over insolubilized conjugated histamine columns. The late pathway of suppression is characterized by the nonspecificity of its effector phase, leading to a depressed anti-FLu antibody response after a challenge with TNP KLH + FLu OVA. These features, which are cyclophosphamide-resistant, are no longer active after passage through insolubilized conjugated histamine columns.

Animals↗

Exteroceptive suppression of masseter muscle: assessment of two methods for quantitating suppression periods.

OBJECTIVES: The late exteroceptive suppression period (ES2) of the masseter muscle is conventionally quantified by a combination of measures of duration, amplitude, or mean activity. The combination of measures makes it difficult to compare ES2s obtained from different set-ups. An unbiased method for quantitating ES2 is introduced allowing ranking of ES2s. The introduced method is utilized to evaluate stimulus and recording conditions under which ES2 is maximal. MATERIAL AND METHODS: Fifteen male volunteers participated in 3 experiments designed to determine the effect of level of teeth clenching, stimulus intensity, and perceived pain intensity on the ES2. RESULTS: Coefficients of variance (1 h/1 month) were: duration: 11%/43%, latency: 9%/12%, and magnitude of suppression: 11%/12%. A level of teeth clenching of 66% of maximal voluntary bite force, and a stimulus intensity below pain detection threshold was associated with maximal magnitude of suppression of ES2. CONCLUSION: The introduced method is reproducible and allows ranking and stimulus-response estimations of ES2. It is suggested that ES2 does not reflect activity along the nociceptive pathways in the trigeminal region.

Adult↗

Thyroid suppression test with serum thyroxine concentration as index of suppression.

A thyroid suppression test is suggested which relies on the change in concentration of serum thyroxine as the index of thyroid response to the administration of triiodothyronine. The test has been carried out in 16 healthy volunteers and in 27 patients referred for routine suppression tests. This index appears to be sensitive and safe and results in a reduction in the required dosage of triiodothyronine. The test can be carried out in fewer patient-visits than the commonly used suppression test; moreover, in remote areas the patient need not attend the specialist centre because the course of triiodothyronine can be given (and the serum samples obtained) locally, the samples then being sent to the appropriate laboratory for assay.

Adult↗

Suppression of urokinase receptor expression by thalidomide is associated with inhibition of nuclear factor kappaB activation and subsequently suppressed ovarian cancer dissemination.

Thalidomide has been used to treat a variety of diseases ranging from alleviation of autoimmune disorders to prevention of metastasis of cancers. It has been shown previously that increased levels of urokinase-type plasminogen activator receptor (uPAR) correlate well with higher invasive phenotype. We examined whether thalidomide is able to suppress the expression of uPAR mRNA and protein in human ovarian cancer cell line HRA and human chondrosarcoma cell line HCS-2/8. Here, we show that: (a) thalidomide suppresses the expression of constitutive and transforming growth factor-beta1 (TGF-beta1)-induced uPAR mRNA and protein; (b) a nuclear factor kappaB (NF-kappaB) activation system (phosphorylation of IkappaB-alpha and degradation of IkappaB-alpha) is necessary for the TGF-beta1-induced increase in uPAR expression, because L-1-tosylamido-2-phenylethyl chloromethyl ketone, a NF-kappaB inhibitor, reduced the uPAR production as well as mRNA expression; (c) thalidomide failed to further strengthen L-1-tosylamido-2-phenylethyl chloromethyl ketone's action; (d) the once-daily i.p. administration of thalidomide (400 microg/g body weight/d) decreased progressive growth of HRA tumors and ascites formation in an in vivo animal model; and (e) the once-daily i.p. administration of thalidomide in combination with paclitaxel (i.p., 100 microg/20 g at days 2 and 5) significantly decreased progressive growth of HRA cells in a synergistic fashion. We conclude that thalidomide down-regulates constitutive and TGF-beta1-stimulated uPAR mRNA and protein expression possibly through suppression of NF-kappaB activation. Furthermore, combination therapy with thalidomide plus paclitaxel may be an effective way to markedly reduce i.p. tumor growth and ascites in ovarian cancer dissemination.

Animals↗

Suppression of the IgE antibody response by glutaraldehyde-modified ovalbumin: dissociation between loss of antigenic reactivity and ability to induce suppression.

Ovalbumin (OA) was substituted with glutaraldehyde (GA) at various GA:OA ratios and several preparations were isolated by gel filtration according to molecular weight. Two GA-substituted but unpolymerized preparations (OA1-L and OA1-H) and 3 polymerized preparations of increasing molecular weight (OA4, OA175 and OA-POL) were obtained and were assessed for their ability to react with IgG and IgE antibodies directed against the native OA molecule, as well as for their ability to suppress the IgE antibody response. The results show that while both polymerized and unpolymerized GA-modified preparations lost their reactivity towards antinative OA antibodies, to a considerable extent, their ability to suppress the OA/IgE antibody response was directly dependent on polymerization. Pretreatment of CBA mice with unpolymerized OA preparations was ineffective while the effect of pretreatment with three polymers (OA4, OA175 and OA-POL) was directly dependent on the size of the polymer. The ability to induce IgG antibodies or delayed hypersensitivity to OA was not suppressed.

Aldehydes↗

Suppression of murine IgE responses with amino acid polymer/allergen conjugates. IV. Suppressive activities in established IgE model systems.

Conjugates of poly-N-methylglycine (polysarcosine) and grass pollen extracts, previously found to be capable of suppressing immature IgE antibody responses in mice, were shown to be highly effective at inhibiting the capacity of immune splenocytes to produce a secondary response in sub-lethally irradiated recipient animals. Anamnestic IgE responses in mice primed without adjuvant were also suppressed, but the effects were modest and of short duration. The predictive value of murine models for selecting clinically appropriate specific IgE suppressive agents and treatment schedules that might be successfully employed for clinical use are discussed.

Allergens↗

Dose-dependent suppression of transplant arteriosclerosis in aorta-allografted, cholesterol-clamped rabbits. Suppression not eliminated by the cholesterol-raising effect of cyclosporine.

Cyclosporine may suppress transplant arteriosclerosis; however, it also raises plasma cholesterol, which could promote the disease. Our aim was to test these hypotheses experimentally. In experiment 1 (n = 34), cholesterol was clamped at a human level of 5 to 7 mmol/L, and rabbits were given either saline or cyclosporine in a low, medium or high dose. In experiment 2 (n = 15), in which dietary cholesterol was fixed at 0.05 g.kg-1.d-1, and experiment 3 (n = 16), in which no dietary cholesterol was added to the chow, rabbits were given either medium-dose cyclosporine, saline, or vehicle. The duration of each experiment was 5 weeks. In experiment 1, cyclosporine attenuated the development of transplant arteriosclerosis dose dependently (trend test: P < .0001). Cyclosporine also suppressed, in a dose-dependent manner, the activation of the immune system (trend test: P < .05) and the presence of T lymphocytes (trend test: P < .0001) and macrophages in the intima (trend test: P < .01). Despite a higher plasma cholesterol level in cyclosporine-treated rabbits compared with saline-treated rabbits in both experiment 2 (4.9 versus 2.9 mmol/L) and experiment 3 (1.6 versus 0.8 mmol/L), transplant arteriosclerosis was significantly reduced by cyclosporine (Mann-Whitney U test; P < .05 and P < .05). These results suggest that cyclosporine suppresses experimental transplant arteriosclerosis dose dependently. Accordingly, in the assessment of the optimal cyclosporine dose to heart-transplanted patients, it should be taken into account that a dose reduction may promote transplant arteriosclerosis.

Animals↗

Comparison of the dexamethasone suppression test and the cortisol suppression index.

Among 50 inpatients, the sensitivity and specificity of the dexamethasone suppression test (DST) were 51.7% and 85.7%, respectively. For the cortisol suppression index they were 10.3% and 91% at 8:00 a.m. and 51.7% and 57.1% at 4:00 p.m. Thus, the cortisol suppression index does not appear to be an adequate substitute for the DST.

Adolescent↗