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Identification et caractérisation des peptides hapténisés avec la benzylpénicilline responsables de l’activation des cellules T naïves et de l’immunisation des patients allergiques à la pénicilline

Abstract : Penicillins are among the most prevalent drug-inducing allergy. According to the hapten hypothesis small chemical molecules needs to bind to proteins to be immunogenic. However, little is known on the process of patients immunization to penicillin-protein conjugates. Our group has recently synthesized benzylpenicillin-human serum albumin (BP-HSA) bioconjugate and demonstrated the existence of naïve CD4+ T lymphocytes specific to BP-HSA in healthy donors. The objective of this work was to identify peptides sequences from HSA haptenized with BP involved in naïve T-cells activation, immunization of patients and consequently the clinical manifestations. Our strategy combines mass spectrometry, molecular modeling and virtual screening, chemical oriented synthesis and biological validation using long-term T-cell lines in healthy donors and the lymphocyte transformation test as well as short-term T-cell lines in allergic patients. This study allowed: (1) the identification of lysine residues involved in the BP binding to HSA using mass spectrometry, (2) the selection of BP-peptides containing the lysine residues likely to induce immune response using an in silico approach, (3) the synthesis of the selected BP-15 mer peptide bioconjugates using a lysine-BP monomer, (4) the identification of epitopes recognized by naïve T cells from healthy donors, (5) the validation of two epitopes located on lysines 159 and 525 in allergic patients to penicillins and (6) the confirmation of HSA as a good model for BP haptenation.
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https://tel.archives-ouvertes.fr/tel-01424844
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Submitted on : Tuesday, January 3, 2017 - 1:03:18 AM
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Marie Eliane Azoury. Identification et caractérisation des peptides hapténisés avec la benzylpénicilline responsables de l’activation des cellules T naïves et de l’immunisation des patients allergiques à la pénicilline. Immunité adaptative. Université Paris Saclay (COmUE), 2016. Français. ⟨NNT : 2016SACLS073⟩. ⟨tel-01424844⟩

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