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Biomedical subjects

F Audibert

Publications and source records attributed to F Audibert.

At least 109 records · Page 6Linked to original sources
PubMed1983

Antibody responses elicited by a polyvalent vaccine containing synthetic diphtheric, streptococcal and hepatitis peptides coupled to the same carrier.

Three synthetic peptides copying fragments of the diphtheria toxin, the M protein of the streptococcus type 24 and the hepatitis B virus surface antigen (HBs) have been conjugated together to the tetanus toxoid. This polyvalent vaccine has been administered to mice. High antibody titers were obtained against the three antigens. No cross-reactivity could be observed between them as demonstrated by the ability of each peptide to inhibit only the antibodies against the natural M protein and the synthetic M protein peptide indicated that the avidity of the antibodies raised against a monovalent streptococcal vaccine were identical to those raised following injection of the polyvalent vaccine. Antibodies raised against the polyvalent streptococcal vaccine were also protective as shown by opsonophagocytic assays.

Animals↗
PubMed1983

Epitope specific immunity elicited by a synthetic streptococcal antigen without carrier or adjuvant.

A polypeptide fragment of type 24 streptococcal M protein (pep M24) has been shown to raise protective anti-streptococcal antibodies in rabbits and humans when administered with adjuvants. More recently, such protective antibodies were shown to be evoked by a synthesized 35-residue sub-peptide fragment (S-CB7 synthetic cyanogen bromide fragment 7) of pep M24. We now show that the weak pep M24 immunogen induces high titers of long lasting antibodies when associated with murabutide, a synthetic derivative of MDP (NAcMur-L-Ala-D-Gln-n-butyl-ester) which is currently undergoing clinical trials. We demonstrate also that the polymerized synthetic S-CB7 administered without adjuvant or carrier evokes a strong epitope specific, protective immune response in mice primed with the parent pep M24. A booster dose of polymerized S-CB7 induced antibodies directed specifically against the S-CB7 structure whereas a booster dose of pep M24 evoked antibodies recognizing additional determinants of the whole pep M24 molecule.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1982

[Enhancement of the activity of hepatitis B virus vaccine by association with murabutide].

Murabutide (N-acetyl-muramyl-L-alanyl-D-glutamine-alpha-butylester), an MDP analogue, is a potential adjuvant for Human immunization. High levels of specific antibodies were obtained in Mouse and Guinea-Pig following administration with murabutide of low dosages of anti-hepatitis B viral vaccine containing the surface antigen (HBs). The effect of murabutide was enhanced without increasing the level of specific IgE by association with suboptimal dosages of aluminium hydroxide.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1982

Analysis of the antigenic relationship of various derivatives of n-acetyl-muramyl-l-ala-d-isoglutamine (MDP), using anti-MDP antibodies.

Antibodies to N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP) were produced in rabbits by injection of MDP conjugated to various carriers [bovine gamma globulin (BGG), methylated BSA or sheep erythrocytes]. The anti-MDP was assayed by a direct enzyme-linked immunosorbent assay (ELISA) using horse radish peroxidase linked to MDP-Lys. Various derivatives of MDP were employed in an inhibition of ELISA for analysis of specificity of antibodies and study of the relationship of configuration to biological activity. The results confirmed previous findings that MDP alone is not immunogenic but can act as a hapten when conjugated to carriers. The antibodies were shown to be primarily directed against the muramyl residue. Modifications of this region of MDP yielded derivatives with weak reactivity against anti-MDP, while some changes of other regions had no effect on its antigenicity. Optical isomers of MDP had reduced activity as compared to MDP and polymeric MDP was a strong inhibitor. The structure and function relationship is discussed for some derivatives.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1982

Successful immunization with a totally synthetic diphtheria vaccine.

Three peptides corresponding to fragments of diphtheria toxin have been synthesized. They include the previously described tetradecapeptide and two structural analogs, the hexadecapeptide and the octadecapeptide. Conjugates of these peptides to proteins or a synthetic carrier have induced in guinea pig protection against the dermonecrotic activity of diphtheria toxin. All of the conjugates were immunogenic when administered either in complete Freund's adjuvant or with N-acetylmuramyl-L-alanyl-D-isoglutamine in aqueous medium. Positive immune response toward the octadecapeptide was obtained in mice as well. In this case, the immunogenic combinations were conjugates with bovine serum albumin administered either in Freund's adjuvant or with the muramyl dipeptide and a complete synthetic conjugate comprising both the octadecapeptide and the muramyl dipeptide covalently attached to a synthetic carrier, multichain poly(DLAla). This last immunogen, which induced the most effective immune response, is a completely synthetic immunogen with built-in adjuvanticity and induces protective antitoxic immunity when administered in a physiological medium.

Adjuvants, Immunologic↗
PubMed1982

Immunological castration of male mice by a totally synthetic vaccine administered in saline.

It had been reported that immunological neutralization of the hypothalamic luteinizing hormone-releasing hormone (LH-RH) can be achieved by injection of the synthetic hormone, a decapeptide, linked to a carrier and administered with Freund's complete adjuvant. Data presented here demonstrate that the resulting immunological castration can be obtained by administering in an aqueous medium the synthetic decapeptide directly conjugated to the synthetic immunomodulator glycopeptide N-acetylmuramyl-L-alanyl-D-isoglutamine. In the group receiving the conjugate, a higher titer of anti-LH-RH antibodies was obtained than in the group receiving LH-RH in Freund's emulsion. Moreover, histological examination showed that seminiferous tubules were atrophied and that no spermatozoides could be observed. This procedure could lead to applications in the veterinary field and also serve as a useful model for other antiviral or antibacterial synthetic vaccines.

Animals↗
PubMed1981

Active antitoxic immunization by a diphtheria toxin synthetic oligopeptide.

Diphtheria toxin (DT) is a single polypeptide chain of molecular weight 62,000 with two disulphide bridges. Immunization against diphtheria rests on the stimulation of antibodies against detoxified toxin which also combine with the native toxin. Because the antibodies differ functionally from each other, however, only some of them are able to neutralize toxicity. We have therefore set out to synthesize part of the amino acid sequence of the toxin whose function as a stimulator of antibodies might be less ambiguous, and have chosen the loop of 14 amino acids subtended by the disulphide bridge nearer the NH2 terminus of the molecule (Fig. 1). There is reason to think that this loop may be involved in the toxicity and immunological specificity of the molecule. We report here our finding that the tetradecapeptide (residues 188-201), when linked covalently with two different carriers, will elicit in guinea pigs antibodies which not only bind specifically with the toxin but neutralize its dermonecrotic and lethal effects. To our knowledge these results constitute the first example of successful active immunization against a lethal bacterial toxin using a synthetic antigen.

Amino Acid Sequence↗
PubMed1981

Properties of reference Escherichia coli endotoxin and its phthalylated derivative in humans.

The properties of a reference bacterial endotoxin prepared from Escherichia coli and its phthalylated derivative were studied in normal human volunteers infected intravenously with the compounds. The minimal pyrogenic dose of the reference endotoxin is about 0.1-0.5 ng/kg. The increase in white blood cell count, absolute granulocyte count, absolute immature granulocyte count, and concentrations of serum amyloid A, cortisol, and growth hormone was directly related to the concentration of reference endotoxin administered. Phthalylated reference endotoxin up to 1,000 ng/kg (at least 500 ng of the patent compound/kg) was administered to normal human volunteers without significant changes in temperature, white blood cell count, absolute granulocyte count, and concentrations of serum amyloid A, cortisol, and growth hormone. Thus, this study defines biologic properties of the new reference bacterial endotoxin in humans and demonstrates effective detoxification by phthalylation of the present compound.

Adult↗
PubMed1981

Persistent enhancement of cell-mediated and antibody immune responses after administration of muramyl dipeptide derivatives with antigen in metabolizable oil.

Circulating antibody titers can be increased when the antigen is administered in an aqueous medium with N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide). Results reported here show that cell-mediated immunity can be demonstrated when this synthetic adjuvant or an active analog is injected with an antigen (ovalbumin) in metabolizable squalane emulsion. Under these conditions a lipophilic derivative of muramyl dipeptide was shown to be even more active and to enhance long-lasting immune responses.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1981

Biological studies of lipophilic MDP-derivatives incorporated in liposomes.

Adjuvant activities of fatty acid derivatives of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) in saline, emulsified in Incomplete Freund Adjuvant (IFA) or incorporated in liposomes were compared. All derivatives were active when given in saline. The potency of MDP-L-Ala-glycerol mycolate was highly enhanced by administration in IFA of after incorporation in liposomes. These procedures had no effect on the activity of MDP-alpha-methyl-gamma-eta-butyl ester and MDP-alpha-methyl-gamma-eta-decyl ester although the presence of MDP could be demonstrated at the surface of the liposomes by anti-MDP antibodies.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1979

Enhancement of certain biological activities of muramyl dipeptide derivatives after conjugation to a multi-poly(DL-alanine)--poly(L-lysine) carrier.

N-Acetylmuramyl-L-Ala-D-Glu-NH2 (muramyl dipeptide) and several of its derivatives are effective immunoactivators that can enhance nonspecific resistance to infection but can also elicit fever. In contrast, one of its stereoisomers, N-acetylmuramyl-D-Ala-D-Glu-NH2, is devoid of both these activities. Our present report demonstrates that macromolecularization of muramyl dipeptide by attachment of several units to a multi-poly(DL-Ala)-poly(L-Lys) carrier potentiates both its pyrogenic and its immunostimulant activity. This branched polymer has been extensively used as carrier to various haptens. Surprisingly, inactive N-acetylmuramyl-D-Ala-D-Glu-NH2, after conjugation under the same conditions, becomes capable of increasing nonspecific immunity although its lack of pyrogenicity is not greatly modified. Moreover, the N-acetylmuramyl-D-Ala-D-Glu--NH2 conjugate remains devoid of adjuvant, sensitizing, or eliciting activity.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1978

In vivo and in vitro stimulation of nonspecific immunity by the beta-D-p-aminophenyl glycoside of N-acetylmuramyl-L-alanyl-D-isoglutamine and an oligomer prepared by cross-linking with glutaraldehyde.

Several biological activities of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP for muramyl dipeptide), a synthetic immunoadjuvant, are inhibited after glycosidation with p-aminophenol. Thus, this glycoside does not induce an increase humoral antibody response in mice when injected in saline, although it retains its stimulatory effect on circulating antibodies and delayed hypersensitivity after administration in a water-in-oil emulsion. The capacity of MDP to stimulate mouse spleen cells is lost, and, moreover, the analogue is unable to increase nonspecific resistance to infection under conditions where MDP is active. After cross-linking of the beta-D-p-aminophenyl glycoside of MDP with glutaraldehyde, several biological activities of MDP are recovered. Moreover, the cross-linked oligomer (molecular weight, approximately 6,000 daltons) is able to stimulate the uptake of thymidine by spleen cells from a strain of mice weakly responsive to MDP and is more active than MDP in protecting mice against bacterial challenge.

Acetylmuramyl-Alanyl-Isoglutamine↗