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Peptides multi-épitopiques d’intérêt vaccinal appliqués aux leishmanioses humaines

Abstract : Leishmaniasis is a neglected tropical disease with a significant impact on human health because of the frequency and the severity of some of their clinical forms. In the absence of effective human vaccines, chemotherapy remains the major tool for the control of leishmaniasis, despite serious side effects and resistance to treatment. Healing is associated with the development of a life-long immunity to infection, arguing for vaccine feasibility.Peptide vaccines based on in silico identification of immunodominant T cell epitopes able to induce T cell specific immune responses constitute a promising strategy because of their specificity, stability and large-scale production/low cost.Our purpose was to evaluate the immunogenicity of multi-epitope peptides composed of T cell epitopes with binding affinities to the most frequent human leukocyte antigen class-I (HLA-I) and -II (HLA-II) alleles. These epitopes were derived from Histone (H2B), Promastigote surface Antigen (PSA) and L. major large RABGTPase (LmLRAB) proteins, which were previously described as potential Leishmania candidate vaccines.12 multi-epitope peptides were designed and were used as peptide pools to stimulate PBMC from individuals with healed cutaneous leishmaniasis. IFN-γ, IL-10, TNF-α and granzyme B (GrB) production was evaluated by ELISA or CBA. The frequency of IFN-γ-producing T cells was quantified by ELISpot. T cells secreting cytokines as well as memory T cells were analyzed by flow cytometry.We showed that 16 of 25 peptide pools containing HLA-I, HLA-II or both HLA-I and -II peptides were able to induce specific and significant IFN-γ but not IL-10 production. 6 peptide pools were selected among those inducing the highest levels of IFN-γ for further characterization. We showed that, some of them were able to induce a significant increase of the percentages of (i) both CD4+ and CD8+ T cells producing IFN-γ (ii) CD4+ T cells producing GrB (iii) bifunctional CD4+ T cells secreting IFN-γ+/TNF-α+ and/or TNF-α+/IL-2+ and (iv) CD4+ and CD8+ central memory T cells.In conclusion, we demonstrated that multi-epitope peptides derived from H2B, PSA and LmlRAB proteins were able to induce both CD4+ and CD8+ T cell responses, both associated with protection against Leishmania infection, suggesting that they may be exploited as potential polytope vaccine candidates against human leishmaniasis.
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Sarra Hamrouni. Peptides multi-épitopiques d’intérêt vaccinal appliqués aux leishmanioses humaines. Médecine humaine et pathologie. Université Montpellier; Université de Carthage (Tunisie), 2019. Français. ⟨NNT : 2019MONTT045⟩. ⟨tel-02479499⟩

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