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F Audibert

Publications and source records attributed to F Audibert.

At least 91 records · Page 5Linked to original sources
PubMed1988

Influence of helical organization on immunogenicity and antigenicity of synthetic peptides.

Using cooperative effects of different peptide structures synthesized in tandem, we have induced an alpha-helical structure in water solution on a peptide which, alone, is unorganized. This structure is particularly relevant in this case as the selected model protein (type 24 M protein of Streptococcus pyogenes) is an extended coiled-coil system. We were thus able to assess the importance of organization or unorganization of a unique amino acid sequence with regards to its immunogenicity and antigenicity. Although in a classical manner, antibodies cross-reacting with the protein can be obtained with the short, unorganized peptide, we demonstrate that conformation-specific antibodies are raised when longer, organized peptides are used as immunogens.

Animals↗
PubMed1987

Modulation of carrier-induced epitopic suppression by Bordetella pertussis components and muramyl peptide.

Synthetic antigens employed in experimental synthetic vaccines are generally small haptenic peptides. Therefore, effective immunization with these antigens usually requires the use of an immunogenic carrier. Tetanus toxoid has been proposed for use as a carrier in future synthetic vaccines due to its high immunogenicity and acceptance for human use. Previous studies employing standard hapten/carrier systems such as DNP/KLH have demonstrated, however, that an epitope-specific suppression occurs when mice previously primed with carrier are subsequently immunized with an haptenic epitope conjugated to the same carrier. These same studies have shown that Bordetella pertussis vaccine administered at the time of carrier priming abrogates epitopic suppression. In the present investigation, epitopic suppression was studied in a synthetic vaccine model employing tetanus toxoid as a carrier. Results from these studies indicated that mice primed with tetanus toxoid 1 month before immunization with a peptide-tetanus toxoid conjugate exhibited enhanced secondary anti-tetanus toxin responses but decreased anti-peptide responses. Furthermore, injection of pertussis vaccine or purified B. pertussis toxin or endotoxin at the time of carrier priming could block the establishment of epitopic suppression. Administration of B. pertussis components enhanced antibody responses to both the carrier and the synthetic peptides as compared with responses of control animals. In addition, administration of an adjuvant-active nonpyrogenic derivative of muramyl dipeptide. Murabutide, with carrier priming reduced epitopic suppression of anti-peptide responses. B. pertussis toxin or endotoxin administered to mice previously suppressed by carrier priming with the first injection of carrier-peptide conjugate overcame epitopic suppression with resultant titers of anti-peptide antibody equal to or greater than nonsuppressed controls. These results suggest that the use of adjuvants with future synthetic vaccines may contribute the additional advantage of overcoming epitopic suppression, thus permitting the use of common, well-tolerated carrier systems such as tetanus toxoid in synthetic vaccine preparations.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

Structural requirements for the induction of "immunological castration" by linear monomeric LHRH-lys-MDP administered in saline.

It was previously shown that "castration" could be obtained in male mice by immunizing them in saline with a conjugate referred to as LHRH-Lys-MDP and containing the decapeptide hypothalamic hormone LHRH covalently linked to the adjuvant glycopeptide MDP-Lys. Since coupling was made using carbodiimide, it could have produced oligomers or isomers as well as monomers. In the present investigation male and female mice were immunized in saline with a linear monomeric MDP linked LHRH molecule obtained by total synthesis. Histological studies showed gonadal alterations in both male and female mice. The study of analogs provided a correlation between the "castrative" activity of LHRH-Lys-MDP and its chemical and antigenic structures. However, because LHRH antibody levels were not very high, mechanisms other than antibody response are discussed. Such totally synthesized molecules including a safe adjuvant could make a clinical use of LHRH immunization possible in endocrine-dependent cancers.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

Covalent linkage of the synthetic adjuvant MDP to the synthetic polypeptide (T,G)-A-L changes the specificity of the immune response at the T and B cell level.

It is now well established that the synthetic molecule MDP (N-acetylmuramyl-L-alanyl-D-isoglutamine) can be a good adjuvant of immunity when covalently linked to antigen. The question raised in this work is whether conjugation of antigen to the immunomodulatory molecule MDP can modify the specificity of the antibodies and T cells induced following immunization. Using the well characterized synthetic polypeptide antigen, poly(L-Tyr,L-Glu)-poly(DL-Ala)--poly(L-Lys) [(T,G)-A--L], we show that immunization of C57B1/6 (H-2b) mice with MDP-(T,G)-A--L conjugate elicits at least two types of antibody directed against the poly(DL-Ala)--poly(L-Lys) (A--L) part of the antigen, and against new determinant(s) formed by MDP and a portion of the (T,G)-A--L molecule. Interestingly, the poly-(L-Try L-Glu) side chains thought to constitute the major antigenic determinants of the (T,G)-A--L molecule were not recognized. Lymph node cells from (T,G)-A--L immunized mice can be equally well stimulated in vitro by (T,G)-A--L or by MDP-(T,G)-A--L, whereas lymph node cells from MDP-(T,G)-A--L primed animals can be stimulated only when challenged by the conjugate used for immunization, and not by the free synthetic polypeptide (T,G)-A--L. The data presented here show that the coupling of a low mol. wt molecule such as MDP (mol. wt approx. 500) to an antigen can greatly modify the immune response directed against this antigen. Furthermore, (1) different antibody specificities are elicited depending upon whether the priming is done with free MDP and antigen or with MDP covalently linked to the antigen; (2) although still accessible on the conjugate, an epitope which represents the major antigenic determinant on the free polypeptide appears to be silent when presented on the conjugate; and (3) new determinant(s) formed by the chemical linkage of the polypeptide to the synthetic adjuvant are involved in the priming of T cells.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

A potential anti-pregnancy vaccine built by conjugation of the beta-subunit of human chorionic gonadotropin to adjuvant-active muramyl peptide.

The beta-subunit of human chorionic gonadotropin (hCG) conjugated to tetanus toxoid is being investigated as a vaccine for human fertility control. Initial clinical trials indicated that the level of antibody response induced by such an immunogen was not always sufficient to prevent pregnancy. Therefore, efforts are being made to evaluate new carriers for the beta-subunit and to select adjuvants to yield a more efficient vaccine. In the present report, we demonstrate that conjugates of the beta-subunit of hCG with muramyl dipeptide (MDP), or its nonpyrogenic derivative murabutide, may have potential as an effective antipregnancy vaccine. The copolymer of beta hCG and MDP administered with Al(OH)3 to mice induced a high anti-beta hCG response, better than that induced by the conjugate of beta hCG to tetanus toxoid given with Al(OH)3. Moreover, the antibodies induced by such an immunogen were competent for neutralizing the biological activity of hCG in vivo. Even more interesting, a copolymer of beta hCG and of murabutide induced high levels of biologically active antibodies. This immunogen may represent a promising candidate for the development of an efficient vaccine for human fertility control.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

Enhanced epitopic response to a synthetic human malarial peptide by preimmunization with tetanus toxoid carrier.

Successful human vaccination by synthetic malarial sporozoite peptides may depend on the choice of an appropriate carrier. Tetanus toxoid (TT) has been proposed because of its safe and widespread use in humans. Paradoxically, however, prior exposure to this toxoid vaccine could produce specific epitopic suppression against synthetic malarial peptides conjugated to this same protein as carrier. Indeed, we have previously reported that such a phenomenon can occur in the case of a synthetic vaccine made with a streptococcal peptide conjugated to TT. Our present study shows that similar results can be observed in mice preimmunized with TT 1 month before the administration of a conjugate containing TT and a Plasmodium knowlesi peptide. Analysis of the isotypic pattern of the antipeptide response showed that the immunoglobulin G1 (IgG1) subclass and especially the IgG2a and IgG2b subclasses were suppressed. In contrast, when a sporozoite peptide from Plasmodium falciparum was coupled to TT, the total antipeptide antibodies and particularly the IgG1 subclass were enhanced by preimmunization by TT. This increase of antipeptide antibodies was correlated with a greater ability of the sera to neutralize sporozoite infectivity. These results indicate that prior exposure to TT does not systematically impair the antibody response against a peptide administered as a peptide-TT conjugate.

Adjuvants, Immunologic↗
PubMed1986

Production of antibodies recognizing a hepatitis B virus (HBV) surface antigen by administration of murabutide associated to a synthetic pre-S HBV peptide conjugated to a toxoid carrier.

The influence of Murabutide, a muramyl peptide analog, on the response of mice to two synthetic hepatitis B virus antigens was compared with the activity of Al (OH)3 and of FCA. The synthetic peptides represented fragments either of the major component of the hepatitis B surface antigen (HBsAg) or of the pre-S region. They were used either conjugated to toxoid carrier or as a totally synthetic preparation, i.e. copolymerized with a streptococcal peptide. Our results demonstrated that treatment with Murabutide increased the levels of antibodies, modulated their specificity and allowed a better recognition of the natural antigens.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1986

Opsonic antibodies evoked by hybrid peptide copies of types 5 and 24 streptococcal M proteins synthesized in tandem.

The protective immunogenicity of a hybrid peptide containing tandem copies of types 5 and 24 epitopes was investigated. Carboxy-terminal peptides of the cyanogen bromide-derived fragment 7 (CB7) of type 24 M protein were chemically synthesized, and then extended to include the first 20 residues of the amino-terminus of type 5 M protein. When emulsified in CFA and injected into rabbits without conjugation to a carrier, each of the synthetic hybrid peptides, designated S-M5(1-20)-S-CB7(23-35)C and S-M5(1-20)-S-CB(19-34), evoked opsonic antibodies against both types 5 and 24 streptococci without raising heart tissue-crossreactive immunity. These results suggest that tandem hybrid peptides may provide a new approach to the development of multivalent vaccines, not only to different serotypes of group A streptococci but perhaps also to a variety of other infectious agents.

Animals↗
PubMed1986

Role of muramyl peptides for the enhancement of synthetic vaccines.

Adjuvants are largely used in human and veterinary medicine with conventional vaccines. Vaccines of the future could be synthetic immunogens which would require the addition of more immunomodulators. Muramyl peptides (MDP) are synthetic glycopeptides which can substitute mycobacteria in FCA and are also adjuvant-active in saline. A derivative, Murabutide, is currently undergoing clinical trials and has been found efficient in several experimental models of conventional and synthetic vaccines. For example, when a Plasmodium knowlesi sporozoite peptide conjugated to tetanus toxoid was administered in saline with Murabutide higher titers of biologically active antibodies were obtained than when the same conjugate was given in FCA. Coupling of MDP or derivatives to the immunogens enhanced their activity and allowed the use of carriers to be diminished or even avoided. In the same malarial model the linkage of a Murabutide derivative to the conjugate stimulated the response to the peptide and decreased the response to the carrier. Promising results were obtained when several peptides copying structures of different pathogens were associated in the same molecule by covalent linkage and administered with Murabutide in saline: biologically active antibodies were demonstrated to three of the corresponding pathogens.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Production of anti-sporozoite antibodies in absence of response to carrier by coupling an MDP derivative to a malaria peptide-tetanus toxoid conjugate.

A synthetic peptide (pep) representing a portion of the Plasmodium knowlesi circumsporozoite protein attached to a tetanus toxoid (TT) carrier, has been shown to be immunogenic when delivered in saline with derivatives of the synthetic adjuvant, muramyl dipeptide (MDP). The present study was designed to determine if the degree of substitution of pep and of MDP derivatives on the tetanus toxoid (TT) carrier, as well as the choice of MDP derivative used play a role in determining anti-pep and anti-TT antibody levels. One of the MDP derivatives used in the conjugates was epsilon-amino-caproic Murabutide, since Murabutide which is currently in clinical trials cannot be conjugated. The results show that low doses of this derivative coupled with pep on TT can be used to stimulate high levels of circulating anti-pep antibodies without augmenting the anti-carrier response. In addition, anti-pep antibodies elicited in response to one of the conjugates were biologically active since they produced shedding of the circumsporozoite coat of live parasites.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Immunological castration by a totally synthetic vaccine: modification of biological properties of LH-RH after conjugation to adjuvant-active muramyl peptide.

Recently, we demonstrated that immunological castration of male mice can be obtained by immunization with Luteinizing Hormone-Releasing Hormone (LH-RH) directly coupled to NAcMur-L-Ala-D-isoGln-L-Lys (MDP-Lys) without carrier and Freund's Complete Adjuvant (FCA) but in the presence of Polyvinyl-Pyrrolidone (PVP). In the present report, we have observed that: (a) immunization by the conjugate, LH-RH-MDP-Lys, was very effective even in absence of PVP, and this conjugate was more active than other conjugates containing MDP coupled to LH-RH fragments; (b) a strong secondary response could be observed by the administration of free LH-RH suggesting that the endogenous secretion of LH-RH might elicit a boosting effect; (c) administration of MDP-Lys coupled to LH-RH decreased the pyrogenicity of the glycopeptide; (d) such a conjugation also decreased the hormonal activity of the antigen although it enhanced its immunogenicity. These results show that a conjugate (2000 dalton) of a decapeptide hormone with a synthetic adjuvant glycopeptide can induce immunological castration in mice after administration in saline. The immunopharmacological properties of the conjugate and its conditions of efficacy suggest that such an approach could find clinical application.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Effects of natural or synthetic microbial adjuvants on induction of autoimmune thyroiditis.

Natural and synthetic adjuvants of microbial origin were compared for their capacity to potentiate the induction of experimental autoimmune thyroiditis (EAT) with the autoantigen mouse thyroglobulin (MTg). Regardless of the immunomodulator used, severe thyroiditis was observed only in EAT-susceptible strains of the k haplotype and not in EAT-resistant strains of the d haplotype. Compared to phenol-extracted lipopolysaccharide, a potent adjuvant for enhancing EAT induction, phthalyl-substituted, detoxified lipopolysaccharide, even at doses 15- to 50-fold greater, led to only low anti-mouse thyroglobulin titers and mild thyroid infiltration. The synthetic adjuvant N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and three of its analogs, N-acetylmuramyl-L-alanyl-D-isoglutamine-L-alanyl-D-glycerol mycolate (MDP-L-Ala-Glyc-Myc), N-acetylmuramyl-L-alanyl-D-glutamyl-(decyl)methyl ester [MDP(decyl)methyl], and N-acetylmuramyl-L-alanyl-D-glutamine-alpha n-butyl ester [MDP-(Gln)-OnBu], designated murabutide, were tested in incomplete Freund adjuvant or in saline. In incomplete Freund adjuvant, MDP-L-Ala-Glyc-Myc was inefficient in inducing EAT, murabutide induced very mild involvement, and MDP and, more so, MDP(decyl)methyl were active but to a lesser degree than CFA. When saline was used, low levels of thyroid infiltration were observed in a few of the MDP-treated animals in only one experiment, whereas no lesions were observed when murabutide was used.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Carrier-induced epitopic suppression, a major issue for future synthetic vaccines.

Synthetic antigens have been shown, in experimental models, to induce protective immunity against a variety of pathogens. These studies have demonstrated that, due to their low immunogenicity, these synthetic antigens required conjugation to carrier molecules. Therefore, the choice of appropriate carriers for human immunization by future synthetic vaccines is a major issue. Tetanus toxoid is generally considered to be an effective potential carrier devoid of side-effects. However, the present study performed in mice with two synthetic vaccine models demonstrates that the immune response against the synthetic epitopes conjugated to tetanus toxoid can be suppressed by pre-existing immunity against this same carrier. Because most humans have been exposed to this antigen, this effect may have important implications for the development of synthetic vaccines.

Animals↗
PubMed1985

Suppression of murine lupus autoantibodies to DNA by administration of muramyl dipeptide and syngeneic anti-DNA IgG.

We evaluated the effect of repeated subcutaneous administration of syngeneic anti-DNA IgG and muramyl dipeptide, a synthetic immunoadjuvant, to 6-mo-old (NZB X NZW)F1 female mice. This treatment had profound effects on both idiotype expression and anti-DNA antibody levels of morbid mice. It was also associated with appearance of anti-idiotypic antibodies specific for the injected antibody. These findings suggest that this approach with the use of synthetic immunomodulators and syngeneic antibodies may be of potential use in the management of autoimmune diseases.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

[Use of muramyl dipeptides in models of synthetic vaccines].

Vaccination represents a great success in clinical immunology and new approaches for designing vaccines of the future are now available. Protective antigens could be obtained by recombinant DNA technology or by synthesis. These new immunogens are likely to be poor immunogens and require the use of carrier and adjuvants. Both carrier and adjuvant present some limitations. In this report we consider how synthetic glycopeptides analogous to muramyl dipeptide (MDP) can be used as adjuvants under suitable conditions and can also overcome some problems due to the carrier. Muramyl dipeptides and chiefly Murabutide (NAcMur-L-Ala-D-Gln-alpha-n-butyl-ester) which is a derivative currently undergoing clinical trials can enhance the immune response to conventional purified vaccines. They can be also used in synthetic vaccines. In this case they are more active when covalently linked to the immunogen. Several examples of semisynthetic monovalent and polyvalent vaccines (Streptococcus, diphtheria toxin, Hepatitis B, Plasmodium) are described as well as totally synthetic vaccines (LH-RH, Foot-and-Mouth disease virus). They demonstrate that by using Murabutide biologically active antibodies can be produced under conditions applicable to human use.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

A monoclonal antibody against a synthetic peptide is specific for the free native human chorionic gonadotropin beta-subunit.

A totally synthetic molecule (109-145 peptide) analogous to the beta-subunit carboxyl terminus was used as an antigen in the development of antibodies by the hybridoma technique. A monoclonal antibody (702 D7) specifically recognized the free native beta-human CG (beta hCG). 702 D7 was of the immunoglobulin G1 subclass and was directed against an antigenic site localized in a 10-amino acid sequence (109-118) or less. The recognition of an epitope located in the 109-118 region could explain the specific recognition of beta hCG observed with 702 D7, in contrast to monoclonal antibodies directed against a 118-145 region with a recognition of both beta hCG and whole hCG, as observed with a second monoclonal antibody (1032) to synthetic peptide. Immunohistochemical results and preliminary data obtained from the immunoradiometric assay show that 702 D7 provides a clinical tool for the detection of free beta-subunit secretion even at low concentrations, and could allow the study of this subunit or its metabolites produced by normal and tumoral cells.

Animals↗