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 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.

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.

scholarly journals An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity

2018 ◽  
Vol 2018 ◽  
pp. 1-22 ◽  
Author(s):  
Chun-Bing Chen ◽  
Riichiro Abe ◽  
Ren-You Pan ◽  
Chuang-Wei Wang ◽  
Shuen-Iu Hung ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Drug Hypersensitivity ◽  
Clinical Manifestations ◽  
Human Leukocyte ◽  
Hypersensitivity Syndrome ◽  
Cell Receptor ◽  
Stevens Johnson Syndrome ◽  
Diagnostic Tools ◽  
Drug Induced ◽  
Skin Reactions

Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.

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 Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions

2021 ◽  
Vol 12 ◽  
Author(s):  
Yueran Li ◽  
Pooja Deshpande ◽  
Rebecca J. Hertzman ◽  
Amy M. Palubinsky ◽  
Andrew Gibson ◽  
...  
Keyword(s):  
T Cell ◽  
Predictive Value ◽  
Large Scale ◽  
Drug Hypersensitivity ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Therapeutic Interventions ◽  
Hypersensitivity Reactions ◽  
Prediction And Prevention

Adverse drug reactions (ADRs) remain associated with significant mortality. Delayed hypersensitivity reactions (DHRs) that occur greater than 6 h following drug administration are T-cell mediated with many severe DHRs now associated with human leukocyte antigen (HLA) risk alleles, opening pathways for clinical prediction and prevention. However, incomplete negative predictive value (NPV), low positive predictive value (PPV), and a large number needed to test (NNT) to prevent one case have practically prevented large-scale and cost-effective screening implementation. Additional factors outside of HLA contributing to risk of severe T-cell-mediated DHRs include variation in drug metabolism, T-cell receptor (TCR) specificity, and, most recently, HLA-presented immunopeptidome-processing efficiencies via endoplasmic reticulum aminopeptidase (ERAP). Active research continues toward identification of other highly polymorphic factors likely to impose risk. These include those previously associated with T-cell-mediated HLA-associated infectious or auto-immune disease such as Killer cell immunoglobulin-like receptors (KIR), epistatically linked with HLA class I to regulate NK- and T-cell-mediated cytotoxic degranulation, and co-inhibitory signaling pathways for which therapeutic blockade in cancer immunotherapy is now associated with an increased incidence of DHRs. As such, the field now recognizes that susceptibility is not simply a static product of genetics but that individuals may experience dynamic risk, skewed toward immune activation through therapeutic interventions and epigenetic modifications driven by ecological exposures. This review provides an updated overview of current and proposed genetic factors thought to predispose risk for severe T-cell-mediated DHRs.

Sign in / Sign up

Export Citation Format

Share Document