RRC ID 63605
Author Shirayanagi T, Aoki S, Fujimori S, Watanabe K, Aida T, Hirasawa M, Kumagai K, Hoshino T, Ito K.
Title Detection of Abacavir-Induced Structural Alterations in Human Leukocyte Antigen-B*57 : 01 Using Phage Display.
Journal Biol Pharm Bull
Abstract The interaction of human leukocyte antigen (HLA) with specific drugs is associated with delayed-type hypersensitivity reactions, which cause severe cutaneous toxicity. Such interactions induce structural alterations in HLA complexes via several different mechanisms such as the hapten theory, p-i concept, and altered peptide repertoire model, leading to the activation of cytotoxic T cells. To date, comprehensive detection of such structural alterations in preclinical studies has been difficult. Here, we evaluated structural alterations in HLA complexes focusing on the interaction between the HLA-B*57 : 01 allele and abacavir (an anti-human immunodeficiency virus drug), representing a model of abacavir hypersensitivity syndrome induced by changes in the peptide repertoire on the HLA molecule. We employed a phage display method using a commercially available antibody library to screen specific phage antibodies able to recognize HLA-B*57 : 01. The affinity of selected phage antibodies increased because of structural alterations in HLA-B*57 : 01 following exposure to abacavir, indicating that specific phage antibodies can identify drug-mediated structural changes in HLA complexes. We also identified an unreported structural change in HLA-B*57 : 01 using the phage display method, whereby abacavir increased the expression of peptide-deficient HLA-B*57 : 01 on the cell surface. These results suggest that phage display technology is a useful method for detecting structural changes in HLA complexes. This technology represents a potential novel strategy for predicting HLA-associated hypersensitivity reactions by drugs in pre-clinical studies.
Volume 43(6)
Pages 1007-1015
Published 2020-1-1
DOI 10.1248/bpb.b20-00102
PMID 32475910
MeSH Anti-HIV Agents / pharmacology* Antibodies / immunology Cell Surface Display Techniques Dideoxynucleosides / pharmacology* HLA-B Antigens / chemistry* HLA-B Antigens / genetics HLA-B Antigens / immunology HeLa Cells Humans
IF 1.863
Human and Animal Cells HeLa