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. 1987 Jan;60(1):141–146.

Synthetic sulpholipopolysaccharides: novel adjuvants for humoral immune responses.

L A Hilgers, H Snippe, M Jansze, J M Willers
PMCID: PMC1453343  PMID: 2880796

Abstract

Referring to the strong immunostimulating activity of combinations of lipophilic agents and dextran sulphate, conjugates with chemical determinants of both types of adjuvants were synthesized and then examined for immunostimulatory capabilities in mice. Saturated fatty acids with varying chain lengths and sulphate groups were coupled covalently at defined ratios to the polysaccharide Ficoll (MW 400,000). Chemical analysis of 60 of the sulpholipopolysaccharides synthesized revealed that the number of sulphate groups per monosaccharide unit varied from 0 to 1.6, and the number of lipid groups from 0 to 0.8. Adjuvanticity of these conjugates for the humoral immune response was determined using sheep red blood cells (SRBC) and dinitrophenyl-haptenated bovine serum albumin (DNP-BSA) as antigens. Five days after intraperitoneal injection of adjuvant and antigen, the numbers of direct anti-SRBC plaque-forming cells (PFC) in the spleen were determined. Anti-DNP antibody titres were measured from 1 to 4 weeks after immunization. PFC responses to 2 X 10(6) SRBC were augmented up to a 100-fold by conjugates of Ficoll and sulphate (sulphopolysaccharides: SPs) or lipid groups (lipopolysaccharides: LPs). Introduction of low or moderate numbers of lipid groups in SPs reduced adjuvanticity. Adjuvant activity of sulpholipopolysaccharides (SLPs) with varying sulphate and high lipid content depended on the sulphate contents and the chain length of the lipids. Sulphate reduced adjuvanticity of the SLPs, and the number of sulphate groups required for complete annihilation increased with the chain length of the lipid. LPs and SLPs, including conjugates that did not enhance anti-SRBC PFC responses, augmented serum antibody responses to DNP-BSA while SPs were hardly effective.

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Selected References

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  1. Arnold B., Miller J. F., Weltzien H. U. Lysolecithin analogs as adjuvants in delayed-type hypersensitivity in mice. I. Characterization of the adjuvant effect. Eur J Immunol. 1979 May;9(5):363–366. doi: 10.1002/eji.1830090505. [DOI] [PubMed] [Google Scholar]
  2. Arnold B., Staber F. G., Miller J. F. Lysolecithin analogs as adjuvants in delayed-type hypersensitivity in mice. II. Studies on the mode of action. Eur J Immunol. 1979 May;9(5):367–370. doi: 10.1002/eji.1830090506. [DOI] [PubMed] [Google Scholar]
  3. Arnon R. Chemically defined antiviral vaccines. Annu Rev Microbiol. 1980;34:593–618. doi: 10.1146/annurev.mi.34.100180.003113. [DOI] [PubMed] [Google Scholar]
  4. Arnon R., Shapira M., Jacob C. O. Synthetic vaccines. J Immunol Methods. 1983 Jul 29;61(3):261–273. doi: 10.1016/0022-1759(83)90220-x. [DOI] [PubMed] [Google Scholar]
  5. Arora M. P., Crowle A. J. Adjuvanticity of Evans blue dye: preliminary characterization of its mechanisms and mode of application in mice. J Reticuloendothel Soc. 1978 Sep;24(3):271–286. [PubMed] [Google Scholar]
  6. Audibert F., Jolivet M., Chedid L., Arnon R., Sela M. Successful immunization with a totally synthetic diphtheria vaccine. Proc Natl Acad Sci U S A. 1982 Aug;79(16):5042–5046. doi: 10.1073/pnas.79.16.5042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Behling U. H., Campbell B., Chang C. M., Rumpf C., Nowotny A. Synthetic glycolipid adjuvants. J Immunol. 1976 Sep;117(3):847–851. [PubMed] [Google Scholar]
  8. Bomford R. Saponin and other haemolysins (vitamin A, aliphatic amines, polyene antibiotics) as adjuvants for SRBC in the mouse. Evidence for a role for cholesterol-binding in saponin adjuvanticity. Int Arch Allergy Appl Immunol. 1980;63(2):170–177. doi: 10.1159/000232623. [DOI] [PubMed] [Google Scholar]
  9. Bonaventure J., Nigam V. N., Brailovsky C. A. In vitro spleen cell proliferation following in vivo treatment with a synthetic glycolipid or lipid A in three mouse strains. Int J Immunopharmacol. 1984;6(4):259–267. doi: 10.1016/0192-0561(84)90041-9. [DOI] [PubMed] [Google Scholar]
  10. Bradfield J. W., Souhami R. L., Addison I. E. The mechanism of the adjuvant effect of dextran sulphate. Immunology. 1974 Feb;26(2):383–392. [PMC free article] [PubMed] [Google Scholar]
  11. Chiller J. M., Skidmore B. J., Morrison D. C., Weigle W. O. Relationship of the structure of bacterial lipopolysaccharides to its function in mitogenesis and adjuvanticity. Proc Natl Acad Sci U S A. 1973 Jul;70(7):2129–2133. doi: 10.1073/pnas.70.7.2129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. DODGSON K. S., PRICE R. G. A note on the determination of the ester sulphate content of sulphated polysaccharides. Biochem J. 1962 Jul;84:106–110. doi: 10.1042/bj0840106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Diamantstein T., Wagner B., Beyse I., Odenwald M. V., Schulz G. Stimulation of humoral antibody formation by polyanions. II. The influence of sulfate esters of polymers on the immune response in mice. Eur J Immunol. 1971 Nov;1(5):340–343. doi: 10.1002/eji.1830010507. [DOI] [PubMed] [Google Scholar]
  14. Duncombe W. G. The colorimetric micro-determination of long-chain fatty acids. Biochem J. 1963 Jul;88(1):7–10. doi: 10.1042/bj0880007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gall D. The adjuvant activity of aliphatic nitrogenous bases. Immunology. 1966 Oct;11(4):369–386. [PMC free article] [PubMed] [Google Scholar]
  16. Gordon W. C., Prager M. D., Carroll M. C. The enhancement of humoral and cellular immune responses by dimethyldioctadecylammonium bromide. Cell Immunol. 1980 Feb;49(2):329–340. doi: 10.1016/0008-8749(80)90034-9. [DOI] [PubMed] [Google Scholar]
  17. Hilgers L. A., Snippe H., Jansze M., Willers J. M. Combinations of two synthetic adjuvants: synergistic effects of a surfactant and a polyanion on the humoral immune response. Cell Immunol. 1985 May;92(2):203–209. doi: 10.1016/0008-8749(85)90001-2. [DOI] [PubMed] [Google Scholar]
  18. Hilgers L. A., Snippe H., Jansze M., Willers J. M. Immunomodulating properties of two synthetic adjuvants: dependence upon type of antigen, dose, and time of administration. Cell Immunol. 1984 Jul;86(2):393–401. doi: 10.1016/0008-8749(84)90394-0. [DOI] [PubMed] [Google Scholar]
  19. Hilgers L. A., Snippe H., Jansze M., Willers J. M. Synergistic effects of synthetic adjuvants on the humoral immune response. Int Arch Allergy Appl Immunol. 1986;79(4):392–396. doi: 10.1159/000234008. [DOI] [PubMed] [Google Scholar]
  20. Hilleman M. R. Newer directions in vaccine development and utilization. J Infect Dis. 1985 Mar;151(3):407–419. doi: 10.1093/infdis/151.3.407. [DOI] [PubMed] [Google Scholar]
  21. Hunter R. L., Bennett B. The adjuvant activity of nonionic block polymer surfactants. II. Antibody formation and inflammation related to the structure of triblock and octablock copolymers. J Immunol. 1984 Dec;133(6):3167–3175. [PubMed] [Google Scholar]
  22. Hunter R., Strickland F., Kézdy F. The adjuvant activity of nonionic block polymer surfactants. I. The role of hydrophile-lipophile balance. J Immunol. 1981 Sep;127(3):1244–1250. [PubMed] [Google Scholar]
  23. Inman J. K., Merchant B., Claflin L., Tacey S. E. Coupling of large haptens to proteins and cell surfaces: preparation of stable, optimally sensitized erythrocytes for hapten-specific, hemolytic plaque assays. Immunochemistry. 1973 Mar;10(3):165–174. doi: 10.1016/0019-2791(73)90005-0. [DOI] [PubMed] [Google Scholar]
  24. Johnson H. G., Johnson A. G. Regulation of the immune system by synthetic polynucleotides. II. Action on peritoneal exudate cells. J Exp Med. 1971 Mar 1;133(3):649–664. doi: 10.1084/jem.133.3.649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jurin M., Tannock I. F. Influence of vitamin A on immunological response. Immunology. 1972 Sep;23(3):283–287. [PMC free article] [PubMed] [Google Scholar]
  26. Kraaijeveld C. A., Snippe H., Harmsen T., Benaissa-Trouw B. Enhancement of delayed-type hypersensitivity and induction of interferon by the lipophilic agents DDA and CP-20,961. Cell Immunol. 1982 Dec;74(2):277–283. doi: 10.1016/0008-8749(82)90028-4. [DOI] [PubMed] [Google Scholar]
  27. Mancino D., Minucci M. Adjuvant effects of iota, kappa, and lambda carrageenans on antibody production in BALB/c mice. Int Arch Allergy Appl Immunol. 1983;72(4):359–361. doi: 10.1159/000234896. [DOI] [PubMed] [Google Scholar]
  28. McCarthy R. E., Arnold L. W., Babcock G. F. Dextran sulphate: an adjuvant for cell-mediated immune responses. Immunology. 1977 Jun;32(6):963–974. [PMC free article] [PubMed] [Google Scholar]
  29. Merchant B., Inman J. K. Hapten-specific hemolytic plaque assays usually fail to detect most of the diversity in the anti-hapten response. J Exp Med. 1977 Feb 1;145(2):372–389. doi: 10.1084/jem.145.2.372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Morein B., Sundquist B., Höglund S., Dalsgaard K., Osterhaus A. Iscom, a novel structure for antigenic presentation of membrane proteins from enveloped viruses. 1984 Mar 29-Apr 4Nature. 308(5958):457–460. doi: 10.1038/308457a0. [DOI] [PubMed] [Google Scholar]
  31. Niblack J. F., Otterness I. G., Hemsworth G. R., Wolff J. S., 3rd, Hoffman W. W., Kraska A. R. CP-20,961: a structurally novel, synthetic adjuvant. J Reticuloendothel Soc. 1979 Dec;26(Suppl):655–666. [PubMed] [Google Scholar]
  32. Nigam V. N., Bonaventure J., Chopra C., Brailovsky C. A. Effects of structural variations in synthetic glycolipids upon mitogenicity for spleen lymphocytes, adjuvancy for humoral immune response and on anti-tumour potential. Br J Cancer. 1982 Nov;46(5):782–793. doi: 10.1038/bjc.1982.271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nigam V. N., Brailovsky C. A., Chopra C. Maltose tetrapalmitate, a nontoxic immunopotentiator with antitumor activity. Cancer Res. 1978 Oct;38(10):3315–3321. [PubMed] [Google Scholar]
  34. Parant M., Audibert F., Parant F., Chedid L., Soler E., Polonsky J., Lederer E. Nonspecific immunostimulant activities of synthetic trehalose-6,6'-diesters (lower homologs of cord factor). Infect Immun. 1978 Apr;20(1):12–19. doi: 10.1128/iai.20.1.12-19.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. RICKETTS C. R. Dextran sulphate--a synthetic analogue of heparin. Biochem J. 1952 Apr;51(1):129–133. doi: 10.1042/bj0510129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rosenstreich D. L., Asselineau J., Mergenhagen S. E., Nowotny A. A synthetic glycolipid with B-cell mitogenic activity. J Exp Med. 1974 Nov 1;140(5):1404–1409. doi: 10.1084/jem.140.5.1404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Shinnick T. M., Sutcliffe J. G., Green N., Lerner R. A. Synthetic peptide immunogens as vaccines. Annu Rev Microbiol. 1983;37:425–446. doi: 10.1146/annurev.mi.37.100183.002233. [DOI] [PubMed] [Google Scholar]
  38. Van Der Meer C., Hofhuis F. M., Willers J. M. Killed Listeria monocytogenes vaccine becomes protective on addition of polyanions. Nature. 1977 Oct 13;269(5629):594–595. doi: 10.1038/269594a0. [DOI] [PubMed] [Google Scholar]

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