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J Estaquier

Publications and source records attributed to J Estaquier.

49 records · Page 3Linked to original sources
PubMed1994

The mixotope: a combinatorial peptide library as a T cell and B cell immunogen.

We report a new approach in peptide vaccine strategy based on combinatorial synthesis. A library of 7.5 x 10(5) related peptides, termed mixotope, was derived from the sequence of the third hypervariable domain (V3 loop) of the human immunodeficiency virus (HIV) envelope protein. This preparation induced a strong immune response in all syngeneic and outbred rodents tested. The response directed against the mixotope included antibodies, CD4+ T helper cells (TH1 and TH2) and CD8+ T cells. In rodents immunized with the mixotope, the T cell response directed against individual V3 peptide sequences (BRU, MN, RF, SF2, and ELI) as measured by T cell proliferation and interleukin (IL)-2 production, was found to be major histocompatibility complex haplotype-dependent. However, additional experiments performed in mice indicated that selectivity was less restrictive when using IL-3 secretion to explore T cell activation. This combinatorial antigen could be considered as a series of agretopic motifs framing a multiplicity of closely related epitopes for T cell recognition and able to elicit a T cell and B cell repertoire. This new construct may therefore provide a basis for the design of future vaccine strategies.

AIDS Vaccines↗
PubMed1994

Antigenicity and immunogenicity of P30-derived peptides in experimental models of toxoplasmosis.

P30, also referred to as SAG-1, is now recognized as a major Toxoplasma gondii antigen potentially important for both diagnosis and immunoprophylaxis of toxoplasmosis. By using predictive algorithms, five synthetic peptides (48-67, 82-102, 213-230, 238-256 and 279-285) derived from P30, were investigated for B- and T-cell determinants in mouse and rat experimental models. Antibody recognition appeared more broadly distributed along the P30 sequence, whereas T-cell recognition was mainly targeted on the 238-256 peptide. In the absence of any carrier protein, this peptide induced a B- and T-cell immune response independent of the route of immunization (oral route or subcutaneous injection). This peptide (238-256) induced multiple antibody isotypes. In contrast with the 238-256 peptide, the 48-67 peptide, either free or in the form of a multiple antigenic peptide (MAP) construct or the 279-295 peptide, elicited antibodies associated with a TH2 response. This study reports for the first time the analysis of the antigenic and immunogenic properties of P30-derived peptides and are potentially useful for vaccinal strategies incorporating the P30 Toxoplasma gondii antigen.

Administration, Oral↗
PubMed1994

Effect of a lipopeptidic formulation on macrophage activation and peptide presentation to T cells.

We studied a 45-69 lipopeptide obtained by N-terminal modification with a N epsilon-palmitoyl lysine residue of the 45-69 peptide derived from the nef protein of HIV. T cells from animals immunized intraperitoneally with 45-69 lipopeptide proliferated in vitro in the presence of 45-69 peptide while no response was obtained after intraperitoneal immunization with 45-69 peptide. The efficiency of the 45-69 lipopeptide is supported by the covalent association to the N epsilon-palmitoyl lysine moiety. The immunogenicity of the 45-69 lipopeptide or of the unmodified peptide is dependent on the route of immunization but is not related to a mitogenic effect on cells or to an increase of the peptide antigenicity. Moreover, only 45-69 lipopeptide induces the secretion of cytokines such as IL-1, IL-6 and TNF-alpha by peritoneal macrophages. Finally, the use of 45-69 lipopeptide permits the activation of highly purified T cells without the addition of antigen-presenting cells. These results have implications for the formulation of synthetic vaccines.

Amino Acid Sequence↗
PubMed1994

From AIDS to parasite infection: pathogen-mediated subversion of programmed cell death as a mechanism for immune dysregulation.

Premature cell death can result either from cell injury or degeneration, leading to necrosis, or from the activation of a physiological cell-suicide process, termed programmed cell death or apoptosis, that is regulated by intercellular signalling. This process plays an essential role in the selection of developing lymphocytes, and is also involved in the function of the mature adaptative immune system. A growing number of experimental findings during the last 4 years has provided support to our hypothesis that inappropriate HIV-mediated dysregulation of programmed T-cell death is relevant to AIDS pathogenesis. A series of recent experimental results also supports the general concept that the persistence and pathogenesis of several infectious pathogens, ranging from retroviruses to parasites, may be related to their capacity to dysregulate programmed cell death in various cell populations including lymphocytes. Subversion by pathogens of the physiological control of programmed cell death provides a paradigm for the pathogenesis of a wide range of infectious diseases that involve immune dysregulation and suggests therapeutic potential for the in vivo modulation of cell signalling.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Comprehensive delineation of antigenic and immunogenic properties of peptides derived from the nef HIV-1 regulatory protein.

The Human Immunodeficiency Virus (HIV-1) nef regulatory protein, a protein involved in AIDS pathology, was used as a model to investigate and analyze B- and T-cell epitopes. In this paper, we describe the potential structural basis of antigenic and immunogenic reactivity of synthetic peptides derived from the macromolecular antigen. The relationship between B- and T-cell determinants in the context of regulatory mechanisms involved in immune recognition, while integrating recent data concerning MHC presentation. As a result of the recent progress in the field of peptide recognition and presentation, the potential of the peptide approach for constructing successful synthetic vaccines needs to be continuously re-evaluated.

Amino Acid Sequence↗
PubMed1992

T helper cell epitopes of the human immunodeficiency virus (HIV-1) nef protein in rats and chimpanzees.

T helper cell antigenic and immunogenic determinants of the nef protein were investigated in the rat and chimpanzee models using recombinant nef protein and five synthetic peptides selected according to their amphipathic and alpha-helicity properties. The nef protein was shown to be immunogenic with both Freund's or aluminium hydroxide adjuvants. After immunization with the nef protein the 45-69 peptide was the most antigenic in rat and monkey models. In contrast, the 98-112 peptide, that required a carrier protein to induce in vitro rat T cell recall proliferation, was able to restimulate monkey T cells in the absence of a carrier. The amino acid sequence carrying the antigenic activity of the 45-69 peptide was further investigated by synthesizing short peptides overlapping this region. The antigenic sequence was precisely located in the middle of the peptide (region 50-59). This sequence was antigenic only when N alpha-acetylated. Circular dichroism analysis of the 45-69 peptide and the in vitro activity of the N-terminus group indicate in this case the involvement of the alpha-helical propensity for antigen presentation. However, the shorter sequence 50-64, able to induce a T cell reactivity, was determined as a beta-pleated sheet structure in aqueous solution. The 45-69 peptide was not only antigenic but also immunogenic and behaved in vivo as a functional T helper cell epitope. Indeed, the priming with the peptide or the transfer of peptide specific T cells to a naive recipient, followed by immunization with the nef protein, enhanced the subsequent antibody response to the nef protein. Together, these data indicate that the 45-69 peptide appears as a candidate for the in vivo elicitation of T cell immunity to the HIV-1 nef regulatory protein.

Amino Acid Sequence↗
PubMed1992

Determination of B-cell epitopes of nef HIV-I protein: immunogenicity related to their structure.

Determination of the B-cell epitopes of the nef molecule encoded by the human immunodeficiency virus type 1 (HIV-1) was undertaken using a set of six synthetic peptides. Sequences that were both antigenic and immunogenic and stimulated the production of antibodies recognizing the full length molecule, were considered as B-cell epitopes. Two peptidic sequences were antigenic both in rodents (mice and rats) and in non-human primates (chimpanzee). They were located in the regions 45-69 and 176-206 of the nef molecule. Two additional antigenic sequences were determined, one in chimpanzees, region 79-94, and the second in rodents, region 148-161. Immunogenicity was investigated in the rodents. Only the 45-69 and 176-206 sequences were immunogenic, and specific antibodies present in the sera of the immunized animals reacted with the nef protein. Therefore, each of these two sequences could be considered as containing at least one B-cell epitope. The fine epitopic specificity was determined using subfragments of these two sequences and it was shown that the antigenic determinants were contained in the C-terminal region of each sequence overlapping with the T-cell epitopes. These results raised the importance of vicinity of B- and T-cell determinants and their immunogenicity.

Amino Acid Sequence↗
PubMedDate not supplied

A combinatorial peptide library around variation of the human immunodeficiency virus (HIV-1) V3 domain leads to distinct T helper cell responses.

The hypervariable domain of the HIV gp120, the V3 loop domain, represents a target for neutralizing antibodies and for HIV vaccine strategies. In this study, we have investigated in murine species the potential cross-reactivity of immune responses elicited by immunization either with individual V3 peptides, derived from distinct HIV sequences (BRU, RF, SF2, MN and ELI sequences), or with a V3 combinatorial peptide library. We observed that individual V3 peptides are immunogenic but elicit a specific B- and T-cell immune response that is mainly restricted to the sequence of the immunizing peptide. In particular, T-cell responses that depend on T-cell receptor recognition of peptides bound to the molecules encoded by the major histocompatibility complex were significantly influenced by small differences in the peptide amino acid sequence. The combinatorial V3 peptide library, previously described as B- and T-cell immunogens, induced a more broadly reactive immune response, specially when T-cell cytokine secretion was used as a readout for restimulation of T-cells with individual V3 peptides. These data suggest that amino acid variations in the sequence of an antigenic peptide could lead to the induction of different transducing signals in the primed T-cell population and to the activation of T-cells with distinct cytokine secretion properties. These observations may have implications in the understanding of antigenic variability and in the design of vaccine strategies.

Amino Acid Sequence↗
PubMedDate not supplied

Improvement of the T-cell response to a non-immunogenic peptide by its tandem association with a highly efficient T-helper peptide.

The 45-69 peptide, an helper T-cell epitope derived from HIV nef protein, is strongly immunogenic. A T-cell proliferative response was observed following immunization of Lou/M rats with 45-69 peptide administered in low dose and without any adjuvant. It is already known that the T-cell response to the 115-131 peptide of Sm28GST antigen, a protein of the parasite Schistosoma mansoni, requires the presence of a carrier or the use of peptidic constructs. We demonstrate here that a T-cell response against the 115-131 peptide can be obtained in the absence of adjuvant using peptidic constructs (115-45 and 45-115 peptides) resulting from tandem synthesis of 115-131 and 45-69 peptides. A covalent association of both peptides is necessary, since the co-injection of 45-69 and 115-131 peptides is not sufficient to induce a detectable anti-115-131 T-cell response. The mutual orientation between the respective tandem peptides (45-115 and 115-45) is critical for the T-cell response. These peptidic constructs possess distinct properties of antigenicity and immunogenicity but both allowed to reveal the existence of a 115-131 specific T-cell response normally undetectable using 115-131 peptide alone. This immunopharmacological approach should be useful in the rational design and construction of vaccines.

Adjuvants, Immunologic↗
PubMedDate not supplied

Improvement of the T-cell response to a non immunogenic peptide by its tandem association with a highly efficient T-helper peptide.

The 45-69 peptide, an helper T-cell epitope derived from the HIV nef protein is strongly immunogenic. A T-cell proliferative response was observed following immunization of Lou/M rats with 45-69 peptide administered in low dose and without any adjuvant. It is already known that the T-cell response to the 115-131 peptide of Sm28GST antigen, a protein of the parasite Schistosoma mansoni, requires the presence of a carrier of the use of peptidic constructs. We demonstrate here that a T-cell response against the 115-131 peptide can be obtained in the absence of adjuvant using peptidic constructs (115-45 and 45-115 peptides) resulting from tandem synthesis of 115-131 and 45-69 peptides. A covalent association of both peptides is necessary, since the coinjection of 45-69 and 115-131 peptides is not sufficient to induce a detectable anti-115-131 T-cell response. The mutual orientation between the respective tandem peptides (45-115 and 115-45) is critical for the T-cell response. These peptidic constructs possess distinct properties of antigenicity and immunogenicity but both allowed to reveal the existence of a specific T-cell response normally undetectable using 115-131 peptide alone. This immunopharmacological approach should be useful in the rational design and construction of vaccines.

Adjuvants, Immunologic↗
PubMedDate not supplied

Gamma-interferon induces apoptosis of the B lymphoma WEHI-279 cell line through a CD95/CD95L-independent mechanism.

Gamma-interferon (IFN-gamma) a cytokine produced by CD4+ T helper type 1 cells, CD8+ T cells and natural killer (NK) cells, plays a central role in the development of humoral and cell-mediated immunity. IFN-gamma participates in the maturation and differentiation of B cells, but it has been previously reported that IFN-gamma may inhibit the early stages of B cell activation. We report that the inhibition of the B lymphoma cell WEHI-279-proliferation induced by IFN-gamma, involves the induction of typical features of apoptosis (nuclear chromatin condensation and fragmentation, cell shrinkage, phosphatidyl-serine (PS) exposure and mitochondrial membrane potential (delta psim) loss). IFN-gamma-mediated B cell apoptosis was decreased by the addition of the T helper type 2 cytokine, IL-4. WEHI-279 cells express CD95 and undergo apoptosis after treatment with either an agonistic anti-CD95 Ab or with a soluble recombinant CD95L. However, incubation with CD95-Fc or TRAIL-R1-Fc fusion proteins, did not prevent IFN-gamma-mediated apoptosis, suggesting that IFN-gamma-mediated apoptosis occurs independently of CD95/CD95L and TRAIL-R/TRAIL interactions. IFN-gamma-mediated apoptosis is associated with caspase-3 activation that can be prevented by the addition of the broad caspase inhibitor zVAD-fmk. These data indicate that IFN-gamma may play a major role in the regulation of B cell apoptosis, and suggest the involvement of an alternative pathway which is independent of the death receptors.

Animals↗
PubMedDate not supplied

Comparison of the immune response elicited by a free peptide and a lipopeptide construct.

Among the synthetic peptides derived from the 28-kDa Schistosoma mansoni gluthatione-S-transferase (Sm28GST), the C-terminal peptide, comprising amino acid residues 190 to 211, represents a major T-cell epitope in both infected humans and Sm28GST-immunized mice. The aim of this study was to determine the nature of the immune response induced by the 190-211 peptide coupled to a fatty acid (lipopeptide construction) in comparison to the free form. We explored B- and T-cell responses elicited by these two peptidic constructions in three different mouse strains (BALB/c, CBA/N and C57B1/6). For all strains, the addition of a lipid chain to the 190-211 peptide greatly modified its immunogenicity. The lipopeptide, compared to the free form, induced a greatly reduced antibody response against the peptide, whereas the production of messenger for cytokines was greatly increased after immunization with the lipopeptide. Immunization with peptide led mainly to a Th1-type cytokine profile following antigenic restimulation in vitro, while lipopeptide, in general, induced a mixed profile, and that occurred most significantly with the production of messengers for the protective cytokines IFN-gamma and IL-2, even without antigenic restimulations. This modification of immunogenicity of a peptide by the addition of a lipid chain could be of value in the development of efficient peptide vaccines.

Animals↗