Biomedical subjects
Publications and source records attributed to D Migliore-Samour.
Some tripeptides obtained by enzymic digestion of caseins possess immunomodulating properties. In order to correlate activity and structure, X-ray analysis has been applied to two of them Leu-Leu-Tyr and Gly-Leu-Phe.
Citrullinogenesis is demonstrated when murine bone marrow cells are incubated with dialyzed secondary mixed leukocyte culture supernatant. The identity of citrulline in bone marrow cell supernatants has been established by gas chromatographic mass spectrometric analysis. It is shown that, in our model, citrulline synthesis proceeds directly from arginine without intermediate ornithine production, ruling out the involvement of ornithine transcarbamylase (EC 2.1.3.3.). Moreover, none of the other enzymatic activities described for catalyzing citrullinogenesis, i.e. arginine deiminase or peptidyl arginine deiminase can be demonstrated. The generation of oxygen radicals is necessary for this enzymatic reaction. It is induced by a thermolabile protein produced during the antiallograft immune response with a molecular weight of about 150,000.
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A hexapeptide obtained from human casein by enzymatic digestion has been purified, sequenced and synthesized; its structure is: Val-Glu-Pro-Ile-Pro-Tyr. In vitro this hexapeptide stimulates the phagocytosis of opsonized sheep red blood cells by murine peritoneal macrophages. Administered intravenously to adult mice, it enhances the resistance to infection with Klebsiella pneumoniae.
The peptides LAla-DGlu (L-alanyl-D-glutamic acid), LAla-DGlu[LLA2pm(Gly)]NH2, i.e. N2-(L-alanyl-D-gamma-isoglutaminyl)-N6-glycyl-LL-2,6-diaminopimelic acid, and LAla-DGlu[LLA2pm(Gly)-D-Ala], i.e. N2-(L-alanyl-D-gamma-glutamyl)-N6-glycyl-LL-alpha-2,6-diaminopimelyl-D-alanine, extracted from a Streptomyces strain and their immunostimulating synthetic lauroyl derivatives were studied by 1H NMR spectroscopy at 270 MHz. The chemical shift analysis confirms (a) the sequence of these compounds, (b) the occurrence of a gamma bond between Glu (or GluNH2) and A2pm, (c) the presence of a carboxamide group on the backbone of the tetrapeptide LAla-DGlu[LLA2pm(Gly)]. Temperature and pH studies strongly suggest that the tetrapeptide and pentapeptide exist under several folded conformations characterized by a proximity between the NH3 group of Gly and the Glu (or GluNH2) residue. THe similarity between the chemical shifts of the corresponding protons in LAla-DGlu, lauroly-LAla-DGlu and muramyl-L:Ala-DGluNH2 shows that the coupling of the dipeptide with a lauroyl or a muramyl group does not induce significant changes in the structure of the peptide moiety. In the lipopeptide series the presence of the lauroyl chain leads to amphipathic substances which form, micelles in aqueous solution as shown by the large increase of the proton linewidths. The immunostimulating properties of this kind of peptide manifest themselves at very low concentration and only after their coupling with a sugar or lipid moiety. These features can be interpreted by the formation of mixed complexes between the immunoadjuvants and cell membrane constituents.
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From crude extracts of a Streptomyces strain exhibiting immunopotentiating effects, a tetrapeptide was isolated and its structure established as L Ala leads to D isoGlu leads to L, L Dap comes from Gly. This peptide was devoid of biological activity but its chemical coupling with lauric acid gave a substance endowed with adjuvant and immunostimulating properties. This substance and the corresponding synthetic lauroyltetrapeptide were as active in this respect as the muramyl-dipeptide, thus far considered as the minimal adjuvant-active structure of bacterial cell walls: the presence of a sugar moiety is therefore not a prerequisite for immunopotentiating activities.
Relatively low molecular weight peptidoglycan fragments extracted from two strains of Mycobacterium tuberculosis var. hominis were chemically coupled with lauric acid. The fatty acid conjugates were compared with the native substances with respect to some immunopotentiating activities. In vitro, the mitogenic effect on murine spleen lymphocytes was significantly enhanced following conjugation. One of the lauric acid conjugates stimulated, upon intravenous administration in mice, the formation of antibody-producing cells in the spleen, while the native substance was devoid of such activity. In adjuvanticity tests performed in the guinea pig in the absence of mineral oil, the fatty acid conjugates generally exerted a higher adjuvant effect on antibody production or on delayed type hypersensitivity reactions than did the native preparations.
Water-soluble peptidoglycan fragments extracted from the cells of two strains of Mycobacterium tuberculosis var. hominis were chemically conjugated with lauric or with palmitic acid. The coupling reaction was confirmed by physicochemical procedures. The native and the fatty acid-conjugated substances were studied for their adjuvant activity in the induction of delayed type hypersensitivity (DTH) reactions in guinea-pigs and on the production of circulating antibodies in the rabbit. Palmitic acid conjugation of one of the substances increased its adjuvanticity on DTH in the presence of mineral oil; lauric or palmitic acid conjugation rendered the substances adjuvant-active on DTH in the absence of mineral oil. Lauric acid, but not palmitic acid conjugation conferred on both substances an adjuvant activity on antibody production in the absence of mineral oil. Furthermore, lauric acid conjugation of one of the substances led to the appearance of an in vitro mitogen-like activity for murine spleen lymphocytes. In conclusion, fatty acid conjugation exerted a significant modifying effect on the immuno-potentiating activities of these peptidoglycan fragments, and such a chemical procedure may lead to the development of substances exerting a full adjuvant activity without the need of injecting them in an oily vehicle.
Experimental allergic encephalomyelitis has been induced in guinea pigs employing bovine myelin basic protein as the antigen and a hydrosoluble tetrasaccharide-heptapeptide from delipidated cells of the human mycobacterial strain H37Ra as adjuvant. The maximum response was observed using 33 mug of antigen and 12.5 mug of adjuvant per animal.
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Experimental allergic encephalomyelitis has been induced in guinea pigs using the encephalitogenic tryptophan peptide as antigen and a hydrosoluble adjuvant extracted from Mycobacterium tuberculosis, var. hominis, strain H37Ra. The maximum response was observed using 100mug of adjuvant per animal. This is a quantity of adjuvant substantially higher than was necessary to induce disease utilizing the whole myelin basic protein as antigen.
The tetrasaccharide-heptapeptide (TH), when injected with mineral oil, exerted a strong adjuvant effect. It stimulated B and T cells, but did not increase the phagocytic activity of the reticulo-endothelial system. While BCG exerted significant preventive effect on the growth of sarcoma 180, leucosarcomatosis an EHRLICH ascitic tumor, TH, at the doses used, was devoid of such activity.
Water-soluble substances have been extracted from two strains of Mycobacterium tuberculosis var. hominis: the native hydrosoluble part (polysaccharide and peptidoglycan), a substance in which the polysaccharide moiety is less abundant than in the latter, the acetylated peptidoglycan and, finally a tetrasaccharide-heptapeptide. All four types of substances, when they were injected together with Freund's incomplete adjuvant, exerted an adjuvant effect on the production of delayed-type hypersensitivity to ovalbumin in the guinea pig and on the production of anti-influenza virus antibodies in the rabbit. Injected intravenously in the mouse, they increased the number of antibody-producing cells in the spleen and enhanced the graft versus host reaction; no effect was seen on the phagocytic activity of the reticulo-endothelial system. By contrast with wax D, the water-soluble substances were devoid of arthritis-inducing activity in the rat. Altogether, these water-soluble substances seem to be endowed with at least some of the adjuvant activities of Freund's complete adjuvant and some of the immunostimulant activities of a live Mycobacterium like BCG.
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Explore the source record for details and available documents.