Tolerance to Bacterial Pyrogens

Beeson, Paul B.

doi:10.1084/jem.86.1.29

Cited by 311 publications

(129 citation statements)

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“…Recently, Wolff and his associates observed that rabbits pretreated with 6-mercaptopurine readily acquired pyrogenic 5 The complementary observation, i.e. that pyrogenic tolerance wanes despite elevated circulating antibody titers to endotoxin (24), is not as crucial an argument against the importance of circulating antibody since a decrease in those antibodies with protective activity might be masked by a high titer of non-protective antibody (20).…”

Section: Discussionmentioning

confidence: 99%

“…The reappearance of pyrogenic responsiveness upon resuming the intravenous infusion of endotoxin on day 2 in man, the rapid waning of pyrogenic unresponsiveness after an initial single intravenous bolus of a small quantity (1.0/~g) of endotoxin in rabbits (35), and the need for daily injections of endotoxin to maintain maximum pyrogenic tolerance (24) all suggest that desensitization to endotoxin at the cellular level is transient. Stetson has previously emphasized the parallelism to maintainence of the desensitized state to tuberculin (18).…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms of Endotoxin Tolerance

Greisman

Woodwards

1965

The Journal of Experimental Medicine

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The mechanisms by which pyrogenic tolerance develops in man and rabbit after a series of intravenous injections of bacterial endotoxin spaced at 24-hour intervals have been studied intensively (1). In contrast, the rapid development of unresponsiveness to the pyrogenic activity of bacterial endotoxlns during continuous intravenous infusions (2) has been virtually neglected. I t is the purpose of this report to characterize this latter form of pyrogenic unresponsiveness and to compare the underlying mechanisms with those which m a y operate when the endotoxin is administered in the more usual manner as a single intravenous bolus at daily intervals. Materials and MethodsThe present studies were initiated as part of an overall program to define the role of endotoxin in the pathogenesis of gram-negative bacterial infections in man. Volunteers for these studies were healthy male inmates of the Maryland House of Correction, Jessup, Maryland. Their ages ranged from 20 to 40. Complete medical evaluation was performed to verify the fitness of each participant. In addition to man, healthy male New Zealand albino rabbits obtained from a uniform source and weighing approximately 2 kg were employed.Syringes and needles were either of the sterile, pyrogen-free disposable type (Burton Medical Products, Bethlehem, Pennsylvania), or were heated overnight in a dry-air oven to 1800C to eliminate extraneous pyrogen. Three endotoxin preparations were employed: Salmondla typhosa (0-282) I, Escherickia coli endotoxin (0127:B8) 2, and Pseudomon~ endotoxin 8.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mechanisms of Endotoxin Tolerance

Greisman

Woodwards

1965

The Journal of Experimental Medicine

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“…The failure of tolerant rabbit serum to transfer high levels of pyrogenic tolerance to normal recipients (8,11,29) does not exclude the importance of specific humoral endotoxin inhibitors; such factors, behaving as opsonins, may induce more intense inhibition in conjunction with the generalized RES stimulation that accompanies pyrogenic tolerance in this species. Moreover, quantitative data are not yet available to evaluate the effects of dilution following passive transfer to normal recipients.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Endotoxin Tolerance

Greisman

Carozza

Hills

1963

The Journal of Experimental Medicine

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Following the demonstration by Beeson that induced tolerance to the pyrogenic activity of bacterial endotoxins could be reversed by reticuloendothelial system (RES) "blockade" (1), evidence has accumulated suggesting that accderated phagocytosis of endotoxin by the RES represents the major mechanism of tolerance.Tolerant animals dear endotoxin more rapidly from the circulation as detected by bioassay of plasma samples (1-3) and by disappearance of lethal doses of radioactively tagged endotoxin (4); the latter studies also demonstrate increased hepatic localization. In the tolerant animal, RES phagocytic activity for colloids is increased (5), weight and histologic appearance indicate 1LES hypertrophy (5), and treatment with a variety of agents which blockade the RES abolishes tolerance (7). Tolerance cannot be correlated with specific antibody titer (8, 9) and can be induced readily in subjects with agammaglobulinemia (10). Serum from tolerant donors confers no detectable (8) or minimal (11) tolerance; moreover, after loss of tolerance following ILES blockade, the in vitro effect of serum on endotoxin pyrogenicity remains unaltered (12).Recently, Freedman reported the successful passive transfer of significant endotoxin tolerance in rabbits employing specific endotoxin dose schedules for inducing tolerance in donor animals (13). Although these data indicate unequivocally the participation of humoral factors in endotoxin tolerance, the importance of such factors and the mechanism by which they operate remain speculative. Freedman suggested that the humoral factors act in rabbits and mice by enhancing RES phagocytic capacity; i.e., transfer of tolerance was correlated with increased ability of the recipient animal to clear colloidal carbon, and hence presumably endotoxin, from the blood (14). In contrast, studies in man indicate that tolerance to the pyrogenic *

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“…The phenomenon of tolerance to LPS was noted early on with respect to the febrile response of the rabbit (Beeson, 1947). It was suggested to be controlled at the cellular level (Greisman et al, 1966) (Freudenberg and Galanos, 1988).…”

Section: Discussionmentioning

confidence: 99%

Role of p52 (NF-kappaB2) in LPS Tolerance in a Human B Cell Line

Wedel¹,

Frankenberger²,

Sulski³

et al. 1999

Biological Chemistry

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Cells of the weakly CD14 positive human B cell line RPMI 8226, clone 1, will mobilize NF-B (p50/p65 and p50/p50) proteins and produce TNF mRNA when stimulated with lipopolysaccharide (LPS). When such cells are precultured with a low amount of LPS (50 -250 ng/ ml) for 3 -4 days followed by a secondary stimulation with a high dose of LPS (1 g/ml) then the cytokine expression is strongly reduced, i. e. the cells have become tolerant.Western blot analysis of proteins of the NF-B/rel family demonstrates cytoplasmic p50 and p65 for naive B cells plus a low level of p52. While with tolerance induction the pattern of p50 and p65 proteins remains essentially unchanged, the LPS tolerant 8226 cells show a dramatic increase of both p52 protein and its p100 precursor in the cytosol. This p52 is found strongly upregulated in Western blots of extracts from purified nuclei of tolerant cells. Also, gelshift analysis with the -605 B motif of the human TNF 5 -region shows an additional high mobility complex in LPS tolerant cells -a complex that is supershifted with an anti-p52 antibody.Functional analysis with the -1064 TNF 5 -region in front of the luciferase reporter gene demonstrates that transactivation of the TNF promoter is strongly reduced in tolerant cells. Also, overexpression of p52 will suppress activity of TNF promoter reporter gene constructs.Taken together these data show that tolerance to LPS in the human RPMI 8226 B cell line involves upregulation of the p52 (NF-B2) gene, which appears to be instrumental in the blockade of TNF gene expression.

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Tolerance to Bacterial Pyrogens

Cited by 311 publications

References 3 publications

Mechanisms of Endotoxin Tolerance

Mechanisms of Endotoxin Tolerance

Mechanisms of Endotoxin Tolerance

Role of p52 (NF-kappaB2) in LPS Tolerance in a Human B Cell Line

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