scholarly journals Novel Concepts for Drug Hypersensitivity Based on the Use of Long-Time Scale Molecular Dynamic Simulation

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Takahiro Murai ◽  
Norihito Kawashita ◽  
Yu-Shi Tian ◽  
Tatsuya Takagi
Keyword(s):  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Md Simulations ◽  
Hypersensitivity Reactions ◽  
Drug Induced ◽  
Leukocyte Antigen ◽  
Cell Clones ◽  
Drug Hypersensitivity Reactions ◽  
Long Time ◽  
Underlying Mechanisms

The discovery that several drug hypersensitivity reactions (DHRs) are associated with specific human leukocyte antigen (HLA) alleles has attracted increasing research interest. However, the underlying mechanisms of these HLA-induced DHRs remain unclear, especially for drug-induced immediate activation of T-cell clones (TCCs). Recently, a novel hypothesis involving partial detachment between self-peptide(s) and the HLA molecule (altered peptide-HLA (pHLA) model) has been proposed to explain these phenomena. In order to clarify this hypothesis, we performed long-timescale molecular dynamics (MD) simulations. We focused on HLA-B⁎57:01-restricted abacavir hypersensitivity reactions (AHRs), one of the most famous DHRs. One of the simulation results showed that this altered-pHLA model might be driven by an increase in the distance not only between HLA and self-peptides but also between the α1 and α2 helices of HLA. Our findings provide novel insights into abacavir-induced immediate activation of TCCs and these findings might also be applied to other DHRs, such as HLA-B⁎58:01-restricted allopurinol hypersensitivity reactions.

scholarly journals HLA Associations and Clinical Implications in T-Cell Mediated Drug Hypersensitivity Reactions: An Updated Review

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Chi-Yuan Cheng ◽  
Shih-Chi Su ◽  
Chi-Hua Chen ◽  
Wei-Li Chen ◽  
Shin-Tarng Deng ◽  
...  
Keyword(s):  
T Cell ◽  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Hypersensitivity Syndrome ◽  
Stevens Johnson Syndrome ◽  
Hypersensitivity Reactions ◽  
Genetic Associations ◽  
Drug Induced ◽  
Hla Alleles ◽  
Drug Hypersensitivity Reactions

T-cell mediated drug hypersensitivity reactions may range from mild rash to severe fatal reactions. Among them, drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS), Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN), are some of the most life-threatening severe cutaneous adverse reactions (SCARs). Recent advances in pharmacogenetic studies show strong genetic associations between human leukocyte antigen (HLA) alleles and susceptibility to drug hypersensitivity. This review summarizes the literature on recent progresses in pharmacogenetic studies and clinical application of pharmacogenetic screening based on associations between SCARs and specific HLA alleles to avoid serious conditions associated with drug hypersensitivity.

Human Leukocyte Antigen Associations in Drug Hypersensitivity Reactions

2018 ◽  
Vol 38 (4) ◽  
pp. 669-677 ◽  
Author(s):  
Ryan J. Schutte ◽  
Yonghu Sun ◽  
Danmeng Li ◽  
Furen Zhang ◽  
David A. Ostrov
Keyword(s):  
Human Leukocyte Antigen ◽  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Hypersensitivity Reactions ◽  
Leukocyte Antigen ◽  
Drug Hypersensitivity Reactions

scholarly journals The Roles of Immunoregulatory Networks in Severe Drug Hypersensitivity

2021 ◽  
Vol 12 ◽  
Author(s):  
Yun-Shiuan Olivia Hsu ◽  
Kun-Lin Lu ◽  
Yun Fu ◽  
Chuang-Wei Wang ◽  
Chun-Wei Lu ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Hypersensitivity Syndrome ◽  
Stevens Johnson Syndrome ◽  
Hypersensitivity Reactions ◽  
Drug Induced ◽  
Johnson Syndrome ◽  
Signaling Receptors ◽  
Systemic Symptoms

The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit drug hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce hypersensitivity reactions including SJS/TEN and DRESS/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of drug hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type drug hypersensitivity in the hope of identifying potential pharmacologic targets.

Epidemiology and Risk Factors for Severe Delayed Drug Hypersensitivity Reactions

2019 ◽  
Vol 25 (36) ◽  
pp. 3799-3812 ◽  
Author(s):  
Eva S.R. Gomes ◽  
Maria L. Marques ◽  
Frederico S. Regateiro
Keyword(s):  
Risk Factors ◽  
Adverse Reactions ◽  
Preventive Measures ◽  
Drug Hypersensitivity ◽  
Hypersensitivity Reactions ◽  
Drug Induced ◽  
Immune Mediated ◽  
Drug Hypersensitivity Reactions ◽  
Severe Cutaneous Adverse Reactions ◽  
Cutaneous Adverse Reactions

: Severe delayed drug hypersensitivity reactions comprise different clinical entities and can involve different immune medSevere delayed drug hypersensitivity reactions comprise different clinical entities and can involve different immune-mediated mechanisms. Common examples are severe cutaneous adverse reactions and druginduced internal organ injuries.iated mechanisms. Common examples are severe cutaneous adverse reactions and drug induced internal organ injuries. The incidence of such reactions is overall low but seems to be on the rise reaching numbers as high as 9 per million individuals-years in the case of SJS/TEN and in DRESS. Such conditions carry an important associated morbidity, and mortality can attain 40% in SJS/TEN patients, making these hypersensitivity reactions important targets when implementing preventive measures. Several risk factors have been identified, some being transverse, for reactions severity as older age and underlying chronic diseases. The recent advances in pharmacogenetics allowed the identification of specific populations with higher risk and permitted strategic avoidance of certain drugs being HLA-B*57:01 screening in patients initiating abacavir the best successful example. In this work we reviewed the epidemiology of SCARs and liver/kidney/lung drug induced immune-mediated reactions. We focus in particular aspects such as prevalence and incidence, drugs involved, mortality and risk factors. : The incidence of such reactions is overall low but seems to be on the rise reaching numbers as high as 9 per million individuals-years in the case of SJS/TEN and DRESS. Such conditions carry an important associated morbidity, and mortality can attain 40% in SJS/TEN patients, making these hypersensitivity reactions important targets when implementing preventive measures. : Several risk factors have been identified for reaction severity; some are transverse, such as older age and underlying chronic diseases. The recent advances in pharmacogenetics allowed the identification of specific populations with higher risk and permitted strategic avoidance of certain drugs being HLA-B*57:01 screening in patients initiating abacavir the best successful example. In this work, we reviewed the epidemiology of SCARs and liver/kidney/lung drug-induced immune-mediated reactions. We focus on particular aspects such as prevalence and incidence, drugs involved, mortality and risk factors.

scholarly journals HLA-DRB1*08:02 Is Associated with Bucillamine-Induced Proteinuria in Japanese Rheumatoid Arthritis Patients

2014 ◽  
Vol 9 ◽  
pp. BMI.S13654 ◽  
Author(s):  
Hiroshi Furukawa ◽  
Shomi Oka ◽  
Kota Shimada ◽  
Shoji Sugii ◽  
Atsushi Hashimoto ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Adverse Reactions ◽  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Drug Induced ◽  
Leukocyte Antigen ◽  
Increased Risk ◽  
Gold Salts ◽  
Drug Hypersensitivity Reaction ◽  
Preliminary Study

Background Drug-induced proteinuria can occur in rheumatoid arthritis (RA) patients treated with d-penicillamine, gold salts, or bucillamine (Buc), and represents a drug hypersensitivity reaction. Striking associations of human leukocyte antigen (HLA) alleles with adverse reactions have recently been reported for many drugs. Methods We investigated the association of HLA class II with Buc-induced proteinuria (BI-Pro) in 485 Japanese RA patients treated with Buc, of whom 25 had developed BI-Pro. Results and Conclusion This preliminary study showed a highly significant association of DRB1*08:02 with BI-Pro ( P = 1.09 × 10−6, corrected P [ Pc] = 1.96 × 10−5, odds ratio [OR] 25.17, 95% confidence interval [CI] 7.98-79.38). DQB1*04:02 was also significantly associated with increased risk of BI-Pro ( P = 2.44 × 10−5, Pc = 2.69 × 10−4, OR 10.35, 95%CI 3.99–26.83). These findings provide useful information for promoting personalized medicine for RA.

scholarly journals The Role of Conformational Dynamics in abacavir-Induced Hypersensitivity Syndrome

2017 ◽  
Author(s):  
James Fodor ◽  
Blake T. Riley ◽  
Itamar Kass ◽  
Ashley M. Buckle ◽  
Natalie A. Borg
Keyword(s):  
Drug Hypersensitivity ◽  
Conformational Dynamics ◽  
Human Leukocyte ◽  
Immune Deficiency Syndrome ◽  
Hypersensitivity Syndrome ◽  
Conformational Space ◽  
Hypersensitivity Reactions ◽  
Drug Induced ◽  
Diverse Range

AbstractAbacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS). However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B*57:01, but not patients carrying closely related alleles. Abacavir’s specificity to HLA-B*57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B*57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B*57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B*57:01 in a highly diverse range of conformations that are not apparent from static crystallographic snapshots. Further, the presence of abacavir has a direct impact on the dynamics and the conformational space available to peptides bound to HLA-B*57:01, likely influencing abacavir-induced immune self-reactivity. Our results support hypersensitivity models in which abacavir-binding alters the equilibrium proportions of neopeptide conformations in a manner favourable to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B*57:01+ HIV patients whilst retaining potent antiretroviral activity.

scholarly journals Hypersensitivity reactions to IL-1 and IL-6 inhibitors are linked to common HLA-DRB1*15 alleles

2020 ◽  
Author(s):  
Jill Hollenbach ◽  
Michael Ombrello ◽  
Adriana Tremoulet ◽  
Jaime S Rosa Duque ◽  
Gilbert T Chua ◽  
...  
Keyword(s):  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Hypersensitivity Reactions ◽  
Diffuse Lung Disease ◽  
Entire Cohort ◽  
Systemic Jia ◽  
Inflammatory Conditions ◽  
Drug Hypersensitivity Reactions ◽  
Hla Dqa1 ◽  
Hla Genotype

In Saper et al (2019), we described systemic JIA patients who developed a high-fatality diffuse lung disease (DLD) while on IL-1 or IL-6 inhibitors. We observed severe delayed drug hypersensitivity reactions (DHR) in a significant subset. Because alleles of the human leukocyte antigen (HLA) loci can mediate DHR, we investigated HLA genotype association with these DHR. We typed subjects treated with these inhibitors: 34 sJIA/DHR/DLD, 11 sJIA/DHR without DLD, 18 drug-tolerant sJIA, and 19 Kawasaki disease (KD) patients in an anti-IL-1(anakinra) trial. We also accessed genotypes from a large sJIA case/control cohort. We first compared White subjects with sJIA/DHR to 550 ancestry-matched sJIA subjects. We found striking enrichments of HLA-DRB1*15:01, HLA-DQA1*01:02, and DQB1*06:02, alleles in near-complete linkage (White individuals). HLA-DRB1*15:01 (as haplotype proxy) was increased in White sJIA subjects with DHR/DLD versus sJIA drug-tolerant controls and was observed upon inclusion of sJIA+DHR-only and KD+DHR White subjects. In our entire cohort regardless of ancestry, 75% carried HLA-DRB1*15:01 or the structurally related DRB1*15:03 and DRB1*15:06, which were absent among drug-tolerant subjects (p=5 x 10-13; Odds Ratio lower bound=20.11). Patients who harbor HLA-DRB1*15 alleles are at high risk of developing DHR to anti-IL-1/IL-6. Our data also suggest DHR maybe a trigger/enhancer of DLD in sJIA patients and support performing prospective HLA screening in sJIA, its adult-onset counterpart, and other inflammatory conditions where these drugs are used, such as KD.

scholarly journals Genotyping for HLA Risk Alleles to Prevent Drug Hypersensitivity Reactions: Impact Analysis

2021 ◽  
Vol 15 (1) ◽  
pp. 4
Author(s):  
Lisanne E. N. Manson ◽  
Wilbert B. van den Hout ◽  
Henk-Jan Guchelaar
Keyword(s):  
The Netherlands ◽  
Impact Analysis ◽  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Cost Effective ◽  
Gene Interaction ◽  
Hypersensitivity Reactions ◽  
Drug Label ◽  
Risk Alleles ◽  
Drug Hypersensitivity Reactions

Human Leukocyte Antigen (HLA) variants can be a risk factor for developing potentially fatal drug hypersensitivity reactions. Our aim was to estimate the potential impact of genotyping for the HLA risk alleles incorporated in the Dutch Pharmacogenetics Working Group (DPWG) guidelines in The Netherlands. We estimated the number of hypersensitivity reactions and associated deaths that can be avoided annually by genotyping for these HLA risk alleles. Additionally, the cost-effectiveness was estimated. Nationwide implementation of genotyping HLA risk alleles before initiating drugs with an actionable drug–gene interaction can potentially save the life of seven allopurinol initiators and two flucloxacillin initiators each year in The Netherlands. Besides these deaths, 28 cases of abacavir hypersensitivity, 24 cases of allopurinol induced SCARs, 6 cases of carbamazepine induced DRESS and 22 cases of flucloxacillin induced DILI can be prevented. Genotyping HLA-B*5701 in abacavir initiators has a number needed to genotype of 31 to prevent one case of abacavir hypersensitivity and is cost-saving. Genotyping HLA-B*5801 in allopurinol initiators has a number needed to genotype of 1149 to prevent one case of SCAR but is still cost-effective. Genotyping before initiating antiepileptic drugs or flucloxacillin is not cost-effective. Our results confirm the need for mandatory testing of HLA-B*5701 in abacavir initiators, as indicated in the drug label, and show genotyping of HLA-B*5801 in allopurinol initiators should be considered.

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