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Alterations in the HLA-B*57:01 Immunopeptidome by Flucloxacillin and Immunogenicity of Drug-Haptenated Peptides.
Puig, Montserrat; Ananthula, Suryatheja; Venna, Ramesh; Kumar Polumuri, Swamy; Mattson, Elliot; Walker, Lacey M; Cardone, Marco; Takahashi, Mayumi; Su, Shan; Boyd, Lisa F; Natarajan, Kannan; Abdoulaeva, Galina; Wu, Wells W; Roderiquez, Gregory; Hildebrand, William H; Beaucage, Serge L; Li, Zhihua; Margulies, David H; Norcross, Michael A.
Affiliation
  • Puig M; Laboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Ananthula S; Laboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Venna R; Laboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Kumar Polumuri S; Laboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Mattson E; Laboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Walker LM; Division of Applied Regulatory Science, Office of Translational Science, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Cardone M; Laboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Takahashi M; Laboratory of Biological Chemistry, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Su S; Laboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Boyd LF; Molecular Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
  • Natarajan K; Molecular Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
  • Abdoulaeva G; Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Wu WW; Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Roderiquez G; Laboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Hildebrand WH; Department of Microbiology and Immunology, School of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
  • Beaucage SL; Laboratory of Biological Chemistry, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Li Z; Division of Applied Regulatory Science, Office of Translational Science, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
  • Margulies DH; Molecular Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
  • Norcross MA; Laboratory of Immunology, Office of Biotechnology Products, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
Front Immunol ; 11: 629399, 2020.
Article de En | MEDLINE | ID: mdl-33633747
ABSTRACT
Neoantigen formation due to the interaction of drug molecules with human leukocyte antigen (HLA)-peptide complexes can lead to severe hypersensitivity reactions. Flucloxacillin (FLX), a ß-lactam antibiotic for narrow-spectrum gram-positive bacterial infections, has been associated with severe immune-mediated drug-induced liver injury caused by an influx of T-lymphocytes targeting liver cells potentially recognizing drug-haptenated peptides in the context of HLA-B*5701. To identify immunopeptidome changes that could lead to drug-driven immunogenicity, we used mass spectrometry to characterize the proteome and immunopeptidome of B-lymphoblastoid cells solely expressing HLA-B*5701 as MHC-I molecules. Selected drug-conjugated peptides identified in these cells were synthesized and tested for their immunogenicity in HLA-B*5701-transgenic mice. T cell responses were evaluated in vitro by immune assays. The immunopeptidome of FLX-treated cells was more diverse than that of untreated cells, enriched with peptides containing carboxy-terminal tryptophan and FLX-haptenated lysine residues on peptides. Selected FLX-modified peptides with drug on P4 and P6 induced drug-specific CD8+ T cells in vivo. FLX was also found directly linked to the HLA K146 that could interfere with KIR-3DL or peptide interactions. These studies identify a novel effect of antibiotics to alter anchor residue frequencies in HLA-presented peptides which may impact drug-induced inflammation. Covalent FLX-modified lysines on peptides mapped drug-specific immunogenicity primarily at P4 and P6 suggesting these peptide sites as drivers of off-target adverse reactions mediated by FLX. FLX modifications on HLA-B*5701-exposed lysines may also impact interactions with KIR or TCR and subsequent NK and T cell function.
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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Peptides / Antigènes HLA-B / Flucloxacilline / Haptènes Limites: Animals / Humans Langue: En Journal: Front Immunol Année: 2020 Type de document: Article Pays d'affiliation: États-Unis d'Amérique

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Peptides / Antigènes HLA-B / Flucloxacilline / Haptènes Limites: Animals / Humans Langue: En Journal: Front Immunol Année: 2020 Type de document: Article Pays d'affiliation: États-Unis d'Amérique