Effect of 6-Mercaptopurine on Endotoxin Tolerance*

Wolff, Sheldon M.; Mulholland, John H.; Ward, Stanley B.; Rubenstein, Melvin; Mott, Peter D.

doi:10.1172/jci105245

Cited by 19 publications

(9 citation statements)

References 17 publications

(16 reference statements)

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“…Studies in our laboratory in rabbits given seven successive daily i.v. injections of 6-MP and ET confirm those of Wolff and co-workers (6) in that a high level of pyrogenic tolerance developed by day 8, comparable to that in non-6-LIP-treated controls. When each of the preceding daily responses was examined, however, it was observed that the 6-MP-treated animals exhibited unaltered early phase pyrogenic tolerance but significant retardation of the late phase, commencing at 72 h, coincident with the onset of impaired circulating anti-endotoxin antibody production and identical with that seen in the splenectomized rabbits.…”

Section: Discussionsupporting

confidence: 85%

“…The findings, considered collectively, indicate that the impairment of the late phase of pyrogenic tolerance after splenectomy is based primarily upon suppression of anti-endotoxin antibody production rather than upon loss of splenic reticuloendothelium required to clear and inactivate endotoxin. In earlier studies in which antibody synthesis was suppressed in rabbits by 6-mercaptopurine (6-AIP), no imllpairnient of pyrogenic tolerance to endotoxini was observed (6). This probably can be attributed to the fact that with the dosages employed (18 mg/kg) 6-MIP does not eliminate anti-endotoxin antibody synthesis and that the tolerant responses were not quantitated uintil 24 h after seven successive daily i.v.…”

Section: Discussionmentioning

confidence: 94%

“…Some investigators have concluded that anti-endotoxin antibodies represent the primary underlying mechanism (1); others have concluded that they play no demonstrable role (2)(3)(4)(5)(6). It is well establislhed that when small quantities of insoluble anti-gens are administered i.v., the spleen constitutes the major site of antibody formation, particularly during the initial week of immunization (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of endotoxin tolerance. The role of the spleen.

Greisman¹,

Young²,

Workman³

et al. 1975

J. Clin. Invest.

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A B S T R A C T Splenectomy markedly impaired the production of circulating anti-endotoxin antibodies during the initial 10 days after i.v. administration of a Boivin preparation of Escherichia coli endotoxin (ET) lated to fall between 1/10 and 1/100 of those used in the splenectomized subjects. The impairment of latephase pyrogenic tolerance after splenectomy appeared to be the result of the concomitant suppression of antiendotoxin antibody production rather than the loss of splenic reticuloendothelium required to clear and inactivate the ET. This was evidenced by: (a) the significant retardation in appearance of humoral factors in the splenectomized rabbits capable of transferring high levels of specific tolerance; (b) the inability to impair the late phase of tolerance in human volunteers with intact spleens until the immunizing doses of endotoxin were reduced to levels that virtually eliminated circulating anti-endotoxin antibody production; (c) the unimpaired development of tolerance in partially hepatectomized rabbits lacking more functional reticuloendothelium than splenectomized animals, but capable of normal anti-endotoxin antibody synthesis.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms of endotoxin tolerance. The role of the spleen.

Greisman¹,

Young²,

Workman³

et al. 1975

J. Clin. Invest.

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“…We have found that 6-mercaptopurine administered at the same time as the endotoxin injections, to a large extent, suppressed the production of specific antibody; titers were approximately 10% of those seen in controls (30). Despite this profound reduction of specific antibody levels, the "suppressed" and control animals developed febrile tolerance of equal magnitude (31). These findings fail to support the idea that some macroglobulin antibody, different from the familiar one directed against the somatic polysaccharide, is the major factor in resistance (26).…”

Section: Resultsmentioning

confidence: 86%

Quantitative Studies of Febrile Tolerance and Levels of Specific Antibody Evoked by Bacterial Endotoxin*

Mulholland¹,

Wolff²,

Jackson³

et al. 1965

J. Clin. Invest.

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“…tolerance despite drastic suppression of circulating antibody to endotoxin (26). Similarly, studies in our laboratory in splenectomized rabbits and man revealed drastic impairment in ability to elaborate specific antibody to E. coli endotoxin but only partial suppression of pyrogenic tolerance (27).…”

Section: Discussionmentioning

confidence: 89%

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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Effect of 6-Mercaptopurine on Endotoxin Tolerance*

Cited by 19 publications

References 17 publications

Mechanisms of endotoxin tolerance. The role of the spleen.

Mechanisms of endotoxin tolerance. The role of the spleen.

Quantitative Studies of Febrile Tolerance and Levels of Specific Antibody Evoked by Bacterial Endotoxin*

Mechanisms of Endotoxin Tolerance

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