Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1963 Sep 1;118(3):425–446. doi: 10.1084/jem.118.3.425

MODIFICATION OF HOST RESPONSES TO BACTERIAL ENDOTOXINS

I. SPECIFICITY OF PYROGENIC TOLERANCE AND THE ROLE OF HYPERSENSITIVITY IN PYROGENICITY, LETHALITY, AND SKIN REACTIVITY

Dennis W Watson 1, Yoon Berm Kim 1
PMCID: PMC2137653  PMID: 14078002

Abstract

Evidence is presented suggesting that the apparent non-specificity of pyrogenic tolerance observed with Gram-negative bacterial endotoxins is due to related antigenic determinants associated with the macromolecular toxins. This is based on results obtained in rabbits from pyrogenic cross-tolerance tests with selected endotoxins. In these tests, purified endotoxins from Escherichia coli (COO8) and Chromobacterium violaceum (CV) gave results one might expect with non-reciprocal cross-reacting antigens in classical immune systems. Additional evidence for an immune mechanism in tolerance is suggested by the highly significant anamnestic response observed. Lipid A, a toxic derivative of the purified COO8 endotoxin, failed to induce pyrogenic tolerance against the parent toxin. These results are explained by assuming that endotoxins have two interdependent activities associated with different portions of the macromolecule; one is assumed to be responsible for the primary toxicity, and the other is involved in secondary toxicity. The latter is dependent on the hypersensitive state of the host. Additional evidence for the role of hypersensitivity in secondary toxicity is based on the observation that adult rabbits are highly sensitive to the pyrogenic, lethal, and skin-reacting activities of endotoxin in contrast to young animals which are more resistant to all of these attributes of toxicity. In adults, the host responses to pyrogenicity, lethality, and skin reactivity could be partially inhibited by the early exposure of the animals to massive doses of endotoxin equivalent to a LD50. The pyrogenic tolerance shown in these animals was specific indicating that the inhibition of the hypersusceptibility to endotoxin involved an immunological mechanism. A mechanism of endotoxin tolerance is proposed and discussed based on the induction of specific antibodies capable of assisting the RES in the clearance and destruction of endotoxin. It is suggested that the present inconsistencies relative to the chemical nature and biological activities of endotoxins might be explained on the basis of these two activities and the failure to recognize the importance of the immunological state of the host in which the toxins are tested.

Full Text

The Full Text of this article is available as a PDF (1.0 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BRAUDE A. I., CAREY F. J., ZALESKY M. Studies with radioactive endotoxin. II. Correlation of physiologic effects with distribution of radioactivity in rabbits injected with radioactive sodium chromate. J Clin Invest. 1955 Jun;34(6):858–866. doi: 10.1172/JCI103141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beeson P. B., Technical Assistance of Elizabeth Roberts TOLERANCE TO BACTERIAL PYROGENS : II. ROLE OF THE RETICULO-ENDOTHELIAL SYSTEM. J Exp Med. 1947 Jun 30;86(1):39–44. doi: 10.1084/jem.86.1.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. CREMER N., WATSON D. W. Influence of stress on distribution of endotoxin in RES determined by fluorescein antibody technic. Proc Soc Exp Biol Med. 1957 Jul;95(3):510–513. doi: 10.3181/00379727-95-23271. [DOI] [PubMed] [Google Scholar]
  4. CRUMPTON M. J., DAVIES D. A. The isolation of D-fucosamine from the specific polysaccharide of Chromobacterium violaceum (NCTC 7917). Biochem J. 1958 Dec;70(4):729–736. doi: 10.1042/bj0700729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cooke R. A., Barnard J. H., Hebald S., Stull A. SEROLOGICAL EVIDENCE OF IMMUNITY WITH COEXISTING SENSITIZATION IN A TYPE OF HUMAN ALLERGY (HAY FEVER). J Exp Med. 1935 Nov 30;62(6):733–750. doi: 10.1084/jem.62.6.733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. DENNIS S. M. Spermicidal activity of bacterial endotoxin. Nature. 1962 Sep 22;195:1227–1228. doi: 10.1038/1951227b0. [DOI] [PubMed] [Google Scholar]
  7. FARR R. S., CLARK S. L., Jr, PROFFITT J. E., CAMPBELL D. H. Some humoral aspects of the development of tolerance to bacterial pyrogens in rabbits. Am J Physiol. 1954 May;177(2):269–278. doi: 10.1152/ajplegacy.1954.177.2.269. [DOI] [PubMed] [Google Scholar]
  8. FELTON L. D. The significance of antigen in animal tissues. J Immunol. 1949 Jan;61(1):107–117. [PubMed] [Google Scholar]
  9. FREEDMAN H. H. Further studies on passive transfer of tolerance to pyrogenicity of bacterial endotoxin. The febrile and leucopenic responses. J Exp Med. 1960 Oct 1;112:619–634. doi: 10.1084/jem.112.4.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. FREEDMAN H. H. Reticuloendothelial system and passive transfer of endotoxin tolerance. Ann N Y Acad Sci. 1960 Jun;88:99–106. [PubMed] [Google Scholar]
  11. GREISMAN S. E., CAROZZA F. A., Jr, HILLS J. D. Mechanisms of endotoxin tolerance. I. Relationship between tolerance and reticuloendothelial system phagocytic activity in the rabbit. J Exp Med. 1963 Apr 1;117:663–674. doi: 10.1084/jem.117.4.663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. HASKINS W. T., LANDY M., MILNER K. C., RIBI E. Biological properties of parent endotoxins and lipoid fractions, with a kinetic study of acid-hydrolyzed endotoxin. J Exp Med. 1961 Nov 1;114:665–684. doi: 10.1084/jem.114.5.665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. JENKIN C. R., ROWLEY D. The role of opsonins in the clearance of living and inert particles by cells of the reticuloendothelial system. J Exp Med. 1961 Sep 1;114:363–374. doi: 10.1084/jem.114.3.363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. LARSON C. L., RIBI E., MILNER K. C., LIEBERMAN J. E. A method for titrating endotoxic activity in the skin of rabbits. J Exp Med. 1960 Jan 1;111:1–20. doi: 10.1084/jem.111.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. MILER I. Changes in susceptibility to bacterial endotoxin and infection during the early postnatal period in rats. Folia Microbiol (Praha) 1962 Jul;7:223–233. doi: 10.1007/BF02930767. [DOI] [PubMed] [Google Scholar]
  16. MOSES J. M., ATKINS E. Studies on tuberculin fever. II. Observations on the role of endogenous pyrogen in tolerance. J Exp Med. 1961 Dec 1;114:939–959. doi: 10.1084/jem.114.6.939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. NETER E., WESTPHAL O., LUDERITZ O., GORZYNSKI E. A., EICHENBERGER E. Studies of enterobacterial lipopolysaccharides; effects of heat and chemicals on erythrocyte-modifying, antigenic, toxic and pyrogenic properties. J Immunol. 1956 May;76(5):377–385. [PubMed] [Google Scholar]
  18. NOLL H., BRAUDE A. I. Preparation and biological properties of a chemically modified Escherichia coli endotoxin of high immunogenic potency and low toxicity. J Clin Invest. 1961 Nov;40:1935–1951. doi: 10.1172/JCI104419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. NOWOTNY A. Relation of structure to function in bacterial O antigens. II. Fractionation of lipids present in Boivin-type endotoxin of Serratia marcescens. J Bacteriol. 1963 Feb;85:427–435. doi: 10.1128/jb.85.2.427-435.1963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. RIBI E., HASKINS W. T., LANDY M., MILNER K. C. Symposium on bacterial endotoxins. I. Relationship of chemical composition to biological activity. Bacteriol Rev. 1961 Dec;25:427–436. doi: 10.1128/br.25.4.427-436.1961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. ROSEN F. S. The endotoxins of gram-negative bacteria and host resistance. N Engl J Med. 1961 May 11;264:980–concl. doi: 10.1056/NEJM196105112641906. [DOI] [PubMed] [Google Scholar]
  22. SMITH R. T., THOMAS L. Influence of age upon response to meningococcal endotoxin in rabbits. Proc Soc Exp Biol Med. 1954 Aug-Sep;86(4):806–809. doi: 10.3181/00379727-86-21239. [DOI] [PubMed] [Google Scholar]
  23. SMITH R. T., THOMAS L. The lethal effect of endotoxins on the chick embryo. J Exp Med. 1956 Aug 1;104(2):217–231. doi: 10.1084/jem.104.2.217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. SPINK W. W. Endotoxin shock. Ann Intern Med. 1962 Oct;57:538–552. doi: 10.7326/0003-4819-57-4-538. [DOI] [PubMed] [Google Scholar]
  25. STETSON C. A., Jr Studies on the mechanism of the Shwartzman phenomenon; similarities between reactions to endotoxins and certain reactions of bacterial allergy. J Exp Med. 1955 Apr 1;101(4):421–436. doi: 10.1084/jem.101.4.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. STUART A. E., COOPER G. N. Susceptibility of mice to bacterial endotoxin after modification of reticulo-endothelial function by simple lipids. J Pathol Bacteriol. 1962 Jan;83:245–254. doi: 10.1002/path.1700830126. [DOI] [PubMed] [Google Scholar]
  27. UHR J. W. The effect of bacterial endotoxin on the newborn guinea pig. J Exp Med. 1962 Apr 1;115:685–694. doi: 10.1084/jem.115.4.685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. WESTPHAL O., LUEDERITZ O., STAUB A. M. Bacterial endotoxins. J Med Pharm Chem. 1961 Dec 8;4:497–504. doi: 10.1021/jm50019a008. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES