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PubMed1977

The production of antibody against human leukocytic pyrogen.

Human peripheral blood leukocytes were stimulated with killed staphylococci in vitro to release leukocytic pyrogen (LP). Supernates from these stimulated leukocytes were concentrated, emulsified in Freund's complete adjuvant, and injected intradermally into rabbits. After seven monthly booster injections, rabbit antiserum destroyed the pyrogenic activity of human LP, and the titer of this neutralizing ability increased in the subsequent 7 mo. The pyrogen-neutralizing capacity of the rabbit antiserum was recovered in the globulin fraction, the IgG and IgM peaks of Sephadex G-200, and the acid-eluted fraction of a goat anti-rabbit IgG immunoadsorbant. The neutralizing antibody was specific for human LP inasmuch as it had no effect on rabbit, guinea pig, or monkey LP. When coupled to Sepharose, this antibody bound human LP; after acid elution from this immunoadsorbant, LP was recovered without loss of biologic or chemical characteristics. The antiserum was also absorbed with stimulated leukocyte supernates which did not contain LP, and this had no effect on the titer of anti-LP. Crude human LP, eluted from immunoadsorbant columns prepared from absorbed antiserum, contained significantly reduced contaminating protein when evaluated by polyacrylamide gel electrophoresis. These studies have established that specific antibody to human leukocytic pyrogen can be produced. This antibody is useful in the further study and purification of leukocytic pyrogen and its role in the pathogenesis of human fever.

Animals↗

PubMed1976

Pyrogen from mouse macrophages causes fever in mice.

Mouse peritoneal macrophages, after phagocytosis, release an endogenous (leucocyte) pyrogen. Intravenous injection of stimulated cell culture supernatant produces a prompt, monophasic fever in mice maintained in a 35 degree environment. The pyrogen is distinct from endotoxin, and resembles cell pyrogens of other species in heat-lability and pronase sensitivity. Human leucocyte pyrogen produces identical responses in mice. Measurement of fever in mice appears to provide a sensitive biological assay for endogenous pyrogens.

Animals↗

PubMed1976

[Effect of cytostatic drugs on fever development following administration of bacterial pyrogen].

A study was made of the development of pyretic reaction to the administration of a bacterial lipopolysaccharide (pyrogenal) after preliminary treatment of rabbits with actinomycin D and cortisone. Such treatment failed to change the reactivity of thermoregulating centres to the endogenous pyrogen. Intravenous injection of bacterial pyrogen was followed by marked shortening of pyretic reaction; the reaction was markedly inhibited in response to its intracysternal administration. An important role played by polymorphonuclear leukocytes in the formation of endogenous pyrogens in the mechanism of pyrexia induced by bacterial pyrogens was shown in this work.

Animals↗

PubMed1975

[The effect of leukocyte pyrogen on thermosensitive neurons of the anterior hypothalamus].

Impulse activity of neurons of the medial preoptic and septal brain areas of rabbits caused by variations in the local temperature and systemic injections of the leukocytic and bacterial pyrogens was studied. The firing rate of the warmsensitive neurons decreased and that of the cold thermodetectors was activated as a result of pyrogen action. As compared with the bacterial pyrogen, leukocytic pyrogen caused a more rapid decrease of the warmthermodetector activity. Thermoneutral neurons failed to react considerably either to the leukocytic or to the bacterial pyrogen.

Animals↗

PubMed1992

[The place of pyrogen therapy in the modern treatment of schizophrenia patients].

The author analyses experience gained with the use of the pyrogenic drugs sulfazin and pyrogenal in the treatment of schizophrenic patients. Pyrogenal and sulfazin were administered to 26 patients with different forms of schizophrenia to overcome psychopharmacotherapeutic resistance and to 11 patients to enhance the sensitivity to insulin during insulin coma therapy. Based on the clinical analysis the author demonstrates the efficacy of the use of the pyrogenic drugs, particularly pyrogenal, in schizophrenic patients in order to overcome the resistance to pharmacotherapy and insulin.

Convulsive Therapy↗

PubMed1978

Further studies on the antipyretic action of polymyxin B in pyrogen-induced fever.

A study of the antipyretic effect of polymyxin B was undertaken to determine how this agent reduces fever in rabbits. It involved the effects of the drug: (1) on fever induced by exogenous pyrogenes (E. coli lipopolysaccharide, synthetic double-stranded ribonucleic acid, sodium nucleinate from yeast) and leucocytic pyrogen, (2) on the release of endogenous pyrogen in vivo and in vitro, and (3) on leucocytic and exogenous pyrogens in vitro. The results indicate that polymyxin B produces an antipyretic effect in endotoxin-induced fever primarily by an interaction of this cationic macromolecule with the anionic endotoxin molecule. Further it is likely that polymyxin B inhibits endogenous pyrogen synthesis and/or release from polymorphonuclear leucocytes.

Animals↗

PubMed1978

[Body temperature and the reaction to pyrogenal in germ-free and ordinary animals].

Body temperature, as well as pyrexia in response to pyrogenal in germfree and conventional mice and miniature piglets were studied. A decrease of the mean body temperature in the intact germ-free mice and miniature piglets in comparison with conventional animals of the corresponding species was revealed. The absence of marked pyretic response to pyrogenal after intraperitoneal injections of 10 minimal pyrogenic doses to mice and after intramuscular injections of 500 minimal pyrogen doses of pyrogenal to miniature piglets was observed in germfree animals. The data obtained indicated an important role of autoflora in the development of the organism capacity to temperature reaction and pyrexia.

Animals↗

PubMed1979

Production of endogenous pyrogen.

The production and release of endogenous pyrogen by the host is the first step in the pathogenesis of fever. Endogenous pyrogen is a low-molecular-weight protein released from phagocytic leukocytes in response to several substances of diverse nature. Some of these agents stimulate production of endogenous pyrogen because they are toxic; others act as antigens and interact with either antibody or sensitized lymphocytes in order to induce its production. Some tumors of macrophage origin produce the molecule spontaneously. Whatever the mechanism involved, endogenous pyrogen is synthesized following transcription of new DNA and translation of mRNA into new protein. Once synthesis is completed, the molecule is released without significant intracellular storage. Recent evidence suggests that following release, molecular aggregates form which are biologically active. In its monomer form, endogenous pyrogen is a potent fever-producing substance and mediates fever by its action on the thermoregulatory center.

Animals↗

PubMed1976

Intraventricular antipyretics and bacterial pyrogen fever.

In adult fowls with cannulae chronically implanted into the IIIrd cerebral ventricle or into the hypothalamus, the effects of various hydrosoluble antipyretics, given intraventricularly, on bacterial pyrogen fever were studied. It has been shown that fever evoked by intrahypothalamic or intraventricular infusion of O somatic antigen of Shigella Dysenteriae was reduced by intraventricular administration of acetylsalicylate-lysine, indomethacin-methylglucamine or ibuprofen-lysine given during the febrile plateau. However, a 3-day intraventricular pretreatment with acetylsalicylate or indomethacin, or a single administration 30 min before, did not prevent fever by subsequent intraventricular or intrahypothalamic injection of pyrogen. On the contrary, intraventricular infusion of indomethacin or acetylsalicylate substantially reduced pyrogen fever when given after pyrogen latency period, e.g. just at the beginning of the febrile response. A possible involvement of E prostaglandins as mediator to pyrogen fever is discussed.

Analgesics↗

PubMed1976

Comparison of the pyrogenicity, Limulus activity mitogenicity and complement reactivity of several bacterial endotoxins and related compounds.

The correlation of mitogenicity, complement activation, pyrogenicity and Limulus amebocyte lysate (LAL) gelation induced by 17 bacterial endotoxins (LPS), modified endotoxins, related compounds, and other B cell mitogens was examined. With the use of these compounds, a significant correlation was found between pyrogenicity and mitogenicity (r = 0.85, p is less than 0.0005), pyrogenicity and LAL reactivity (r = 0.84, p is less than 0.0005), and mitogenicity and LAL reactivity (r = 0.72, p is less than 0.0025). In contrast, complement activation by these compounds did not correlate with mitogenicity, pyrogenicity or LAL reactivity (r = 0.09, p is greater than 0.4; r = -0.17, p is greater than 0.3; r = 0.17, p is greater than 0.3, respectively). These results suggest that a specific chemical configuration may induce mitogenicity, pyrogenicity, and LAL reactivity which differs from that responsible for complement activation.

Animals↗

PubMed1985

Crystal-induced endogenous pyrogen production. A further look at gouty inflammation.

We found previously that crystals of sodium urate and silicon dioxide (silica) can stimulate the production of endogenous pyrogen (EP), now called interleukin-1 (IL-1), the polypeptide mediator of fever and other aspects of inflammation. We have confirmed and extended the work with urate crystals and have examined 2 other crystals associated with joint problems, hydroxyapatite (HA) and calcium pyrophosphate dihydrate (CPPD). The crystals were added to suspensions of human blood leukocytes (2.5 X 10(6) monocytes/dose, with 10% fresh autologous plasma); after 18 hours of incubation, the EP content of the supernatants was assayed in the rabbit pyrogen test. HA and CPPD crystals neither induced EP production nor reduced the amount of staphylococci-induced EP. Presized (10 - 40 micron) urate crystals were pyrogenic, but less so than the unsized and aggregated urate crystals investigated previously and reexamined here. On ultrasonication, the aggregated urate crystals became first more pyrogenic and then less so as the crystals were dispersed and broken down. Ultrasound did not impart pyrogenicity to HA or CPPD crystals: their failure to stimulate EP/IL-1 production from leukocytes in vitro indicates a difference in their phlogistic properties, compared with crystals of urate or silica. The results with urate crystals have pathogenetic implications in a number of areas of gouty inflammation: initiation of the acute attack, other aspects of the acute-phase response, polyarticular involvement, and the inflammatory consequences of chronic stimulation by tophaceous material.

Calcium Pyrophosphate↗

PubMed1992

Determination of cytokine release after in vivo and in vitro administration of Deodan (a preparation from Lactobacillus bulgaricus "LB51") by the rabbit pyrogen test.

We investigated the in vivo and in vitro cytokine inducing effects of Deodan, an oral preparation from Lactobacillus bulgaricus "LB-51", using the rabbit pyrogen test. In the first experimental approach we administered Deodan, or its chromatographically purified fraction, via the i.m. or i.v. routes. Low doses of Deodan i.m. caused the formation of a single temperature peak, whereas large doses produced a biphasic temperature curve. Intravenous injection of Deodan produced a monophasic fever in all tested doses. Chromatographically purified Deodan injected i.v. to rabbits caused a febrile response with a dose-dependent pattern, strikingly similar to that of lipopolysaccharide. LAL-testing of Deodan, however, showed that the preparation does not contain endotoxin. In in vivo neutralization studies we demonstrated that IL-1, TNF alpha, and IL-6 mediate the rabbit febrile response to Deodan. Interestingly, the effects of Deodan on the production of TNF alpha and IL-6 were more pronounced than its IL-1 inducing activity. In the second approach, we injected supernatants from mononuclear cells incubated with nonpyrogenic doses of Deodan, intravenously to rabbits ("monocyte type" of pyrogen test). Rapid-onset monophasic fevers were observed, typical for the rabbit pyrogen reaction to i.v. administration of exogenous IL-1 and TNF. Finally, we demonstrated the presence of pyrogenic cytokines in the supernatants from macrophages of Deodan-treated mice. Together, these results indicate that Deodan induces the production of cytokines with endogenous pyrogenic activity.

Adjuvants, Immunologic↗

PubMed1991

Molecular analysis of pyrogenic exotoxins from Streptococcus pyogenes isolates associated with toxic shock-like syndrome.

Toxic shock-like syndrome (TSLS) is characterized by hypotension or shock, fever, multiorgan system involvement, and a concurrent group A streptococcal infection. We analyzed 34 streptococcal strains isolated from patients with clinically well-documented TSLS for their pyrogenic toxin profiles and M-protein types. Although strains of nine different M types were represented in the sample, 74% of the isolates were of either M type 1 or 3. It was determined that 53% produced streptococcal pyrogenic exotoxin type A under in vitro growth conditions and that 85% contained the gene encoding this toxin. These values are in contrast to the published value of 15% for the incidence of this gene in a sample of general group A streptococcal isolates. As has been found with all group A streptococci examined to date, regardless of disease association, 100% of TSLS-associated isolates contained the gene encoding pyrogenic exotoxin type B. This toxin was detectably produced by 59% of isolates. The gene encoding pyrogenic toxin type C was found in only 21% of isolates. We conclude that the pyrogenic exotoxin type A gene is associated with group A streptococcal strains isolated from patients with TSLS and may play a causative role in this illness. However, other factors are also likely to be important, since not all strains from patients with TSLS contained the A toxin gene.

Antigens, Bacterial↗

PubMed1978

A new sensitive method for detecting human endogenous (leukocyte) pyrogen.

Endogenous, or leukocyte pyrogen (EP), the mediator of fever, is currently detected by injection of pyrogen-containing supernatants into rabbits. This assay has been of little value in the study of human fever because it required injection of relatively large amounts of pyrogen. We now report that injection of medium containing human EP produces fever in mice. Supernatant from 1 c 10(5) granulocytes, stimulated by phagocytosis of staphylococci and incubated overnight, or 1 x 10(4) monocytes similarly treated, produce clear pyrogenic responses. This method for detecting EP is about 100-fold more sensitive than the rabbit assay, and it appears to be specific for EP. Preliminary studies of EP released by small samples of needle liver biopsies from febrile and afebrile patients suggests that this sensitive assay may be useful for investigations into the mechanisms of clinical fever.

Animals↗

PubMed1977

Partial purification of human leukocytic pyrogen.

Human leukocytes stimulated in vitro release leukocytic pyrogen (LP), a protein which is the mediator of fever. In order to study human leukocytic pyrogen, we attempted to purify this molecule from the large quantity and variety of proteins which are present in leukocyte supernates. Human peripheral leukocytes were stimulated in vitro by phagocytosis of killed staphylococci, and several methods were used to isolate the pyrogen protein. First, using isoelectric focusing, it was found that crude leukocyte supernates contained two molecular species of LP which were separable by precipitation in cold alcohol. Isoelectric focusing, although used for confirmation of the molecular homogeneity of LP, could not be employed as a preparative purification technique. Following alcohol precipitation, human LP was chromatographed on ion-exchange materials at various pH with modest recovery of initial activity but marked increase in specific activity. Gel-filtration was also employed and yielded partially purified LP. When alcohol precipitation was combined with ion exchange at alkaline pH and followed by gel-filtration, resulting LP preparations contained 5 or 6 contaminating proteins. These results demonstrate that human LP can be partially purified from the large quantity and variety of proteins present in crude leukocyte supernates and during purification procedures, the pyrogen did not change in either molecular weight or isoelectric point. This work provides reliable techniques for initial purification of human LP.

Chemical Precipitation↗

PubMed1978

Naloxone does not antagonize leukocytic pyrogen.

In a crossover experiment, cats were given third cerebral ventricular injections of 500 microgram naloxone hydrochloride or saline vehicle followed in 15 min by i.v. injections of saline solution or leukocytic pyrogen. The pyrogen produced comparable fevers after both saline and naloxone pretreatment. Intravenous administration of naloxone hydrochloride (5 mg/kg) likewise did not prevent febrile responses to leukocytic pyrogen. These results indicate that endogenous opioid peptides are not likely central mediators of pyrogen-induced fevers.

Animals↗

PubMed1979

Sites of clearance of leucocyte pyrogen in the rabbit.

1. The dose-response curve for sustained infusions of leucocyte pyrogen has been demonstrated, and an optimum dose indicated for leucocyte pyrogen clearance experiments. 2. The lungs, liver and small bowel are not significantly involved in removal of leucocyte pyrogen from the circulation in conscious rabbits. 3. A single circulation through one kidney removes up to half of the infused dose of leucocyte pyrogen.

Animals↗

PubMed1979

Production of pyrogenic exotoxin by groups of streptococci: association with group A.

Several groups of streptococci were tested for production of pyrogenic exotoxins (SPE) with Ouchterlony immunodiffusion, a newly developed passive hemagglutination inhibition assay, and an assay for pyrogenicity and capacity to enhance lethal endotoxin shock. With use of these assays, 68 (91%) of 75 group A streptococcal strains were positive for one or more of SPE types A, B, and C; seven were negative for both the known SPE types and antigenically unrelated pyrogenic exotoxins. Group A strains producing both SPE B and C were the most common, and strains producing A alone or AB and AC together were the least common. All of 11 rheumatogenic group A streptococci elaborated SPE C either alone or together with one or both of SPE types A and B. The 10 nephritogenic strains tested were positive for SPE B; five were positive for B alone. In contrast to group A streptococci, non-group A strains (41 tested) did not produce the known SPE types, and 19 of 19 tested were negative for antigenically unrelated pyrogenic exotoxins. Group A strains from Holland, India, and Japan also elaborated SPE. Several group A streptococci used widely in laboratory experiments were tested for SPE types produced.

Animals↗