臺灣博碩士論文加值系統

Increasing studies revealed that HLA alleles are the major genetic determinants of drug hypersensitivity; however, the underlying molecular mechanism remains unclear. Here, we adopt the HLA-B*1502 genetic predisposition to carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) as a model to study the pathological role of HLA in delayed-type drug hypersensitivity. We in vitro expanded CBZ-specific cytotoxic T lymphocytes (CTLs) from CBZ-SJS/TEN patients and analyzed the interaction between HLA-B and CBZ/analogs by CTLs response, surface plasmon resonance, peptide binding assay, site-direct mutagenesis, and computer modeling. The majority of aromatic anti epileptic drugs (AEDs)-specific T cells generated from CBZ-SJS/TEN patients was CD8+ cytotoxic T lymphocyte (CTL) with massive expression of cytolytic components, such as granulysin, perforin, and granzyme B. The endogenous peptides-loaded HLA-B*1502 molecule presented aromatic AEDs to CTLs without the involvement of intracellular drug metabolism or antigen processing. The HLA-B*1502/peptide/??m protein complex showed binding affinity toward chemicals sharing 5-carboxamide on the tricyclic ring as CBZ. However, modifications of the ring structure of CBZ altered HLA-B*1502 binding and CTLs response. In addition to HLA-B*1502, other HLA-B75 members could also present CBZ to activate CTLs, whereas members of HLA-B62 and B72 could not. Three residues (Asn63, Ile95, and Leu156) in the peptide-binding groove of HLA-B*1502 were involved in CBZ presentation and CTLs activation. In particular, Asn63 shared by members of B75 was the key residue. Computer simulations revealed a preferred molecular conformation of 5-carboxamide group of CBZ and the side chain of Arg62 on the B pocket of HLA-B*1502. Besides, Asn63 also responded to the interaction between HLA-B*1502 and PHT or LTG. In conclusion, this study demonstrates a direct interaction of HLA with drugs, provides a detailed molecular mechanism of HLA-B*1502-associated drug hypersensitivity, and has clinical correlations for CBZ-induced SJS/TEN and the cross-reactivity to aromatic AEDs.

Contents

Signature Page I
Thesis approval form II
Acknowledgement i
Table of Contents ii
List of Tables vi
List of Figures vii
List of Abbreviation ix
Abstract xi

Chapter 1. Introduction 1
1.1 Adverse drug reactions (ADRs) 1
1.2 Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 2
1.2.1 Clinical features 2
1.2.2 Pathogenesis 3
1.2.3 Epidemiology 3
1.3 Carbamazepine-induced drug hypersensitivity 4
1.3.1 Carbamazepine (CBZ) 4
1.3.2 Carbamazepine-induced hypersensitivity syndrome (HSS) 5
1.3.3 Carbamazepine-SJS/TEN 5
1.3.4 Cross-reactivity of aromatic anti-epileptic drugs (AEDs) 6
1.4 Pharmacogenomic studies on ADRs 7
1.4.1 Strong association between HLA-B*1502 and CBZ-SJS/TEN 8
1.4.2 Association between HLA-B*1502 and aromatic AEDs-induced SCARs 9
1.4.3 Association between HLA-B*75 and CBZ-SJS/TEN 9
1.4.4 HLA association of drug hypersensitivity is ethnicity- and phenotype- specific 10
1.5 The role of HLA in drug hypersensitivity 11
1.5.1 Human Leukocyte Antigen (HLA) 11
1.5.2 Antigen presentation by HLA 12
1.5.3 Drug presentation mechanisms: the hapten/prohapten concept 13
1.5.4 Drug presentation mechanisms: the p-i concept 13
1.5.5 The roles of HLA-loaded peptides in drug hypersensitivity 14
1.6 Specific aims 15
Chapter 2. Materials and Methods 16
2.1 Clinical samples 16
2.2 Chemicals and antibodies 16
2.3 Constructs 17
2.4 Cell lines 18
2.5 Electroporation 19
2.6 Class I HLA enzyme-linked immunosorbent assay (ELISA) 20
2.7 SDS pages 20
2.8 Western blotting 21
2.9 Immunoprecipitation assay 22
2.10 Generation of CBZ-specific T cell lines and clones 22
2.11 Lymphocyte transformation test 22
2.12 T cell proliferation assays 23
2.13 T cell cytotoxic assays 23
2.14 Purification of soluble HLA-B proteins 24
2.15 Surface plasmon resonance (SPR) measurement and analyses 25
2.16 HLA-B*1502 peptide-binding assay 25
2.17 Enzyme-linked immunosorbent assay (ELISA) 25
2.18 Enzyme-linked immunospot (ELISpot) assay 26
2.19 In silico modeling of drugs and the peptide-loaded HLA-B*1502 complex 26
2.20 Flow analysis 27
Chapter 3. Results 28
3.1 Characteristics of CBZ-specific CTLs in CBZ-SJS/TEN 28
3.2 HLA-B*1502-dependent activation of CBZ-specific CTLs in CBZ-SJS/TEN 29
3.3 No involvement of intracellular metabolism or antigen processing in the CTLs activation
in CBZ-SJS/TEN 30
3.4 HLA-B*1502 protein directly binds to CBZ and its structural analogs to activate CTLs in
CBZ-SJS/TEN 31
3.5 The 5-carboxamide chemical moiety of CBZ is required for HLA-B*1502 presentation 31
3.6 HLA-B75 members exhibit binding ability to CBZ for antigen presentation in CBZ-
SJS/TEN 32
3.7 Key residues in the peptide-binding groove of HLA-B*1502 for CBZ presentation 33
3.8 Endogenous peptides loaded on HLA-B*1502 proteins are required for CBZ presentation
and CTLs activation in CBZ-SJS/TEN 34
3.9 In silico modeling highlights the molecular map of CBZ in HLA-B*1502 34
3.10 CBZ-specific T cells cross-reacted to phenytoin and lamotrigine 35
3.11 T cells of CBZ-SJS/TEN patients showed cross-reactivity to aromatic AEDs with a
conserved HLA-B*1502 genetic background 36
3.12 PHT and LTG are presented to T-cells in the absence of antigen processing pathway 37
3.13 PHT and LTG directly interact with peptide-loaded HLA-B*1502 38
3.14 Simulation of PHT and LTG binding sites on HLA-B*1502 39
Chapter 4. Discussion 40
4.1 The CBZ presentation mechanism 40
4.2 Direct interaction between HLA-B*1502 and aromatic AEDs 42
4.3 5-carboxamide group is critical for the interaction of CBZ analogs with HLA-B*1502 43
4.4 Licarbazepine is a weaker allergen 44
4.5 Cross-reactivity with aromatic AEDs 45
4.6 HLA class I loaded peptides are important for HLA/drug recognition 46
4.7 Difference between CBZ-SJS/TEN and CBZ-MPE/HSS 47
4.8 Why skin is the major target for ADRs 49
4.9 Circulating CBZ-specific T cells generated in the study share the same mechanism or
phenotype as infiltrating T cells in SJS lesions 50
4.10 Drug interaction with HLA and TCR 51
4.11 CBZ-specific TCR 51
4.12 The pathological role of HLA-A*3101 52
4.13 Limitation of in vitro T cells study 53
4.14 Summary and significance 53
Chapter 5. References 55
Chapter 6. Tables 64
Chapter 7. Figures 73

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