Microbial Adjuvants and Immune Responsiveness

  • Arthur G. Johnson


My concern with immunomodulation began in 1952 as a member of a research team headed by Dr. Maurice Landy at Walter Reed Army Medical Center. Our objective was to purify the two known immunogenic components of typhoid vaccine, the Vi and 0 antigens, such that effective immunogenicity might be retained with elimination of the well known toxicity of the whole organism vaccine in use at that time. The Vi antigen turned out to be an aminogalactouronic acid which was highly effective in mouse protection tests, and presented no problem with regard to toxicity. In purifying the 0 antigen, we started with the Voivin product and with the expertise of our two biochemists, Drs. Marion Webster and Jerry Sagin, and through ammonium sulfate precipitations in the presence of high concentrations of sodium chloride we ended up with a product with only 0.6% nitrogen of which 0.4% was attributable to hexosamine (49). Such lipopolysaccharides (LPS) proved to be very active as antigens, but were much less protective than the Vi. They also exhibited potent endotoxic activity with extraordinary, diverse properties (30, 31).


Antibody Formation Pertussis Vaccine Bacterial Endotoxin Adjuvant Action Thymus Weight 
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  1. 1.
    Adye, J. C., and Springer, G. F., 1977, Binding of endotoxin ( LPS) by glycerophosphatides from human platelets and leukocytes. Naturwissenschaften 64: 150.PubMedCrossRefGoogle Scholar
  2. 2.
    Allison, A. C., and Davies, A. T. S., 1972, Requirements of thymus dependent lymphocytes for potentiation by adjuvants of anytibody formation. Nature 233: 330.CrossRefGoogle Scholar
  3. 3.
    Armerding, D., and Katz, D. H., 1974, Activation of T and B lymphocyte in vitro. I. Regulatory influence of bacterial lipopolysaccharide (LPS) on specific T cell helper function. J. Exp. Med. 139: 24.PubMedCrossRefGoogle Scholar
  4. 4.
    Behling, U. H., and Nowotny, A., 1977, Immune adjuvancy of lipopolysaccharide and a nontoxic hydrolytic product demonstrating oscillating effects with time. J. Immunol. 118: 1905.PubMedGoogle Scholar
  5. 5.
    Bick, P. H., and Johnson, A. G., 1977, Poly A:U-induced secretion of T lymphocyte helper factors. Scand. J. Immuno1. 6: 1133.CrossRefGoogle Scholar
  6. 6.
    Braude, A. I., Carey, F. J., Sutherland, D., and Zalesky, M., 1955, Studies with radioactive endotoxin. II. Correlation of physiologic effects with distribution of radioactivity in rabbits injected with lethal doses of E. coli endotoxin labelled with radioactive sodium chromate. J. Clin. Invest. 34: 858.PubMedCrossRefGoogle Scholar
  7. 7.
    Braun, W., Ishizuka, M., Yajima, Y., Webb, D., and Winchurch, R., 1971, Spectrum and mode of action of poly A:U in the stimulation of immune responses, in: “Biological Effects of Polynucleotides”, R. F. Beers and W. Braun, ed., Springer-Verlag, NY, pp. 139.Google Scholar
  8. 8.
    Braun, W., and Nakano, M., 1967, Antibody formation: stimulation by polyadenylic and polycytidylic acids. Science 157: 819.PubMedCrossRefGoogle Scholar
  9. 9.
    Chedid, L., Audibert, F., Bona, C., Damais, C., Parant, F., and Parant, M., 1975, Biological activities of endotoxins detoxified by alkylation. Infect. Immun. 12: 712.Google Scholar
  10. 10.
    Chen, C. H., Johnson, A. G., Kasai, N., Key, B. A., Levin, J., and Nowotny, A., 1973, Heterogeneity and biological activity of endotoxin glycolipid from Salmonella minnesota R595, J. Inf. Dis. 1285: 35.Google Scholar
  11. 11.
    Chiller, J. M., Skidmore, B. J., Morrison, D. C., and Weigle, W. O., 1973, Relationship of the structure of bacterial lipo-polysaccharide to its function in mitogenesis and adjuvanticity. Proc. Natl. Acad. Sci. 70: 2129.PubMedCrossRefGoogle Scholar
  12. 12.
    Chun, M., Pasanen, V., Hammerling, U., Hammerling, G. F., and Hoffman, M. K., 1979, Tumor necrosis serum induces a sero-logically distinct population of NK cells. J. Exp. Med. 150: 426.PubMedCrossRefGoogle Scholar
  13. 13.
    Cone, R. E., and Johnson, A. G., 1971, Regulation of the immune system by snythetic polynucleotides. III. Action on antigen reactive cells of thymus origin. J. Exp. Med. 133: 649.CrossRefGoogle Scholar
  14. 14.
    Coutinlu, A., Forni, L., and Watanabe, T., 1978, Genetic and functional characterization of an antiserum to the lipid A specific triggering receptor on murine B lymphocytes. Eur. J. Immunol. 8: 63.CrossRefGoogle Scholar
  15. 15.
    Coutinlu, A., Meo, A., and Watanabe, T., 1977, Independent segregation of two functional markers expressed on the same B cell subset in the mouse: the Mis determinants and the LPS receptors. Scand. J. Immuno1. 6: 1005.CrossRefGoogle Scholar
  16. 16.
    Cremer, N., and Watson, D. W., 1957, Influence of stress on dis-tribution of endotoxin in RES determined by fluorescein antibody technic. Proc. Soc. Exp. Biol. Med. 95: 510.PubMedGoogle Scholar
  17. 17.
    Field, A. K., Tytell, A. A., Lampson, G. P., and Hilleman, M. R., 1967, Inducers of interferon and host resistance. II. Multi- stranded synthetic polynucleotide complexes. Proc. Natl. Acad. Sci. 58: 1004.PubMedCrossRefGoogle Scholar
  18. 18.
    Fleming, D. S., Greenberg, L., and Beith, E. M., 1948, The use of combined antigens in the immunization of infants. Canad. Med. Assoc. J. 59: 101.Google Scholar
  19. 19.
    Haas, G. P., Johnson, A. G., and Nowotny, A., 1978, Suppression of the immune response in C3H/HeJ mice by protein free lipopoly-saccharides. J. Exp. Med. 148: 1081.Google Scholar
  20. 20.
    Han, I. H., and Johnson, A. G., 1975, The mitogenic activity of polyadenylicpolyuridylic acid complexes. Ann. N.Y. Acad. Sci. 249: 370.PubMedCrossRefGoogle Scholar
  21. 21.
    Johnson, A. G., 1976, The adjuvant action of synthetic poly-nucleotides on the immune response, in: “Immune RNA”, E. P. Cohen, ed., Cleveland: CRC Press, Inc., Cleveland, OH, pp. 17.Google Scholar
  22. 22.
    Johnson, A. G., 1979, Modulation of the immune system by synthetic polynucleotides, in: “Seminars in Immunopathology”. P. Miescher, ed., New York: Springer-Verlag.Google Scholar
  23. 23.
    Johnson, A. G., Cone, R. E., Friedman, H. M., Han, I. H., Johnson, H. G., Schmidtke, J. R., and Stout, R. D., 1971, Stimulation of the immune system by homopolyribonucleotides, in: “Biological Effects of Polynucleotides”, R. F. Beers and W. Braun, ed. New York: Springer-Verlag, pp. 157.Google Scholar
  24. 24.
    Johnson, A. G., Gaines, S., and Landy, M., 1956, Studies on the 0 antigen of Salmonella typhosa. V. Enhancement of antibody response to protein antigens by the purified lipopolysaccharide, J. Exp. Med. 103: 225.PubMedCrossRefGoogle Scholar
  25. 25.
    Johnson, A. G., and Hoekstra, G., 1967, Acceleration of the primary antibody response, in: “Ontogeny of Immunity”, R. T. Smith, R. A. Good, P. A. Miescher, ed. Gainesville: University of Florida Press, pp. 187.Google Scholar
  26. 26.
    Johnson, A. G., and Nowotny, A., 1964, Relationship of structure to function in bacterial 0 antigens. III. Biological properties of endotoxoids. J. Bact. 87: 809.PubMedGoogle Scholar
  27. 27.
    Johnson, H. M., and Baron, S., 1976, The nature of the suppressive effect of interferon and interferon inducers on the in vitro immune response, Cell. Immunol. 25: 106.Google Scholar
  28. 28.
    Kagnoff, M. F., Billings, P., and Cohn, M., 1974, Functional characteristics of Peyers patch lymphoid cells. II. Lipopolysaccharide is thymus dependent. J. Exp. Med. 139: 407.PubMedCrossRefGoogle Scholar
  29. 29.
    Kind, P. D., and Johnson, A. G., 1949, Studies on the adjuvant action of bacterial endotoxins. I. Time limitation of enhancing effect and restoration of antibody formation in X-irradiated rabbits, J. Immunol 82: 415.Google Scholar
  30. 30.
    Landy, M., and Johnson, A. G., 1955, Studies on the 0 antigen of Salmonella typhosa. IV. Endotoxic properties of the purified antigen, Proc. Soc. Exp. Biol. Med. 90: 57.Google Scholar
  31. 31.
    Landy, M., Johnson, A. G., Webster, M. E., and Sagin, J. F., 1955, Studies on the 0 antigen of Salmonella typhosa. II. Immunological properties of the purified antigen, J. Immunol. 74: 466.PubMedGoogle Scholar
  32. 32.
    McGee, J. R., Farrar, J. J., Michalek, S. M., Mergenhagen S.E., and Rosenstreich, D. L., 1979, Cellular requirements for lipopolysaccharide adjuvanticity. A role for both T lymphocytes and macrophages for in vivo responses to particulate mitogens. J. Exp. Med. 148: 793.CrossRefGoogle Scholar
  33. 33.
    McMaster, P. D., and Franzl, R. E., 1968, The primary immune responses of lymphoid tissues accompanying the enhancement or complete suppression of antibody formation by a bacterial endotoxin. J. Exp. Med. 127: 1109.PubMedCrossRefGoogle Scholar
  34. 34.
    Mergenhagen, S., Berry, L. J., and Rosenstreich, D., 1979, ASM Conference on endogenous mediators in host responses to bacterial endotoxins.Google Scholar
  35. 35.
    Merritt, K., and Johnson, A. G., 1965, Studies on the adjuvant action of bacterial endotoxins. IV. Enhancement of antibody formation by nucleic acids. J. Immunol. 94: 416.PubMedGoogle Scholar
  36. 36.
    Mizel, S. B., 1979, Physiochemical characterization of lymphocyte activating factor (LAF). J. Immunol. 122: 2167.PubMedGoogle Scholar
  37. 37.
    Moatamed, F., Karnowsky, M. J., and Unanue, E. R., 1975, Early cellular responses to mitogens and adjuvants in the mouse spleen. Lab. Invest. 32: 303.PubMedGoogle Scholar
  38. 38.
    Moller, G., ed. 1972, Lymphocyte activation by mitogens. Transpl. Rev. 11.Google Scholar
  39. 39.
    Morris, C. K., and Johnson, A. G., 1978, Regulation of the immune system by synthetic polynucleotides. VII. Suppression induced by pre-treatment with poly A: U. Cell. Immunol. 39: 345.PubMedCrossRefGoogle Scholar
  40. 40.
    Reitschel, E. H., 1976, Absolute configuration of 3-hydroxy fatty acids present in lipopolysaccharides from various bacterial groups. Eur. J. Biochem. 64: 423.CrossRefGoogle Scholar
  41. 41.
    Rowlands, D. T., Claman, H. T., and Kind, P. D., 1965, The effect of endotoxin on the thymus of young mice. Am. J. Path. 46: 165.PubMedGoogle Scholar
  42. 42.
    Rubenstein, H. S., Fine, J., and Coons, A. H., 1962. Localization of endotoxin in the walls of the peripheral vascular system during lethal endotoxemia. Proc. Soc. Exp. Biol. Med. 111: 458.PubMedGoogle Scholar
  43. 43.
    Schenck, J. R., Hargie, M. P., Brown, M. S., Ebert, D. S., Yoo, A. L., and Mclntire, F. C., 1969, The enhancement of antibody formation by Escherichia coli lipopolysaccharide and detoxified derivative. J. Immunol. 102: 1411.PubMedGoogle Scholar
  44. 44.
    Togawa, A., Oppenheim, J. J., and Mizel, J. B., 1979, Characterization of lymphocyte activating factor ( LAF) produced by human mononuclear cells: Biochemical relationship of high and low molecular weight forms of LAF. J. Immunol. 122: 2112.Google Scholar
  45. 45.
    Uccini, S., Ruco, L., Saravito, G., Aderini, L., Doria, G., and Barani, C. D., 1976, Cell selection in the thymus of mice treated with Escherichia coli lipopolysaccharide (LPS). Adv. Exp. Med. Biol. 66: 95.Google Scholar
  46. 46.
    Ward, P. A., Abell, M. R., and Johnson, A. G., 1961, Studies on the adjuvant action of bacterial endotoxins on antibody formation. IV. Histologic study of cortisone treated rabbits. Am. J. Path. 38: 189.PubMedGoogle Scholar
  47. 47.
    Ward, P. A., Johnson, A. G., and Abell, M. R., 1959, Studies on the adjuvant action of bacterial endotoxins on antibody formation. III. Histologic response of the rabbit spleen to a single injection of a purified protein antigen. J. Exp. Med. 109: 463.PubMedCrossRefGoogle Scholar
  48. 48.
    Watson, J., 1979, in ASM Conference on Endotoxin Mediators, (in press).Google Scholar
  49. 49.
    Webster, M. E., Sagin, J. F., Landy, M., and Johnson, A. G., 1955, Studies on the 0 antigen of Salmonella typhosa. I. Purification of the antigen. J. Immunol. 74: 455.Google Scholar

Copyright information

© Plenum Press, New York 1981

Authors and Affiliations

  • Arthur G. Johnson
    • 1
  1. 1.Department of Medical Microbiology/Immunology School of MedicineUniversity of MinnesotaDuluthUSA

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