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Special Issue "Drug Hypersensitivity"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2017)

Special Issue Editor

Guest Editor
Prof. Dr. Werner J. P Pichler

ADR-AC GmbH, Adverse Drug Reactions, Analysis and Consulting, Bern, Switzerland
Website | E-Mail
Interests: drug hypersensitivity; T cell activation; p-i concept; drug binding to HLA or TCR; T cell activation; IgE reaction with drugs; pseudo-allergy; clinic of drug hypersensitivity

Special Issue Information

Dear Colleagues,

The old immunological dogma that small molecules do not interfere with the specific immune system was recently challenged by studying patients with drug hypersensitivity reactions: Drugs were found to be able to directly bind to immune receptors like HLA or TCR and thus lead to immune activations (pharmacological interaction with immune receptors, p-i concept). This finding was surprising as it opened a new area of basic immunology, namely how small molecules interact with the immune system; and it demonstrated once again that an in depth study of an acquired, human disease can also contribute to our understanding of basic scientific principles.

In this Special Issue of IJMS, a collection of papers will address the various mechanism of drug hypersensitivity: By linking molecular and clinical research of drug hypersensitivity, the role of small molecules in specific immunity in general may be better clarified. This should have an impact on incidence and severity and prediction of drug hypersensitivity reactions and may also help to understand other, environmental or man-made diseases.

Prof. Dr. Werner J. Pichler
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • p-i concept
  • hapten
  • pseudo-allergy
  • DRESS
  • SJS/TEN
  • basophil activation test
  • T cell stimulation
  • gvhd

Published Papers (6 papers)

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Research

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Open AccessArticle Structural Elements Recognized by Abacavir-Induced T Cells
Int. J. Mol. Sci. 2017, 18(7), 1464; https://doi.org/10.3390/ijms18071464
Received: 27 April 2017 / Revised: 13 June 2017 / Accepted: 27 June 2017 / Published: 7 July 2017
Cited by 5 | PDF Full-text (1293 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Adverse drug reactions are one of the leading causes of morbidity and mortality in health care worldwide. Human leukocyte antigen (HLA) alleles have been strongly associated with drug hypersensitivities, and the causative drugs have been shown to stimulate specific T cells at the
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Adverse drug reactions are one of the leading causes of morbidity and mortality in health care worldwide. Human leukocyte antigen (HLA) alleles have been strongly associated with drug hypersensitivities, and the causative drugs have been shown to stimulate specific T cells at the sites of autoimmune destruction. The structural elements recognized by drug-specific T cell receptors (TCRs) in vivo are poorly defined. Drug-stimulated T cells express TCRs specific for peptide/HLA complexes, but the characteristics of peptides (sequence, or endogenous or exogenous origin) presented in the context of small molecule drugs are not well studied. Using HLA-B*57:01 mediated hypersensitivity to abacavir as a model system, this study examines structural similarities of HLA presented peptides recognized by drug-specific TCRs. Using the crystal structure of HLA-B*57:01 complexed with abacavir and an immunogenic self peptide, VTTDIQVKV SPT5a 976–984, peptide side chains exhibiting flexibility and solvent exposure were identified as potential drug-specific T cell recognition motifs. Viral sequences with structural motifs similar to the immunogenic self peptide were identified. Abacavir-specific T cell clones were used to determine if virus peptides presented in the context of abacavir stimulate T cell responsiveness. An abacavir-specific T cell clone was stimulated by VTQQAQVRL, corresponding to HSV1/2 230–238, in the context of HLA-B*57:01. These data suggest the T cell polyclonal response to abacavir consists of multiple subsets, including T cells that recognize self peptide/HLA-B*57:01 complexes and crossreact with viral peptide/HLA-B*57:01 complexes due to similarity in TCR contact residues. Full article
(This article belongs to the Special Issue Drug Hypersensitivity)
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Review

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Open AccessReview Pro and Contra: Provocation Tests in Drug Hypersensitivity
Int. J. Mol. Sci. 2017, 18(7), 1437; https://doi.org/10.3390/ijms18071437
Received: 21 May 2017 / Revised: 24 June 2017 / Accepted: 27 June 2017 / Published: 4 July 2017
Cited by 3 | PDF Full-text (1260 KB) | HTML Full-text | XML Full-text
Abstract
Drug provocation test (DPT) is the controlled administration of a drug to diagnose immune- or non-immune-mediated drug hypersensitivity and the last step for accurate recognition of drug hypersensitivity reactions when the previous diagnostic evaluations are negative or unavailable. A DPT is performed only
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Drug provocation test (DPT) is the controlled administration of a drug to diagnose immune- or non-immune-mediated drug hypersensitivity and the last step for accurate recognition of drug hypersensitivity reactions when the previous diagnostic evaluations are negative or unavailable. A DPT is performed only if other conventional tests fail to yield conclusive results. In each clinical presentation, “to provoke or not to provoke” a patient should be decided after careful assessment of the risk–benefit ratio. Well-defined benefits of DPT include confirmative exclusion of diagnoses of drug hypersensitivity and provision of safe alternatives. However, disadvantages such as safety, difficulty in interpretations of results, lack of objective biomarkers, risks of resensitization, efficiency in daily practice, and lack of standardized protocols, are poorly debated. This review summarizes the current published research concerning DPT, with particular emphasis on the advantages and disadvantages of DPT in an evidence-based manner. Full article
(This article belongs to the Special Issue Drug Hypersensitivity)
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Open AccessReview Drug Hypersensitivity and Desensitizations: Mechanisms and New Approaches
Int. J. Mol. Sci. 2017, 18(6), 1316; https://doi.org/10.3390/ijms18061316
Received: 2 May 2017 / Revised: 13 June 2017 / Accepted: 14 June 2017 / Published: 20 June 2017
Cited by 6 | PDF Full-text (2972 KB) | HTML Full-text | XML Full-text
Abstract
Drug hypersensitivity reactions (HSRs) are increasing in the 21st Century with the ever expanding availability of new therapeutic agents. Patients with cancer, chronic inflammatory diseases, cystic fibrosis, or diabetes can become allergic to their first line therapy after repeated exposures or through cross
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Drug hypersensitivity reactions (HSRs) are increasing in the 21st Century with the ever expanding availability of new therapeutic agents. Patients with cancer, chronic inflammatory diseases, cystic fibrosis, or diabetes can become allergic to their first line therapy after repeated exposures or through cross reactivity with environmental allergens. Avoidance of the offending allergenic drug may impact disease management, quality of life, and life expectancy. Precision medicine provides new tools for the understanding and management of hypersensitivity reactions (HSRs), as well as a personalized treatment approach for IgE (Immunoglobuline E) and non-IgE mediated HSRs with drug desensitization (DS). DS induces a temporary hyporesponsive state by incremental escalation of sub-optimal doses of the offending drug. In vitro models have shown evidence that IgE desensitization is an antigen-specific process which blocks calcium flux, impacts antigen/IgE/FcεRI complex internalization and prevents the acute and late phase reactions as well as mast cell mediator release. Through a “bench to bedside” approach, in vitro desensitization models help elucidate the molecular pathways involved in DS, providing new insights to improved desensitization protocols for all patients. The aim of this review is to summarize up to date information on the drug HSRs, the IgE mediated mechanisms of desensitization, and their clinical applications. Full article
(This article belongs to the Special Issue Drug Hypersensitivity)
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Open AccessReview Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and Immune System
Int. J. Mol. Sci. 2017, 18(6), 1243; https://doi.org/10.3390/ijms18061243
Received: 24 April 2017 / Revised: 30 May 2017 / Accepted: 2 June 2017 / Published: 9 June 2017
Cited by 11 | PDF Full-text (4033 KB) | HTML Full-text | XML Full-text
Abstract
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe multiorgan hypersensitivity reaction mostly caused by a limited number of eliciting drugs in patients with a genetic predisposition. Patients with DRESS syndrome present with characteristic but variable clinical and pathological features.
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Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe multiorgan hypersensitivity reaction mostly caused by a limited number of eliciting drugs in patients with a genetic predisposition. Patients with DRESS syndrome present with characteristic but variable clinical and pathological features. Reactivation of human herpesviruses (HHV), especially HHV-6, is the hallmark of the disease. Anti-viral immune responses intertwined with drug hypersensitivity make the disease more complicated and protracted. In recent years, emerging studies have outlined the disease more clearly, though several important questions remain unresolved. In this review, we provide an overview of DRESS syndrome, including clinical presentations, histopathological features, pathomechanisms, and treatments. Full article
(This article belongs to the Special Issue Drug Hypersensitivity)
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Open AccessReview Reclassifying Anaphylaxis to Neuromuscular Blocking Agents Based on the Presumed Patho-Mechanism: IgE-Mediated, Pharmacological Adverse Reaction or “Innate Hypersensitivity”?
Int. J. Mol. Sci. 2017, 18(6), 1223; https://doi.org/10.3390/ijms18061223
Received: 12 April 2017 / Revised: 1 June 2017 / Accepted: 2 June 2017 / Published: 7 June 2017
Cited by 9 | PDF Full-text (718 KB) | HTML Full-text | XML Full-text
Abstract
Approximately 60% of perioperative anaphylactic reactions are thought to be immunoglobulin IgE mediated, whereas 40% are thought to be non-IgE mediated hypersensitivity reactions (both considered non-dose-related type B adverse drug reactions). In both cases, symptoms are elicited by mast cell degranulation. Also, pharmacological
[...] Read more.
Approximately 60% of perioperative anaphylactic reactions are thought to be immunoglobulin IgE mediated, whereas 40% are thought to be non-IgE mediated hypersensitivity reactions (both considered non-dose-related type B adverse drug reactions). In both cases, symptoms are elicited by mast cell degranulation. Also, pharmacological reactions to drugs (type A, dose-related) may sometimes mimic symptoms triggered by mast cell degranulation. In case of hypotension, bronchospasm, or urticarial rash due to mast cell degranulation, identification of the responsible mechanism is complicated. However, determination of the type of the underlying adverse drug reaction is of paramount interest for the decision of whether the culprit drug may be re-administered. Neuromuscular blocking agents (NMBA) are among the most frequent cause of perioperative anaphylaxis. Recently, it has been shown that NMBA may activate mast cells independently from IgE antibodies via the human Mas-related G-protein-coupled receptor member X2 (MRGPRX2). In light of this new insight into the patho-mechanism of pseudo-allergic adverse drug reactions, in which as drug-receptor interaction results in anaphylaxis like symptoms, we critically reviewed the literature on NMBA-induced perioperative anaphylaxis. We challenge the dogma that NMBA mainly cause IgE-mediated anaphylaxis via an IgE-mediated mechanism, which is based on studies that consider positive skin test to be specific for IgE-mediated hypersensitivity. Finally, we discuss the question whether MRGPRX2 mediated pseudo-allergic reactions should be re-classified as type A adverse reactions. Full article
(This article belongs to the Special Issue Drug Hypersensitivity)
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Open AccessReview The Value of In Vitro Tests to Diminish Drug Challenges
Int. J. Mol. Sci. 2017, 18(6), 1222; https://doi.org/10.3390/ijms18061222
Received: 4 May 2017 / Revised: 31 May 2017 / Accepted: 2 June 2017 / Published: 7 June 2017
Cited by 11 | PDF Full-text (1493 KB) | HTML Full-text | XML Full-text
Abstract
Drug hypersensitivity reactions have multiple implications for patient safety and health system costs, thus it is important to perform an accurate diagnosis. The diagnostic procedure includes a detailed clinical history, often unreliable; followed by skin tests, sometimes with low sensitivity or unavailable; and
[...] Read more.
Drug hypersensitivity reactions have multiple implications for patient safety and health system costs, thus it is important to perform an accurate diagnosis. The diagnostic procedure includes a detailed clinical history, often unreliable; followed by skin tests, sometimes with low sensitivity or unavailable; and drug provocation testing, which is not risk-free for the patient, especially in severe reactions. In vitro tests could help to identify correctly the responsible agent, thus improving the diagnosis of these reactions, helping the physician to find safe alternatives, and reducing the need to perform drug provocation testing. However, it is necessary to confirm the sensitivity, specificity, negative and positive predictive values for these in vitro tests to enable their implementation in clinical practice. In this review, we have analyzed these parameters from different studies that have used in vitro test for evaluating drug hypersensitivity reactions and estimated the added value of these tests to the in vivo diagnosis. Full article
(This article belongs to the Special Issue Drug Hypersensitivity)
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