Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific... – Bacterium or component thereof or substance produced by said...
Patent
1992-04-03
1994-08-09
Wityshyn, Michael G.
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
Bacterium or component thereof or substance produced by said...
514 9, 514 21, 514 23, 514 61, 514 8, 530322, 530344, 530345, 435863, A61K 3710, A61K 3702
Patent
active
053366662
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to a novel immunostimulant drug having as active ingredients polar glycopeptidolipids (pGPL) of Mycobacterium chelonae.
BACKGROUND OF THE INVENTION
The invention relates to a novel immunostimulant drug having as active ingredients polar glycopeptidolipids (pGPL) of Mycobacterium chelonae.
It is known that pGPL, present in the cell wall of atypical Mycobacteria, have high species-specificity.
Glycopeptidolipids (GPL) are compounds which combine fatty acids, peptides, and sugars.
Extensive studies of GPL have been carried out with the aim of classifying and identifying Mycobacteria.
Investigators have shown a decrease in the proliferative response induced by nonspecific mitogens, in splenocytes of mice treated with Mycobacterium avium pGPL (see Brownback and Barrow, Infection and Immunity, 56, 1044-1050 (1988)). The same investigators showed a decrease in the proliferative response of these cells when the cells are co-stimulated in vitro with the aforesaid pGPL and mitogens.
Immunostimulant properties of living M. chelonae on the immunocompetent cells have been demonstrated (see Biozzi et al., Rev. Franc. Etudes Clin. Biol., 5, 867-890 (1960); Pilet and Goret, J. Reticuloendoth Soc., 3, 305-309 (1966); al., Comp. Immunol. Infect. Dis., 12, 63-70 (1989)).
SUMMARY OF THE INVENTION
It has been discovered, in connection with the present invention, that PGPL of M. chelonae has immunostimulant properties, in contrast to M. avium, the latter which does not have such properties.
It is known that GPL of most atypical Mycobacteria have in common the following structure: fatty acid, the alaninol group is connected to a sugar, and the allo-threonine group (aThr) is either connected to a sugar (in the case of a non-polar GPL) or to an oligosaccharide (in the case of a PGPL). This glycopeptidolipid structure is the same, in particular, in all Mycobacteria in the MAIS complex (Mycobacterium avium intracellulare scrofulaceum) and in the two subspecies of Mycobacterium chelonae (see Brennan and Goren, J. Biol. Chem., 254, 4205-4211 (1979); Brennan, Rev. Infect. Dis., 3, 905-913 (1981); Brennan, The Mycobacteria: A Source Book, Part A, Kubica and Wayne Eds., Marcel Dekker, New York and Basel, 467-489 ( 1984 ); Tsang et al., Int. J. Syst. Bacteriol., 34, 35-44; and Asselineau and Asselineau, The Mycobacteria: A Source Book, Kubica and Wayne Eds., Marcel Dekker, New York and Basel, pp. 345-360, ( 1984 ).
The PGPL of M. chelonae were described by Tsang et al., loc. cit. Because the species variations of pGPL in atypical Mycobacteria relate to the osidic part, the same authors studied the osidic part in M. chelonae, and they proposed the following structure for the oligosaccharide: 3,4-di-O-methylrhamnose-(1-.fwdarw.?)-rhamnose-(.alpha.-1.fwdarw.2)-6-deox ytalose.
pGPL have been used in the identification and differentiation of M. chelonae in the complex M. fortuitum-M. chelonae, by thin layer chromatography (Tsang et al., loc. cit. ), and by the ELISA method (Yanagihara et al., 1985 J. Clin. Microbiol., 21, 569-574).
Basically, the pGPL of M. chelonae correspond to formula 1: ##STR1## wherein Phe represents phenylalanine, link to the aThr and the alaninol, respectively, and wherein the C-terminal COOH group of the alanine is connected to the alaninol by an amide linkage.
The most accurate structure for the oligosaccharide is that given by Tsang et al., as indicated above, but in it the position of the link between the rhamnose and the dimethylrhamnose is not known.
In natural pGPL, the sugars of the oligosaccharide part are acetylated.
In the pGPL of M. chelonae, as in the GPL of other Mycobacteria, the nature of the fatty acids depends on the culture medium, the temperature, and the duration of the culture (see, e.g., Ratledge, 1982, "Lipids: Cell Composition, Fatty Acid Biosyntheses" in "The Biology of the Mycobacteria" Vol 1 Ratledge and Stanford Eds., Academic Press, London ( 1982 ), pages 53-93; and the references cited supra).
The natural pGPL are in fact mixtures of comp
REFERENCES:
Tsang et al., Int. J. Syst. Bacteriol., vol. 34, No. 1, pp. 35-44, Jan. 1984.
Brennan et al., J. Biol. Chem., vol. 254, No. 10, pp. 4205-4211, May 25, 1979.
T. Neway et al.: "Immunomodulatory properties of a strain of mycobacterium chelonae I. Mouse lymphocyte responses in vitro", Biological Abstracts, vol. 89, No. 1, Ref. No. 4236, Jan. 1990 (Phila., Pa.).
A. Y. Tsang et al.: "Antigenic relationships of the mycobacterium fortuitum-mycobacterium chelonae complex", Chemical Abstracts, vol. 100, No. 17, Apr. 23, 1984 (Columbus Ohio).
P. E. Brownback et al.: "Modified lymphocyte response to mitogens after intraperitoneal injection of glycopeptidolipid antigens from mycobacterium avium complex", Injection & Immunity, vol. 56, No. 5, May 1988, (Washington, D.C.).
Neway Tsehay
Pilet Charles
Mohamed Abdel A.
Wityshyn Michael G.
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