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PubMed1985

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced immunotoxicity.

The selective toxicity of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) for the thymus, consisting primarily of immature T-cells, led us to search for an analogous selective toxicity for the immature B-lymphocytes in the bone marrow. In the dose-response study C57B1/6 male mice were injected with either vehicle alone (corn oil), 30, 60, or 120 micrograms/kg of TCDD i.p. The mice were killed by cervical dislocation 7 days later. In the time-response study, mice were injected with either saline or 120 micrograms/kg i.p. TCDD, 3, 7, 14, or 21 days before killing. In both studies, the following were analyzed: change in body weight, thymus weight, spleen and bone marrow cellularity, and spleen and marrow B-lymphocyte function, measured using the in vitro B-lymphocyte colony forming unit in culture assay, with the mitogen lipopolysaccharide (LPS) from Salmonella typhosa, and the in vitro plaque forming cell assay, with the thymus independent antigen, TNP-LPS. In the dose-response study there was a reduction in thymic weight, spleen B-cell functional response (per spleen), and bone marrow B-cell functional response to 14%, 35-54%, and 20-32% of control, respectively, at a dosage of 120 micrograms/kg. In the time-response study, thymic weight and bone marrow B-cell functional response (per femur) were reduced to 6% and 18% of control, respectively, at day 21. The results indicate that TCDD was selectively more toxic to the immature B-cells in the bone marrow than the more mature B-cells in the spleen. This immunotoxicity was dose-dependent.

Animals↗

PubMedDate not supplied

Hypothalamic Na+ and Ca++ ions and temperature set-point: new mechanisms of action of a central or peripheral thermal challenge and intrahypothalamic 5-HT, NE, PGEi and pyrogen.

The effects of changes in ambient and central temperature, amines, PGEu and pyrogen were investigated with respect to the mechanism of Na+-Ca++ ratio in the posterior hypothalamus of the unrestrained cat. Guide tubes were implanted bilaterally above the posterior hypothalamic area of 23 cats so as to accommodate push-pull cannulae. After a Na+ or Ca++ sensitive site was identified by perfusion at 50 mul/min of an artificial CSF containing 10.4 mM excess Ca++ ions or 13.6 mM excess Na+ ions, several types of experiments were undertaken with the results summarized as follows: if the cat was exposed to a cold or warm environmental temperature as the posterior hypothalamus was perfused with excess cation, the typical hypothermia was produced by Ca++ and hyperthermia by Na+ ions. However, if the cat was exposed to peripheral cooling or warming 30 min prior to the perfusion, the fall or rise produced by Ca++ or Na+ was attenuated or prevented. In other experiments, 1.0 muCi 45Ca++ was injected in the ion sensitive site in the posterior hypothalamus to label stores of the cation. Raising of ambient temperature caused a retention of 45Ca++ in this hypothalmic area, whereas a cold environmental temperature enhanced the efflux of 45Ca++ at the same perfusion site. The magnitude of change in 45Ca++ efflux depended upon the intensity of the thermal challenge. Similarly, warming of the anterior hypothalmic, preoptic area by means of implanted thermodes caused an immediate diminution in 45Ca++ efflux in the posterior hypothalamus, whereas cooling of this anterior region augmented the extrusion of 45Ca++ ions from the posterior area. When substances which produce a temperature change were applied to the same thermosensitive zone, the direction of shift in 45Ca++ flux in the posterior area corresponded to the signal for heat production or heat loss. That is, the microinjection of 5-HT, PGE1 or Salmonella typhosa into the anterior hypothalamus enhanced the efflux of 45Ca++ in the posterior hypothalamus as hyperthermia developed, whereas a similar microinjection of norepinephrine reduced the 45Ca++ output from the same sites. Finally, locally anesthetizing the cells of the anterior hypothalamus by the nerve blocker, procaine, prevented the cold and heat-induced 45Ca++ eflux and retention, respectively. These results suggest that if the Na+-Ca++ ratio in the posterior hypothalamus establishes and maintains the set-point for body temperature of 37 degrees -38 degrees C, the mechanism of lability of Ca++ through changes in binding characteristics, transport, or metabolism of the cation serves two purposes: (1) the active defense of the set-point temperature through gradations in ion shifts; and (2) the upward or downward change in set-point value, pathological or normal, triggered by virtue of impulses relayed from the anterior hypothalamus.

Animals↗

PubMed1987

Induction of metallothionein synthesis in human peripheral blood leukocytes.

Metallothionein (MT), a low molecular weight, metal-binding protein, has recently been shown to protect murine mononuclear phagocytic cells from the cytotoxic effects of bacterial lipopolysaccharides (LPS), the endotoxic component of Enterobacteriaceae. MT appears to function intracellularly as an antioxidant since autolysis results from lipid peroxidation initiated by free radicals of O2. Since this activity is distinct from MT's capacity to specifically sequestrate heavy metals, we examined whether MT synthesis can be induced by direct membrane activation or through interaction with soluble leukocyte mediators. Normal human monocytes, polymorphonuclear neutrophils (PMN), and lymphocytes, isolated from heparinized whole blood, were incubated with and without LPS from Escherichia coli and Salmonella typhosa. MT in cell lysates was quantitated using a 203Hg-binding assay employing Sephadex G-10 "minicolumns." When incubated with monocytes, PMN, or lymphocytes, neither preparation of LPS (10-100 micrograms/ml) was capable of enhancing 203Hg-binding activity after 24 or 72 hr incubation. CdCl2 (2 micrograms/ml), however, increased binding activity in monocyte and lymphocyte cultures 4- and 15-fold, respectively. When monocytes and lymphocytes were cocultured with LPS, 203Hg-binding activity was not enhanced. Addition of human interleukin 1 (endogenous pyrogen) to these cultures had no significant effect. Leukocyte endogenous mediator (LEM), a product of LPS-activated PMN that possesses hypozincemic activity in vivo, did not induce MT synthesis. Collectively, these results demonstrate that leukocyte MT does not arise from direct LPS activation or from interaction with products secreted by LPS-activated cells. De novo synthesis of MT observed during endotoxemia and gram negative sepsis appears, therefore, to be induced by endogenously released corticosteroids.

Adult↗

PubMed1979

Immune response after vaginal application of antigens in the rhesus monkey.

The immune response after vaginal application of antigens was investigated in six sexually mature female rhesus monkeys. Two model antigens, i.e., lipopolysaccharide (LPS) OF Salmonella typhosa and abortive type T-4 coliphages were applied with or without adjuvant. A plastic sponge used as the antigen carrier was introduced into the upper vagina and placed against the ectocervix. For primary immunization, each monkey received 18 vaginal antigen applications and 10 applications for each booster course. For comparison, three other female rhesus monkeys were immunized systemically. Alum or LPS was used as adjuvant. Blood was obtained two times and cervical mucus three times weekly from each monkey. Antibodies were only barely detectable in cervical mucus after the primary vaginal immunization. However, booster treatments resulted in definite antibody responses. Specific antibodies were also detected in the circulating blood after vaginal booster immunization. The antibody level in cervical secretion in three of four cases was higher than that in circulatin blood. Systemic immunization resulted in high levels of circulating antibodies, but less than 10% appeared in cervical secretions. A characteristic decrease in antibody levels in cervical mucus was usually observed at midcycle after local immunization as well as after systemic immunization. More than 90% of T-4 coliphages applied vaginally were absorbed within 48 hours. Although alum appeared to retard the absorption of antigens, it seemed to enhance the local response. More than 90% of the antibodies to the T-4 coliphages could be removed from the serum and cervial mucus by treatment with anti-immunoglobuin G antiserum. The lymphocyte response to antigens was studied by measuring the 3H-thymidine uptake by peripheral blood lymphocytes in culture. A positive response was observed in three of three systemically immunized and in only two of six locally immunized aminals. In general, the immune response was significantly weaker after local vaginal immunization than after systemic immunization.

Animals↗

PubMed1982

Adjuvant action of bacterial lipopolysaccharide in induction of delayed-type hypersensitivity to protein antigens. II. Relationships of intensity of the action to that of other immunological activities.

Various kinds of lipopolysaccharides (LPS) isolated from different bacterial strains exhibited more or less an adjuvant action in induction of delayed-type footpad response to ovalbumin (OA) in mice when antigen was injected subcutaneously together with LPS. There was a wide diversity in strength of the adjuvant action of LPS, and the action of the 03 antigen isolated from the culture supernatant fluid of Klebsiella was the most potent of eleven kinds of LPS tested. Besides this substance, LPS extracted from Escherichia coli 08, 09 and 0128, and Salmonella typhosa exhibited relatively strong action. The difference in strength of the action of the high and low active LPS in induction of delayed-type hypersensitivity could be observed at any doses of OA and LPS. The strength of the adjuvant activity of LPS in induction of delayed-type hypersensitivity roughly correlated with that of their adjuvant activity in augmenting immunological memory for the secondary antibody response to OA and also their ability to enlarge the regional lymph node, whereas it did not apparently correlate with that of their activity to stimulate B cells polyclonally and their ability to enlarge the spleen.

Adjuvants, Immunologic↗

PubMed1995

Local skin reactivity after induction of Shwartzman reaction in rabbits.

A local Shwartzman response was elicited in rabbits by an intradermal injection of the Salmonella typhosa endotoxin lipopolysaccharide (LPS) followed 24 hours later by an intravenous challenge injection with zymosan. After the intravenous challenge, necrotizing vasculitis developed in the prepared skin sites which was characterized by microthrombi, accumulation of neutrophil granulocytes, fibrin deposition and extravasation of red blood cells. Evans' blue extravasation into the altered tissue was significantly reduced, and histologically, the intensity of the Shwartzman reaction in the skin was reduced by pretreatment with thalidomide and dexamethasone. The mechanism of reduction of an LPS-induced local Shwartzman reaction by thalidomide is discussed.

Animals↗

PubMed2004

New approach to an ovine model of hypodynamic endotoxaemia.

BACKGROUND AND OBJECTIVE: Since the moribund hypodynamic phase of septic shock has primarily been studied in small animal models, the objective of this study was to investigate the usefulness of infusing Salmonella typhosa endotoxin at incrementing doses to establish an ovine model of hypodynamic endotoxaemia. METHODS: In a prospective laboratory experiment, eight adult ewes were instrumented for a chronic study. Following a baseline measurement in the healthy state, a continuous endotoxin infusion was started with 10 ng kg(-1) min(-1) and was doubled every hour seven times. Haemodynamics, key variables of oxygen transport, and arterial lactate concentrations were determined every hour. RESULTS: In a dose-dependent manner, endotoxin infusion caused pulmonary hypertension, decreased cardiac output and mean arterial pressure, increased heart rate, and to a certain extent, systemic vascular resistance index. Following 4h of endotoxaemia, the maximum decrease in cardiac output occurred (4.8+/-0.2 vs. 7.6+/-0.3 Lmin(-1); P < 0.001). This was accompanied by tissue dysoxia, represented by decreases in oxygen delivery (797+/-20 vs. 1041+/-28 mLmin(-1)), oxygen consumption (277+/-14 vs. 396+/-15 mLmin(-1)) and oxygen extraction rate (0.35+/-0.01 vs. 0.38+/-0.01%; each P < 0.01), as well as an increase in arterial lactate concentration (1.7+/-0.1 vs. 0.7+/-0.1 mmolL(-1); P < 0.05). CONCLUSIONS: This large animal model may be helpful to study the pathophysiology responsible for cardiovascular failure, and also new therapeutic approaches relevant to management of hypodynamic circulation in the common setting of progressed systemic inflammation.

Animals↗

PubMed1987

Cyclic AMP-regulating agents inhibit endotoxin-mediated cartilage degradation.

The influence of cyclic AMP on cartilage degradation was investigated by using phosphodiesterase inhibitors [theophylline and 3-isobutyl-1-methylxanthine (IBMX)], forskolin (which activates the catalytic subunit of adenylate cyclase) and cyclic AMP analogues (dibutyryl and 8-bromo). Breakdown was assessed by quantification of proteoglycans released into the media of 8-day bovine nasal-septum cartilage cultures. Theophylline (1-20 mM), IBMX (0.01-2 mM) and dibutyryl cyclic AMP (0.1-2 mM) had little or no influence on the rate of proteoglycan release from unstimulated (no-endotoxin) cartilages. A small but detectable increase in breakdown was observed with 8-bromo cyclic AMP (0.5-2 mM) and forskolin (50-75 micrograms/ml). To examine potential inhibitory influences of these agents, the cyclic AMP modulators were added to cultures simultaneously treated with Salmonella typhosa endotoxin (12-25 micrograms/ml), a potent stimulator of cartilage degradation. The 3-4-fold stimulation of breakdown by endotoxin was strikingly inhibited by all three classes of cyclic AMP regulators. Optimal inhibition was found at 10-20 mM-theophylline, 1-2 mM-IBMX, 50-75 micrograms of forskolin/ml, 2 mM-dibutyryl cyclic AMP and 2 mM-8-bromo cyclic AMP. Inhibition was shown to be reversible, indicating that cartilages were viable after treatment. Sepharose CL-2B chromatography of proteoglycan products released from treated cartilages showed that the endotoxin-stimulated shift to lower average Mr was significantly prevented by cyclic AMP analogues and phosphodiesterase inhibitors. Together, these results show that agents which increase cyclic AMP inhibit both quantitative and qualitative aspects of endotoxin-mediated cartilage degradation.

1-Methyl-3-isobutylxanthine↗

PubMed1997

Comparative effects of nitric oxide synthesis inhibition and catecholamine treatment in a rat model of endotoxin shock.

Catecholamines and volume repletion are currently used for the treatment of septic shock. However, the prognosis of patients suffering from this condition is very poor. An overproduction of nitric oxide (NO) seems to be related to the hypotension and tissue damage of endotoxin shock. Thus, treatment with NO synthase inhibitors has been proposed. Using a rat model of septic shock we have studied the effects of noradrenaline or the NO synthase inhibitor, NG-nitro-L-arginine methylester (L-NMMA) on arterial pressure, tissue damage and NO production. Anaesthetized rats treated with Salmonella typhosa showed a decrease in blood pressure accompanied by an increase in the plasma concentration of cytosolic enzymes (transaminases and lactate dehydrogenase, markers of cell disruption) and nitrite plus nitrate (NO2-/NO3-, markers of NO production). A large proportion of these animals (40%) died before the end of the experiment. Co-treatment with noradrenaline resulted in temporary maintenance of arterial pressure followed by a decline, despite the dose being increased progressively. No differences were observed in plasma cytosolic enzymes, NO2-/NO3- or mortality compared with animals treated with lipopolysaccharide (LPS) alone. In contrast, administration of L-NMMA (10 mg kg-1) to septic animals prevented the fall in blood pressure and death caused by endotoxin. This treatment markedly diminished cell disruption, as measured by the plasma levels of necrosis enzymes, and partially, but significantly, reduced the production of NO as assessed by plasma NO2-/NO3-. We conclude that tissue damage in septic shock is related to the overproduction of NO and not exclusively to the hypotension that follows this increased production. Thus, maintenance of blood pressure with catecholamines fails to improve cellular damage. Instead, partial inhibition of NO generation is sufficient to ameliorate the haemodynamic and tissue-damaging effects of septic shock and improves survival in this model of endotoxaemia.

Animals↗

PubMed1973

Stimulation of steroid secretion in adrenal tumor cells by choleragen.

Choleragen, the pure protein from cholera toxin, stimulates steroid secretion by Y-1 adrenal tumor cells in culture. The secreted steroids are the same as seen after addition of adrenocorticotropic hormone. Half-maximal stimulation occurs at 15 pM; stimulation is essentially irreversible by washing and partially reversible (for about 1 hr) by antibody, and there is a latent period of about 60 min before stimulation is seen. Stimulation of adenylate cyclase occurs at about 30-fold higher choleragen concentrations. Gangliosides inhibit choleragen stimulation when added before but not after the toxin. Lipopolysaccharides from Escherichia coli, Salmonella typhosa, and Serratia marcescens also stimulate steroid secretion, but are less potent than choleragen.

Adenylyl Cyclases↗

PubMed1996

Arrest of endotoxin-induced hypotension by transforming growth factor beta1.

Septic shock is a cytokine-mediated process typically caused by a severe underlying infection. Toxins generated by the infecting organism trigger a cascade of events leading to hypotension, to multiple organ system failure, and frequently to death. Beyond supportive care, no effective therapy is available for the treatment of septic shock. Nitric oxide (NO) is a potent vasodilator generated late in the sepsis pathway leading to hypotension; therefore, NO represents a potential target for therapy. We have previously demonstrated that transforming growth factor (TGF) beta1 inhibits inducible NO synthase (iNOS) mRNA and NO production in vascular smooth muscle cells after its induction by cytokines critical in the sepsis cascade. Thus, we hypothesized that TGF-beta1 may inhibit iNOS gene expression in vivo and be beneficial in the treatment of septic shock. In a conscious rat model of septic shock produced by Salmonella typhosa lipopolysaccharide (LPS), TGF-beta1 markedly reduced iNOS mRNA and protein levels in several organs. In contrast, TGF-beta1 did not decrease endothelium-derived constitutive NOS mRNA in organs of rats receiving LPS. We also performed studies in anesthetized rats to evaluate the effect of TGF-beta1 on the hemodynamic compromise of septic shock; after an initial 25% decrease in mean arterial pressure, TGF-beta1 arrested LPS-induced hypotension and decreased mortality. A decrease in iNOS mRNA and protein levels in vascular smooth muscle cells was demonstrated by in situ hybridization and NADPH diaphorase staining in rats treated with TGF-beta1. Thus these studies suggest that TGF-beta1 inhibits iNOS in vivo and that TGF-beta1 may be of future benefit in the therapy of septic shock.

Animals↗

PubMed1979

Detection of gap junctions between the progeny of a canine macrophage colony-forming cell in vitro.

An in vitro monocyte-macrophage colony-forming cell (M-CFC) has been detected in canine bone marrow (BM). The colonies derived from these progenitor cells were similar to murine-derived M-CFC (MacVittie and Porvaznik, 1978, J. Cell Physiol. 97:305--314) colonies, since they showed a singular macrophage line of differentiation, a lag of 14--16 days before initiating colony formation, and they survived significantly longer in culture in the absence of colony-stimulating factor (CSF) than granulocyte-macrophage colony-forming cells (GM-CFC). Endotoxin (Salmonella typhosa lipopolysaccharide W)-stimulated dog serum was used as the CSF (7% vol/vol). Canine-derived M-CFC progeny were identified as macrophages on the basis of morphology, phagocytosis, and the presence of Fc receptors for IgG. Gap junctions were observed only in canine BM, M-CFC-derived colonies using freeze-fracture and lanthanum tracer techniques. They were not observed in any GM-CFC-derived colonies. The number of gap junctions observed in freeze-fracture replicas of BM, M-CFC-derived colonies (21 colonies from three different dogs) showed a significantly positive correlation (Kendall's tau = 0.70, P less than 0.001) with the size of the colony fracture plane area. Gap junctions were observed displaying hexagonal lattices of 9.3 nm +/- 0.08 (SE) particles with a center-to-center spacing of 10.4 nm +/- 1.0 (SE) on membrane P-fracture faces. On membrane E-fracture faces, highly ordered arrays of pits with 8.7 nm +/- 0.12 (SE) center-to-center spacing were observed. Arrays of both particles and pits were also observed in fracture-face breakthroughs within a gap junction. Thus, gap junctions can form in vitro between the cells of macrophage progeny of a canine M-CFC under appropriate growth conditions. The significance of this observation is that there may be a structural basis for cell-to-cell collaboration between BM macrophages and other capable cells that either pass into the tissue for modification or develop there into mature cell forms.

Animals↗

PubMed1956

Reversible changes in the susceptibility of mice to bacterial infections. I. Changes brought about by injection of pertussis vaccine or of bacterial endotoxins.

MICE WERE INJECTED INTRAPERITONEALLY WITH ONE OF THE FOLLOWING BACTERIAL PRODUCTS HAVING ENDOTOXIN ACTIVITY: pertussis vaccine, a suspension of heat-killed cells of Klebsiella pneumoniae (type C), or a purified lipopolysaccharide prepared from cultures of Salmonella typhosa. Following treatment with either one of these materials, the animals were infected intravenously with virulent cultures of coagulase-positive staphylococci, with bovine tubercle bacilli, or Friedländer bacilli. The effect of treatment with endotoxin materials on resistance to Friedländer bacilli, staphylococci, or tubercle bacilli was estimated by observing the mortality rates in infected animals, and by determining quantitatively the numbers of living bacteria in the organs at different periods of time after infection. It was found that mice receiving the infective dose of virulent culture a few hours after treatment with the endotoxin material, were usually more susceptible to infection than were untreated animals. In contrast, mice infected at a later period proved far more resistant to infection than did untreated animals. The duration of the negative and of the positive phase of resistance was affected by the amount of endotoxin injected. Marked increase in resistance of mice to infection with staphylococci or tubercle bacilli was still evident several weeks after treatment with pertussis vaccine or with purified lipopolysaccharide extracted from typhoid bacilli.

Animals↗

PubMed1958

Studies on antibody synthesis initiated in vitro.

Ten microg. of the lipopolysaccharide endotoxin of Salmonella typhosa was given to rabbits intravenously to enhance the subsequent antibody response to an unrelated substance. The spleens were removed 24 hours later, diced, and incubated 1 hour with the antigen, bovine-gamma-globulin (BGG), in a protein-free medium. After washing, the tissues either were extracted at once or planted and the fluids and tissues harvested 1 to 3 days later. Antibody was determined by a modification of the Boyden hemagglutination technique. Small amounts of antibody were synthesized as early as 1 hour after the addition of antigen. The antibody formed could be specifically inhibited with BGG, was not dialyzable, and did not sediment at 105,000 g for 2 hours. Dose-response studies revealed no antibody formation when the BGG concentration was 0.005 or 0.05 mg./ml. The best responses were obtained at concentrations of 0.5 to 5.0 mg./ml. These results were found irrespective of whether the animal had previously received BGG in vivo. Forty per cent autologous serum increased antibody formation about 9-fold over that secured with protein-free medium or with 40 per cent homologous serum. Antibody formed with this system could be detected by 50 per cent complement fixation test, although at much lower titer than found by hemagglutination. While spleens from rabbits previously given BGG did not produce more antibody than spleens from normal rabbits, they differed in that they produced antibody without the involvement of endotoxin. Under appropriate circumstances, endotoxin was effective in vitro in enabling spleen fragments to produce antibody to BGG. Cortisone acetate administered to rabbits prior to the removal of the spleen severely inhibited antibody production in vitro. Sodium prednisolone phosphate added in vitro showed a similar irreversible effect at concentrations as low as 2 x 10(-5)M. Nitrogen mustard inhibited antibody formation at concentrations as low as 10(-4)M.

Animals↗

PubMed1962

The stimulation of non-specific host resistance to infection by chemically modified endotoxin.

An acetylated derivative prepared from Salmonella typhosa O-901 endotoxin has been found to retain the ability to stimulate non-specific host resistance to a variety of bacterial infections. Relative to the parent endotoxin, the derivative has been reduced in the gross in its pyrogenicity to rabbits and lethality to mice. With the use of this chemically modified preparation under a variety of conditions, the direct dissociation of the toxic properties of endotoxin from its protective capacity appears evident. In young male mice, the endotoxin and its derivative produced a leucocytosis but no leucopenia. However, no direct correlation could be found with the level of the peripheral white blood cells and resistance to infection with Escherichia coli. Furthermore, under the conditions employed, passive transfer of early resistance to infection by serum or plasma was not detectable.

Animals↗

PubMed1963

Fetal response to antigenic stimulus. II. Antibody production by the fetal lamb.

The fetal lamb in utero is able to form large amounts of specific antibody in response to antigenic stimulus as early as the 66th to 70th day of the 150 day gestation period. Among the several antigens employed, the fetal lamb responded earliest, and with the highest titers, to bacteriophage varphiX. Slightly less effective as an antigen was horse ferritin, while ovalbumin proved to be a weak antigen, especially in younger fetuses. Ineffective in stimulating an antibody response at any time during fetal or early neonatal life were diphtheria toxoid, Salmonella typhosa, and BCG. Thus, it may not be feasible to fix precisely the time of onset of immunologic responsiveness in a species, inasmuch as it appears to differ so greatly from one antigen to another. The quantity of antibody found 10 days after varphiX immunization was not significantly different in fetuses injected at 60 to 120 days of gestation. The earliest anti-phage antibody produced by the lamb fetus is a macroglobulin sensitive to the action of 2-mercaptoethanol. Only in older fetuses with longer lasting stimuli were appreciable amounts of 7S gamma-globulin antibodies formed. The conformity of these observations to theories on the ontogenesis of the immune response is discussed.

Amphotericin B↗

PubMed1992

A Trypanosoma cruzi membrane protein shares an epitope with a lymphocyte activation antigen and induces crossreactive antibodies.

Chagas' disease results from the infection of the protozoan parasite Trypanosoma cruzi and affects several million people in South America. Several alterations of the immune response have been described in this disease, such as severe immunosuppression of both cellular and humoral responses and massive polyclonal stimulation with the generation of autoantibodies crossreacting with host cells and tissues. We have obtained monoclonal antibodies (mAbs) from T. cruzi-infected mice that recognized a 50/55-kD antigen (GP50/55) on the T. cruzi membrane, but not in other parasites of the family Trypanosomatidae. One of these GP50/55-specific mAbs (C10) crossreacts with a 28-kD antigen (p28) expressed on the membrane of greater than 85% of activated mouse T and B lymphocytes, after in vitro activation with concanavalin A, Salmonella typhosa lipopolysaccharide, phorbol dibutyrate ester, or antigen, and on several murine T and B lymphocyte cell lines. Human T and B lymphocytes also express upon activation with phytohemagglutinin or Staphylococcus aureus Cowan I (SAC) a similar antigen recognized by mAb C10, although in a lower proportion of cells (30-40%). Furthermore, this mAb was able to suppress mouse and human T and B cell proliferation to any of those stimuli. In addition, sera from chagasic patients and T. cruzi-infected mice, but not from control patients or littermates, contain antibodies that recognize a similar p28 antigen on B lymphocytes. Furthermore, the immunoglobulin fractions of some chagasic sera also suppress the proliferation of human T lymphocytes. These results suggest a possible pathological role of autoantibodies as an alternative mechanism for T. cruzi-associated immunosuppression.

Animals↗

PubMed2001

Alanyl-glutamine dipeptide does not affect hemodynamics despite a greater increase in myocardial heat shock protein 72 immunoreactivity in endotoxemic sheep.

The possible beneficial effect of supplemental glutamine (Gln) in critically ill patients has been suggested to be mediated by the induction of the cytoprotective heat shock proteins (HSP)32 and HSP72. There is evidence that HSP72 and HSP32 have opposite effects on the hemodynamic situation during endotoxemia. Therefore, the effect of Gln supplementation on the cardiovascular system is not clear. We investigated the effect of alanyl-Gln (Ala-Gln) dipeptide on cardiovascular function in healthy and endotoxemic sheep. Ten sheep catheterized for chronic studies received Ala-Gln 700 mg/(kg x d) [equal to 470 mg/(kg x d)Gln] on 4 consecutive days, and 10 sheep received NaCl (9 g/L) as the control solution. On d 4, four sheep of each group were killed and myocardial samples were taken for immunohistochemistry. The remaining sheep received a continuous infusion of endotoxin [Salmonella typhosa, 10 ng/(kg x min)]. Hemodynamic parameters were measured before application of Ala-Gln or the control solution, and during endotoxemia. Myocardial HSP72 immunoreactivity was determined by immunohistochemistry. After 24 h of endotoxemia, the sheep exhibited a hyperdynamic circulation. No difference was found in the hemodynamic parameters between treatment and control group. Ala-Gln treated sheep had a greater increase in myocardial HSP72 immunoreactivity compared with controls after (P < 0.05) but not before endotoxemia. In summary, Ala-Gln increased HSP72 immunoreactivity after endotoxemia, but did not alter hemodynamic parameters. Thus, Ala-Gln supplementation does not seem to aggravate the hyperdynamic circulation in endotoxemic shock.

Animals↗