Detection of Abacavir-Induced Structural Alterations in Human Leukocyte Antigen-B*57 : 01 Using Phage Display.

Published on Jun 1, 2020in Biological & Pharmaceutical Bulletin1.863
· DOI :10.1248/BPB.B20-00102
Tomohiro Shirayanagi1
Estimated H-index: 1
(Chiba University),
Shigeki Aoki7
Estimated H-index: 7
(Chiba University)
+ 6 AuthorsKousei Ito29
Estimated H-index: 29
(Chiba University)
Sources
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.
📖 Papers frequently viewed together
11 Citations
201242.78Nature
455 Citations
2 Citations
References32
Newest
#1Jie Geng (UM: University of Michigan)H-Index: 17
#2Anita J. Zaitouna (UM: University of Michigan)H-Index: 10
Last. Malini Raghavan (UM: University of Michigan)H-Index: 5
view all 3 authors...
Major histocompatibility complex class I (MHC-I) molecules present antigenic peptides to CD8+ T cells, and are also important for natural killer (NK) cell immune surveillance against infections and cancers. MHC-I molecules are assembled via a complex assembly pathway in the endoplasmic reticulum (ER) of cells. Peptides present in the cytosol of cells are transported into the ER via the transporter associated with antigen processing (TAP). In the ER, peptides are assembled with MHC-I molecules vi...
15 CitationsSource
#1Jie Geng (UM: University of Michigan)H-Index: 17
#2John D. Altman (Emory University)H-Index: 78
Last. Malini Raghavan (UM: University of Michigan)H-Index: 5
view all 4 authors...
The immune system keeps tabs on everything that happens in our body, looking for potential signs of threat. To alert it to any problems, almost every cell produces specific proteins on its surface called human leukocyte antigens class I, or HLA-I for short. These HLA-I molecules are bound to small protein fragments called peptides that have been exported from within the cell and are presented to the cells of the immune system for scanning. When cells are healthy, the peptides all stem from norma...
16 CitationsSource
#1Takeshi Susukida (Chiba University)H-Index: 5
#2Shigeki Aoki (Chiba University)H-Index: 7
Last. Kousei Ito (Chiba University)H-Index: 29
view all 8 authors...
Immune-mediated idiosyncratic drug toxicity (IDT) is a rare adverse drug reaction, potentially resulting in death. Although genome-wide association studies suggest that the occurrence of immune-mediated IDT is strongly associated with specific human leukocyte antigen (HLA) allotypes, these associations have not yet been prospectively demonstrated. In this study, we focused on HLA-B*57:01 and abacavir (ABC)-induced immune-mediated IDT, and constructed transgenic mice carrying chimeric HLA-B*57:01...
4 CitationsSource
#1Mahiuddin Ahmed (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 12
#2Andres Lopez-Albaitero (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 2
Last. Nai-Kong V. CheungH-Index: 80
view all 13 authors...
: EBV infection is associated with a number of malignancies of clinical unmet need, including Hodgkin lymphoma, nasopharyngeal carcinoma, gastric cancer, and posttransplant lymphoproliferative disease (PTLD), all of which express the EBV protein latent membrane protein 2A (LMP2A), an antigen that is difficult to target by conventional antibody approaches. To overcome this, we utilized phage display technology and a structure-guided selection strategy to generate human T cell receptor-like (TCR-l...
17 CitationsSource
#1Ren-You Pan (Memorial Hospital of South Bend)H-Index: 6
#2Ro-Lan Dao (Memorial Hospital of South Bend)H-Index: 7
Last. Wen-Hung ChungH-Index: 53
view all 4 authors...
Cutaneous idiosyncratic drug reactions (CIDRs) are usually unpredictable, ranging from mild maculopapular exanthema (MPE) to severe cutaneous adverse drug reactions (SCARs) such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Increasing evidences suggest HLA alleles are strongly associated with drug-induced-CIDRs. The pathomechanisms for CIDRs include genetic polymorphisms affecting complex immune specific HL...
19 CitationsSource
#1George Van Den Driessche (NCSU: North Carolina State University)H-Index: 4
#2Denis Fourches (NCSU: North Carolina State University)H-Index: 35
Background Human leukocyte antigen (HLA) surface proteins are directly involved in idiosyncratic adverse drug reactions. Herein, we present a structure-based analysis of the common HLA-B*57:01 variant known to be responsible for several HLA-linked adverse effects such as the abacavir hypersensitivity syndrome.
30 CitationsSource
A clinical association between a specific human leukocyte antigen (HLA) allele and idiosyncratic adverse drug reactions (IADRs) is a strong indication that IADRs are mediated by the adaptive immune system. For example, it is well-established that HLA-B*15:02 and HLA-B*57:01 are associated with carbamazepine-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and abacavir-induced hypersensitivity/flucloxacillin-induced liver injury, respectively. Drug-specific T-cells whose re...
16 CitationsSource
#1Qi Zhao (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 46
#2Mahiuddin Ahmed (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 12
Last. Nai-Kong V. Cheung (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 80
view all 8 authors...
Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential
59 CitationsSource
Background The clinical and economic impact of severe drug hypersensitivity is huge for both healthcare and pharmaceutical industry; however, no method for predicting culprit candidate t drugs under clinical development exists currently. As genetic variants in human-leukocyte antigens (HLA) have been linked to inter-individual differences in the risk of drug hypersensitivity, we ascertained whether HLA library can serve as a drug screening tool for their potential to cause severe drug hypersensi...
2 CitationsSource
#1Emmanuelle Génin (Paris Diderot University)H-Index: 37
#1E. Genin (Paris Diderot University)H-Index: 97
Last. J.-C. Roujeau (University of Paris)H-Index: 22
view all 18 authors...
HLA-A*31:01 and different types of carbamazepine-induced severe cutaneous adverse reactions: an international study and meta-analysis
128 CitationsSource
Cited By1
Newest
#1Takeshi Susukida (University of Toyama)H-Index: 5
#1Takeshi Susukida (University of Toyama)
Last. Kousei Ito (Chiba University)H-Index: 29
view all 6 authors...
Various types of transgenic mice carrying either class I or II human leukocyte antigen (HLA) molecules are readily available, and reports describing their use in a variety of studies have been publ...
Source