Skip to main content
Infection and Immunity logoLink to Infection and Immunity
. 1987 Jun;55(6):1426–1430. doi: 10.1128/iai.55.6.1426-1430.1987

Anti-infectious activity of liposomal muramyl dipeptides in immunodeficient CBA/N mice.

N C Phillips, L Chedid
PMCID: PMC260531  PMID: 3553001

Abstract

Two muramyl dipeptides, N-acetylmuramyl-L-alanyl-D-isoglutamine and its adjuvant-inactive isomer N-acetylmuramyl-D-alanyl-D-isoglutamine, were examined for their ability to protect mice carrying the CBA/N immune deficiency gene (xid) against lethal bacterial challenge. Prophylactic treatment with N-acetylmuramyl-L-alanyl-d-isoglutamine gave significant protection against Streptococcus pneumoniae, Salmonella typhimurium, and Salmonella enteritidis infection. N-Acetylmuramyl-D-alanyl-D-isoglutamine was unable to confer protection. Incorporation of the lipophilic glycerol dipalmitate derivatives of the two muramyl dipeptides within liposomal carriers resulted in a significant enhancement of anti-infectious activity, both with respect to number of survivors and length of survival. Liposomal muramyl dipeptides were 10- to 15-fold more potent than free muramyl dipeptide; enhanced potency was most evident with N-acetylmuramyl-D-alanyl-D-isoglutamine. Prophylactic treatment with liposomes containing the lipophilic muramyl dipeptides resulted in enhanced clearance of bacteria from the blood (greater than 3-fold increase in rate) when compared with that of hydrosoluble N-acetylmuramyl-L-alanyl-D-isoglutamine, indicating a correlation between reticuloendothelial stimulation and anti-infectious activity.

Full text

PDF
1426

Selected References

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

  1. Ambler L., Hudson A. M. Pharmacokinetics and metabolism of muramyl dipeptide and nor-muramyl dipeptide [3H-labelled] in the mouse. Int J Immunopharmacol. 1984;6(2):133–139. doi: 10.1016/0192-0561(84)90008-0. [DOI] [PubMed] [Google Scholar]
  2. Brown G. L., Foshee H., Pietsch J., Polk H. C., Jr Muramyl dipeptide enhances survival from experimental peritonitis. Arch Surg. 1986 Jan;121(1):47–49. doi: 10.1001/archsurg.1986.01400010053006. [DOI] [PubMed] [Google Scholar]
  3. Chedid L., Audibert F., Lefrancier P., Choay J., Lederer E. Modulation of the immune response by a synthetic adjuvant and analogs. Proc Natl Acad Sci U S A. 1976 Jul;73(7):2472–2475. doi: 10.1073/pnas.73.7.2472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chedid L., Parant M., Parant F., Lefrancher P., Choay J., Lederer E. Enhancement of nonspecific immunity to Klebsiella pneumoniae infection by a synthetic immunoadjuvant (N-acetylmuramyl-L-alanyl-D-isoglutamine) and several analogs. Proc Natl Acad Sci U S A. 1977 May;74(5):2089–2093. doi: 10.1073/pnas.74.5.2089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ellouz F., Adam A., Ciorbaru R., Lederer E. Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem Biophys Res Commun. 1974 Aug 19;59(4):1317–1325. doi: 10.1016/0006-291x(74)90458-6. [DOI] [PubMed] [Google Scholar]
  6. Fraser-Smith E. B., Eppstein D. A., Larsen M. A., Matthews T. R. Protective effect of a muramyl dipeptide analog encapsulated in or mixed with liposomes against Candida albicans infection. Infect Immun. 1983 Jan;39(1):172–178. doi: 10.1128/iai.39.1.172-178.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fraser-Smith E. B., Matthews T. R. Protective effect of muramyl dipeptide analogs against infections of Pseudomonas aeruginosa or Candida albicans in mice. Infect Immun. 1981 Dec;34(3):676–683. doi: 10.1128/iai.34.3.676-683.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fraser-Smith E. B., Waters R. V., Matthews T. R. Correlation between in vivo anti-Pseudomonas and anti-Candida activities and clearance of carbon by the reticuloendothelial system for various muramyl dipeptide analogs, using normal and immunosuppressed mice. Infect Immun. 1982 Jan;35(1):105–110. doi: 10.1128/iai.35.1.105-110.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Humphres R. C., Henika P. R., Ferraresi R. W., Krahenbuhl J. L. Effects of treatment with muramyl dipeptide and certain of its analogs on resistance to Listeria monocytogenes in mice. Infect Immun. 1980 Nov;30(2):462–466. doi: 10.1128/iai.30.2.462-466.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hunter K. W., Jr, Finkelman F. D., Strickland G. T., Sayles P. C., Scher I. Defective resistance to Plasmodium yoelii in CBA/N mice. J Immunol. 1979 Jul;123(1):133–137. [PubMed] [Google Scholar]
  11. Iribe H., Koga T., Onoue K., Kotani S., Kusumoto S., Shiba T. Macrophage-stimulating effect of a synthetic muramyl dipeptide and its adjuvant-active and -inactive analogs for the production of T-cell activating monokines. Cell Immunol. 1981 Oct;64(1):73–83. doi: 10.1016/0008-8749(81)90459-7. [DOI] [PubMed] [Google Scholar]
  12. Krahenbuhl J. L., Sharma S. D., Ferraresi R. W., Remington J. S. Effects of muramyl dipeptide treatment on resistance to infection with Toxoplasma gondii in mice. Infect Immun. 1981 Feb;31(2):716–722. doi: 10.1128/iai.31.2.716-722.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lamont P. M., Schrodt G. R., Galland R. B., Kaufman C. M., Cheadle W. G., Polk H. C., Jr Enhancement of the local inflammatory response to bacterial infection by muramyl dipeptide. Br J Exp Pathol. 1984 Jun;65(3):319–325. [PMC free article] [PubMed] [Google Scholar]
  14. Morahan P. S., Dempsey W. L., Volkman A., Connor J. Antimicrobial activity of various immunomodulators: independence from normal levels of circulating monocytes and natural killer cells. Infect Immun. 1986 Jan;51(1):87–93. doi: 10.1128/iai.51.1.87-93.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Morozumi P. A., Brummer E., Stevens D. A. Immunostimulation with muramyl dipeptide and its desmethyl analogue: Studies of non-specific resistance to pulmonary blastomycosis in inbred mouse strains. Mycopathologia. 1983 Jan 17;81(1):35–39. doi: 10.1007/BF00443907. [DOI] [PubMed] [Google Scholar]
  16. Nayar R., Fidler I. J. The systemic activation of macrophages by liposomes containing immunomodulators. Springer Semin Immunopathol. 1985;8(4):413–428. doi: 10.1007/BF01857394. [DOI] [PubMed] [Google Scholar]
  17. O'Brien A. D., Scher I., Campbell G. H., MacDermott R. P., Formal S. B. Susceptibility of CBA/N mice to infection with Salmonella typhimurium: influence of the X-linked gene controlling B lymphocyte function. J Immunol. 1979 Aug;123(2):720–724. [PubMed] [Google Scholar]
  18. O'Brien A. D., Scher I., Metcalf E. S. Genetically conferred defect in anti-Salmonella antibody formation renders CBA/N mice innately susceptible to Salmonella typhimurium infection. J Immunol. 1981 Apr;126(4):1368–1372. [PubMed] [Google Scholar]
  19. Onozuka K., Saito-Taki T., Nakano M. Augmentation of protective and antibacterial activity induced by muramyl dipeptides in CBA/N defective mice with X-linked immunodeficiency for Salmonella enteritidis infection. Infect Immun. 1984 Aug;45(2):424–427. doi: 10.1128/iai.45.2.424-427.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Oppenheim J. J., Togawa A., Chedid L., Mizel S. Components of mycobacteria and muramyl dipeptide with adjuvant activity induce lymphocyte activating factor. Cell Immunol. 1980 Mar 1;50(1):71–81. doi: 10.1016/0008-8749(80)90007-6. [DOI] [PubMed] [Google Scholar]
  21. Parant M., Parant F., Chedid L., Yapo A., Petit J. F., Lederer E. Fate of the synthetic immunoadjuvant, muramyl dipeptide (14C-labelled) in the mouse. Int J Immunopharmacol. 1979;1(1):35–41. doi: 10.1016/0192-0561(79)90028-6. [DOI] [PubMed] [Google Scholar]
  22. Parant M., Riveau G., Parant F., Chedid L. Inhibition of endogenous pyrogen-induced fever by a muramyl dipeptide derivative. Am J Physiol. 1984 Sep;247(3 Pt 1):C169–C174. doi: 10.1152/ajpcell.1984.247.3.C169. [DOI] [PubMed] [Google Scholar]
  23. Phillips N. C., Bahr G. M., Modabber F. Z., Chedid L. Modulation of the growth of murine thymoma cell lines having different Lyt-phenotypes by MDP and MDP(D-D): macrophage-mediated inhibition of in vitro cell growth. Int J Immunopharmacol. 1984;6(6):577–585. doi: 10.1016/0192-0561(84)90068-7. [DOI] [PubMed] [Google Scholar]
  24. Phillips N. C., Moras M. L., Chedid L., Lefrancier P., Bernard J. M. Activation of alveolar macrophage tumoricidal activity and eradication of experimental metastases by freeze-dried liposomes containing a new lipophilic muramyl dipeptide derivative. Cancer Res. 1985 Jan;45(1):128–134. [PubMed] [Google Scholar]
  25. Phillips N. C., Thomas D. P., Knight C. G., Dingle J. T. Liposome-incorporated corticosteroids. II. Therapeutic activity in experimental arthritis. Ann Rheum Dis. 1979 Dec;38(6):553–557. doi: 10.1136/ard.38.6.553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Scher I. The CBA/N mouse strain: an experimental model illustrating the influence of the X-chromosome on immunity. Adv Immunol. 1982;33:1–71. doi: 10.1016/s0065-2776(08)60834-2. [DOI] [PubMed] [Google Scholar]
  27. Wahl S. M., Wahl L. M., McCarthy J. B., Chedid L., Mergenhagen S. E. Macrophage activation by mycobacterial water soluble compounds and synthetic muramyl dipeptide. J Immunol. 1979 Jun;122(6):2226–2231. [PubMed] [Google Scholar]
  28. Waters R. V., Ferraresi R. W. Muramyl dipeptide stimulation of particle clearance in several animal species. J Reticuloendothel Soc. 1980 Nov;28(5):457–471. [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES